Alternative Substrates in the Critically Ill Subject

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:

• Show that it is possible to recruit patients to receive a ketogenic feed
• Show that it is possible for researchers to reconstitute the modular ketogenic feed on ICU.
• Show that it is possible to administer ketogenic feed to ICU patients without ill effect.
• Characterise the time-course of ketone generation (and related changes in related metabolic pathways) in response to the ketogenic feed.
• Show that collection of outcome measures relevant for the subsequent substantive study will be feasible.

Inclusion criteria

• 18 years or older
• due to receive enteral nutrition via nasogastric or nasojejunal tube as part of routine care
• mechanically ventilated and likely to remain so for >48 hours
• likely to remain on the ICU for >5 days
• likely to survive for at least 10 days and
• multi-organ failure (Sequential Organ Failure Assessment Score [SOFA] score >2 in 2 or more domains).

Exclusion criteria

• primary neuromyopathy or significant neurological impairment at the time of ICU admission that would preclude physical activity
• uni- or bilateral lower limb amputation
• requiring sole or supplemental parenteral nutrition
• need for specialist nutritional intervention
• patients with known inborn errors of metabolism
• participation in another clinical trial