Clinical trial NCT04101071: Alternative Substrates in the Critically Ill Subject
Official title: Alternative Substrates in the Critically Ill Subject
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Critical Illness
Keywords: Critical care
enteral feeding
nasogastric
ketogenic feed
feasibility
Lead sponsor: Barts & The London NHS Trust
Sponsor class: OTHER
Collaborators: name: Bristol Royal Infirmary
name: Institute of Child Health
First posted: 2019-09-24
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: SIngle blinded, randomised, controlled feasibility study
Primary purpose: OTHER

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Feasibility of patient recruitment; number eligible from screening
timeFrame: 15 months
measure: Feasibility of patient recruitment; percentage eligible from screening
timeFrame: 15 months
measure: Feasibility of patient recruitment; number from consent process
timeFrame: 15 months
measure: Feasibility of patient recruitment: percentage from consent process
timeFrame: 15 months
measure: Feasibility of patient retention during the 10 day study period: number of participants
timeFrame: 15 months
measure: Feasibility of patient retention during the 10 day study period; percentage of participants
timeFrame: 15 months
measure: Feasibility of provision of ketogenic feed: staff-completed questionnaire
timeFrame: 15 months
measure: Incidence of Adverse Events/Serious Adverse Events, gastric intolerance, glucose variation
timeFrame: 15 months
measure: Coefficient of Glucose Variation (scored as mean/standard deviation)
timeFrame: 15 months
measure: Timescale for the development and establishment of ketosis during 10 days of intervention or control feed; beta-hydroxybutyrate
timeFrame: 15 months
measure: Timescale for the development and establishment of ketosis during 10 days of intervention or control feed; acetoacetate
timeFrame: 15 months
measure: Timescale for the development and establishment of ketosis during 10 days of intervention or control feed; pyruvate
timeFrame: 15 months
measure: Timescale for the development and establishment of ketosis during 10 days of intervention or control feed, fat
timeFrame: 15 months
measure: Timescale for the development and establishment of ketosis during 10 days of intervention or control feed, glucose
timeFrame: 15 months
measure: Timescale for the development and establishment of ketosis during 10 days of intervention or control feed, lactate
timeFrame: 15 months
Secondary outcomes:
measure: Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data: blood gases
timeFrame: 15 months
measure: Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data; biochemistry
timeFrame: 15 months
measure: Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data; haematology
timeFrame: 15 months
measure: Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data; bedside physiology
timeFrame: 15 months
measure: Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data; nutritional data
timeFrame: 15 months
measure: Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data; Propofol
timeFrame: 15 months
measure: Feasibility of performing quadriceps ultrasound scans: muscle mass
timeFrame: 15 months
measure: Feasibility of performing functional assessment at hospital discharge by Two- or Six-Minute Walk Test
timeFrame: 15 months
measure: Feasibility of performing functional assessment at hospital discharge by Short Physical Performance Battery
timeFrame: 15 months
measure: Feasibility of performing functional assessment at hospital discharge by CPAx score
timeFrame: 15 months
measure: Feasibility of collecting metabolic data on ICU: indirect calorimetry
timeFrame: 15 months
measure: Feasibility of collecting follow-up data by telephone re quality of life: ED5Q survey
timeFrame: 18 months
measure: Feasibility of collecting follow-up data by telephone re job status: Questions on employment status
timeFrame: 18 months
measure: Feasibility of collecting follow-up data from medical records: number of GP/nurse visits
timeFrame: 18 months
measure: Biochemical analysis of urine
timeFrame: 18 months
measure: Biochemical analysis of plasma metabolites, beta-hydroxy butyrate, acetoacetate, leucine, and alanine (all measured in the same Arbitrary Units [AU]).
timeFrame: 18 months
Other outcomes:
Locations:
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
city: London
country: United Kingdom
facility: Royal London Hospital
Study officials:
affiliation: Royal London Hospital
name: Angela McNelly, PhD
role: PRINCIPAL_INVESTIGATOR
References: