A randomised controlled trial of prevention of acute muscle wasting in critically ill adults with ketogenic feeding: the Alternative Substrates In the Critically Ill Subject II (ASICS-II)

Research question: In critically ill patients, can a 10-day ketogenic feed regimen increase the number of repetitions in a 30 second sit to stand test 30 days from randomisation, compared to a standard feed regimen? Background Every month 50000 patients stay for >7 days in hospital, losing muscle mass, developing new physical impairment and need for social care support. The most seriously ill patients in intensive care lose 1-2 kilograms of muscle every day. Of the 120,000 patients/year that survive critical illness, 98% suffer loss of physical independence. New physical impairments cost the UK health and social care system £25 billion per year. Many high-quality trials have failed to yield an intervention that improves physical independence. Muscle protein synthesis is ATP dependent, and critical illness induced bioenergetic failure leads to muscle wasting and loss of physical independence from both decreased muscle protein synthesis and unchecked muscle protein breakdown. Substrate utilisation is impaired due to i) impaired glucose conversion to pyruvate ii) mitochondrial beta oxidation downregulation and iii) impaired pyruvate reconstitution from amino acids. The sole potential alternative substrate for ATP production under such conditions is ketones. We seek to test the efficacy of a ketogenic feed in preventing muscle wasting in intensive care patients, optimising physical function, and decreasing loss of independence. If successful, this could be applied to the wider hospital population. Our NIHR-RFPB funded trial demonstrated ketogenic feeding to be safe, feasible, and resulted in an advantageous metabolic profile, which may translate into improved patient outcomes. Aims/Objectives • Primary clinical: To assess the efficacy of the ketogenic feed versus standard feed in increasing sit-to-stand repetitions performed in 30 seconds, 30 days from randomisation in critically ill patients. • Secondary clinical: To confirm induction of ketosis by determining between-group serum concentrations of ketone bodies seven-days post randomisation in a blinded fashion. • Mechanistic: Liquid Chromatography-Mass Spectrometry based targeted metabolomics examining efficacy along the causal pathway (differential ketone and amino acid flux, urea cycle flux and Tri-Carboxylic Acid cycle intermediate generation). Methods Eight-centre, double-blinded randomised trial recruiting 282 patients Inclusion criteria: Adults at risk of acute muscle wasting: • Acute respiratory failure (PaO2/FiO2 ratio of <39.9kPA during first 24 hours) • Expected to require advanced respiratory support (High-Flow Nasal Oxygen, Non-Invasive or Invasive Ventilation for >48 hours) • Evidence of inflammation (C-reactive Protein =75mg/l). • Nasogastric feeding planned for >48 hours. Timelines Trial set up: 6 months. Recruitment/follow up: 30 months. Trial closure, analysis and dissemination: 6 months Impact and dissemination First intervention to effectively improve physical independence for the 120,000/year ICU survivors in the UK. Data informing i) a future effectiveness trial ii) trials in the wider hospitalised patient cohort (16000/day) and iii) new knowledge/methodology informing research on the MRC/NIHR translational pathway to prevent muscle wasting of diverse causes. The multi-national industrial partnership will rapidly overcome regulatory and distribution issues. Dissemination will be via social media, open access publications and international presentations.