Title: A Study to Investigate the Feasibility of Inducing Ketosis Using an Enteral Feed, and Its Effects on Skeletal Muscle Wasting and Other Clinical Outcomes in Critical Illness
Funder: Department of Health and Social Care

Abstract: The 135,000 UK individuals surviving Intensive Care Unit (ICU) admission annually face long-standing reductions in physical function and health-related quality of life. Patients, clinicians and researchers recognise muscle wasting as a major contributor to this functional deficit, considered a public health issue partly due to substantial healthcare costs. Muscle wasting is determined by severity of illness, largely driven by infection and inflammation. Trials investigating the effect of nutritional interventions on muscle wasting or functional outcomes in critical illness are conflicting, whilst those of early exercise have not delivered improvements in functional outcomes. Identifying therapeutic strategies that cost-effectively reduce the magnitude of this critical illness-associated physical morbidity is a research priority for the National Institute of Health and Clinical Excellence. Ketones, produced by the body in response to starvation or metabolic stress, enhance metabolic efficiency, and immune/inflammatory responses, and thus may reduce muscle wasting. Enteral feed containing a specific type of fat (medium-chain triglycerides) can help the body produce ketones. The over-arching aim of this study is to investigate the feasibility of reconstituting and administering a modular ketone-inducing (ketogenic) enteral feeding regimen to ICU patients; to show that this feed does increase blood ketones; and that it is feasible to collect the desired outcomes. This will allow us to determine in a subsequent randomised controlled trial whether using this ketogenic feed improves ICU outcomes (including ICU-related muscle loss). Methods: A two centre feasibility study conducted over 30 months. Patients will be recruited (over 15 months) within 48 hrs of ICU admission, and randomised to either ketogenic enteral feed or standard enteral feed, after obtaining agreement from a consultee (due to lack of capacity resulting from critical illness). Data will be collected during the 10 days that ketogenic feed will be provided and at 3, 6 and 12 months post ICU-discharge. Inclusion criteria: (i)>18 years old (ii)to receive enteral nutrition as part of routine care (iii)mechanically ventilated and likely to remain so for >48 hours (iv)likely to remain on the ICU for >5 days and (v)likely to survive for at least 10 days (vi)multi-organ failure (SOFA score >2) . Exclusion criteria: (i)primary neuromyopathy or significant neurological impairment on ICU admission precluding physical activity (ii)uni- or bilateral lower limb amputation (iii)requiring sole/supplemental parenteral nutrition (iv)need for specialist nutrition (v)patients with known inborn errors of metabolism. Intervention: The components for the modular ketogenic enteral feed, supplied by Vitaflo&reg; (an established manufacturer of ketogenic feeds used clinically), will be reconstituted on the ICU for each patient. Sample Size: We will require a minimum of 24 (up to 30) ICU patients recruited to receive either ketogenic or standard enteral feed and complete the 10-day study period. Allowing for a dropout rate of 34%, up to 37 eligible patients will be recruited. Site-specific data and past trial experience suggest that recruitment is readily achievable in 15 months (previous recruitment average for interventional feeding study: 1.25 patients/month/site). Timetable: Total 30 months. Regulatory approvals, training: 3 months (funded); recruitment/gathering data: 15 months, including commencing ketone analysis; completion of analysis: 5 [4+1] months; data analysis, dissemination of results, preparing funding application for definitive interventional randomised controlled trial (RCT): 24 [8+5+11] months. Summary of Potential benefits to Patients and NHS: If using ketogenic feed in ICU patients is shown to be safe and feasible, it may mitigate the muscle loss seen in early critical illness, providing a new treatment to improve function and well-being in ICU survivors. This will prevent the limitation in life opportunities frequently occurring amongst the 135,000 newly-discharged survivors each year, and reduce resulting excess healthcare utilisation and costs (c&pound;110 million yearly) for the NHS to bear.

Lay abstract: Patients on Intensive Care Units (ICU) commonly suffer rapid early muscle loss (averaging 20% of muscle in the first 10 days) - which increases time in ICU and hospital. Of the 135,000 UK individuals surviving to go home each year, many remain weak: half can t return to work within a year, and a third need help with basic daily activities (e.g. using the toilet). Patients think that these problems should be prevented. One reason for their muscle loss seems to be that ICU patients can t use carbohydrates or some types of fat to produce energy needed to keep muscle. Ketones are chemicals naturally-produced in the body that help cells produce energy more efficiently. Giving patients a special feed containing a type of fat which produces ketones may reduce muscle loss so improving outcomes. A ketone-producing diet is safely and routinely used by athletes and some hospital patients, including children. We aim to see whether giving ICU patients feed to help the body make ketones is safe and acceptable. Our method will be to give adult ICU patient volunteers at two hospitals a special feed which causes the body to make ketones. We will see how many patients join and stay in the study; how quickly ketones are made; and how easily we can gather information from medical records and test results to show how safe and acceptable the feed is for these patients. Patients and carers helped us design this study, and will review and help report results. They will help refine the final study design. Results will be shared through publication in high-quality journals and presentation at conferences/patient support groups. This work should lead to a future trial to see if this feed could help ICU patients keep muscle, and increase their activity levels and well-being after hospital discharge.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;GENERIC HEALTH RELEVANCE