Alternative Substrates in the Critically Ill Subject
Condition: Critical Illness
MeSH terms: Critical Illness
Study type: Interventional

Summary: 
      The over-arching aim of this study is to investigate the feasibility of administrating
      alternative substrates to intensive care unit (ICU) patients. This includes 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 this intervention improves ICU outcomes (including ICU-related
      muscle loss).
    

Detailed description: 
      Aggressive muscle wasting occurs early in critical illness, and is associated with a greater
      number of days on a ventilator, increased length of intensive care unit (ICU) and/or hospital
      stay, and subsequent functional impairment which may last years. Hospital care costs, and
      ongoing costs of community-based primary healthcare utilisation, are increased. No known
      interventions prevent this wasting.

      Bioenergetic failure in critical illness and the potential for alternative substrate use:

      Muscle protein synthesis is highly energy-dependent.The bioenergetic state of the
      critically-ill patient is compromised leading to decreased Adenosine Tri-Phosphate (ATP)
      synthesis. Alterations in mitochondrial function have been described repeatedly in the
      literature which, with other altered cellular processes, impair the utlilisation of metabolic
      substrates for ATP production.

      Carbohydrate utilisation is impaired in critical illness, partly through impaired
      nuclear-to-membrane translocation of glucose transporter-4 and increased insulin resistance.
      Hypoxia signalling and inflammation block activity of pyruvate dehydrogenase by upregulation
      of pyruvate dehydrogenase kinase, increasing glucose availability thus driving pyruvate
      metabolism to lactate - the Pasteur effect.

      The investigator's recently published data suggest that critical illness also impairs
      mitochondrial oxidation of fatty acids in skeletal muscle, and that the majority of lipids
      delivered in feed are not utilized for ATP production. This may be of clinical importance,
      given that lipids contribute 29-43% of the energy content of enteral, and 50% of parenteral,
      formulae. Lastly, oxidation of amino acids may produce ATP. However, this is not necessarily
      in the best interest of the patient: these amino acids are then no longer available for
      muscle protein synthesis. Further, most amino acid oxidation results in pyruvate production
      and therefore the same issues as those related to carbohydrate metabolism apply. Provision of
      a new metabolic substrate such as Ketone Bodies (KBs) may address these limitations.

      Potential for Muscle Sparing Offered by Ketone Bodies:

      During periods of starvation they may provide up to 50% of total body basal energy, enabling
      the high energy requirement of human brain to be met whilst sparing muscle. Additionally KBs
      may act as metabolic modulators, improving mitochondrial efficiency (also impaired by
      critical illness), and reducing reactive oxygen species and free radical formation. They also
      have anti-inflammatory effects (intramuscular inflammation is a driver of altered protein
      homeostasis, and anti-apoptotic activity. Together, these additional mechanistic effects may
      prove useful in ameliorating skeletal muscle wasting. Further, pilot data demonstrate a
      significant decrease in the plasma concentrations of beta-hydroxybutyrate and acetoacetate in
      early critical illness, consistent with increased KB uptake and utilisation early in critical
      illness.

      Ketone bodies have diverse extra-mitochondrial metabolic effects. These include immune
      enhancement functions: specifically, to bacterial infection. Infection and inflammation are
      drivers of muscle wasting and amelioration of these may impact on this and other outcome
      measures. Thus, the critically ill patient may benefit from a ketogenic diet which have been
      used safely in other population groups, including healthy subjects the obese, and in patients
      with trauma, epilepsy, cardiovascular disease, Type-2 diabetes and Metabolic Diseases.

      The objectives/aims are to:

        1. Show that it is possible to recruit patients to receive a ketogenic feed

        2. Show that it is possible for researchers to reconstitute the modular ketogenic feed on
           ICU.

        3. Show that it is possible to administer ketogenic feed to ICU patients without ill
           effect.

        4. Characterise the time-course of ketone generation (and related changes in related
           metabolic pathways) in response to the ketogenic feed.

        5. Show that collection of outcome measures relevant for the subsequent substantive study
           will be feasible.
    

Intervention name(s): Modular ketogenic feed; Standard feed
Intervention type(s): Other; Other
Intervention description(s): Dietician prescribed, and consisting of Betaquik® (from Vitaflo, Nutritional company) to provide medium chain triglycerides), Renapro Shot® (protein), Maxijul® (carbohydrate) and multivitamins according to nutritional need (energy and protein requirements) based on clinical status of the participant. Ketogenic feed to be given continuously via nasogastric tube for 10 days; Standard Enteral feed. Dietician prescribed based on clinical status of the participant, as per individual Trust protocols. Standard feed to be given continuously via nasogastric tube for 10 days
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: SIngle blinded, randomised, controlled feasibility study
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Other
Keywords: Critical care; enteral feeding; nasogastric; ketogenic feed; feasibility