NCT04101071

Alternative Substrates in the Critically Ill Subject

• Status: Completed
• Phase: N/A
• Study type: Interventional
• Enrollment: 29 (actual)
• Sponsor: Barts & The London NHS Trust · Academic / Other
• Sex: All
• Age: 18 Years – 99 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Critical Illness

Interventions

Type	Name	Description
OTHER	Modular ketogenic feed	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
OTHER	Standard feed	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

Timeline

• Start date: 2019-10-02
• Primary completion: 2022-04-27
• Completion: 2022-04-27
• First posted: 2019-09-24
• Last updated: 2022-08-01

Locations

2 sites across 1 country: United Kingdom