Title: A Study to Investigate the Effect of ß-Hydroxy-ß-Methylbutyrate on Skeletal Muscle Wasting in Early Critical Illness.
Funder: Health Education England

Abstract: Background A greater number of patients are surviving critical illness due to advances in medical treatment. However, this survival is often coupled with physical and functional disability which can last from months to years and has a significant impact on quality of life (QoL). Skeletal muscle wasting occurs early and rapidly in critically ill patients and contributes to this disability. Recently, it has been shown that critically ill patients are in a net catabolic balance during the first week of critical illness, even in the presence of adequate nutrition support Nutritional supplements, such as -hydroxy--methylbutyrate (HMB) have been recently shown to improve muscle mass, strength and function in healthy and catabolic populations. HMB specifically inhibits pathways of catabolism and may therefore prove beneficial to critically ill patients. We hypothesise that, during the early stage of critical illness, HMB will reduce skeletal muscle wasting and improve muscle strength and function that will enable improvements in quality of life following discharge from hospital. Objectives To determine the effect of HMB on skeletal muscle mass, strength, function and quality of life in critically ill patients. To investigate the effect of HMB on muscle protein signaling and muscle protein turnover To establish the feasibility of such an intervention with the view to designing a multicentre randomised controlled trial (RCT) Methods This will be a single-centre, randomised controlled placebo study undertaken in the adult Intensive Care Unit (ICU) of a large London teaching hospital aiming to recruit 54 patients over 21 months. Patients will be included if they are expected to be mechanically ventilated for more than 48 hours, have multi-organ failure and are likely to remain in the ICU for more than 7 days. Within 24 hours of admission, patients will be randomised to receive either 3g HMB (1.5g twice daily) or placebo in equivalent amounts until hospital discharge or 28 days, whichever comes first. Outcomes have been chosen based on feasibility, scientific rigor and importance to the patient. Muscle wasting will be measured using ultrasound of the Rectus Femoris Cross Sectional Area (RFCSA) on day 1, 7 and 10 of ICU admission as well as ICU and hospital discharge. Strength and function will be measured using volitional techniques such as the Medical Research Council Sum Score (ICU and hospital discharge), Six-minute walk test (ICU discharge), Chelsea Physical Assessment Tool (ICU and hospital discharge) and the Short-Performance Physical Battery (ICU and hospital discharge). Finally, Health related quality of life, using the Short-Form 36 point questionnaire will be measured retrospectively within 48 hours of admission to the ICU and at 90-days following ICU discharge. Acute and chronic protein synthesis and breakdown will also be measured over the first week of ICU admission in a subgroup of 10 patients. Established techniques using stable isotopes 13C6 Phenylalanine and Deuterium Oxide will be used. Muscle biopsies will also be taken in these same patients on days 1 and 7 of ICU admission to determine histological changes in muscle size and analysed for investigation of the anabolic and catabolic signaling. Analysis A statistical analysis plan has been devised with a senior statistician and includes a priori adjustments for nutritional risk and time on HMB and sub-group analysis for age ( Benefits to Patients and the NHS This study will uncover the impact of HMB on muscle protein turnover and muscle loss and important patient-related outcomes such as physical function. The study will also provide preliminary data on long term physical function and QoL that will help power a definitive RCT using these as primary outcomes.

Lay abstract: More patients admitted to the Intensive Care Unit (ICU) are surviving due to improvements in the treatments they receive. However, it is common for these patients to develop weakness after being on the ICU. This weakness can last for a long time, sometimes years after leaving the ICU and it makes it harder for patients to return to their normal lives when they leave hospital. We know that patients lose a lot of muscle while on an ICU and this contributes to the weakness. All patients receive feeding through a feeding tube while on the ICU, but this does not stop all of the muscle loss. There are many nutritional supplements available to help build muscle and to stop muscle from breaking down. One of these supplements is called -hydroxy--methylbutyrate or HMB for short. HMB is not a drug, in fact you can buy it in health food stores. We think this supplement may be useful to prevent weakness from developing in patients who are on ICU for longer than 1 week and we would like to find out if this is true. We would like to compare muscle loss in patients who receive HMB with those who do not receive HMB. The patients in the group not receiving HMB will receive a powder that looks identical to HMB. This is called a placebo. We would like the patients to take HMB or the placebo until they are discharged from the hospital, or up to 28 days. While the patients are in the ICU, the nursing staff will give the HMB or placebo through the feeding tube. When on the wards, we will ask the patients to take the HMB or placebo as a powder mixed with water. To measure muscle loss we will use ultrasound to look at the size of the thigh muscle (the rectus femoris). The ultrasound is painless, safe and has no known side effects (it is the same machine used to scan pregnant women). We will measure this on day 1, 7 and 10 of ICU stay as well as on discharge from the ICU and hospital. To provide more detail on the effect of HMB on muscle loss, in a small number of patients we would like to take some muscle biopsies (samples of tissue) from the thigh. We would like to take two biopsies on the first day of ICU admission and two one week later. In addition to this, we would like to give the patients specially labeled protein both intravenously (directly into the blood stream) and orally (through the nasogastric tube). We would then take some blood and urine samples which allow us to measure how much protein is being broken down and built up in the body. We have used these methods in previous studies with no concerns being raised. Previous ICU patients have told us that it's important to find a treatment which helps improve weakness and physical function. We think if HMB helps to stop muscle loss, it will also improve both of these aspects. To measure this, we would like to look at how these patients are able to do certain exercises when they are in the ICU and once they move to the ward. These exercises will be done with the assistance of a trained physiotherapist at specific time points with the last measurement being taken at or just before hospital discharge. The exercises will include walking, getting up from a chair and certain exercises to measure strength. Lastly, we would like to contact the patients 3 months after they leave the ICU to complete a questionnaire about their quality of life and function at that time. This will help us to understand more about the impact of muscle loss from a stay in the ICU and whether HMB has worked. We hope that the results of this study will be used to decide elements of a larger study using HMB to see if muscle loss can be reduced in ICU patients and improve their long-term outcomes and reduce the weakness they experience.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: MUSCULOSKELETAL