Alternative Substrates in the Critically Ill Subject (ASICS)

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).

Study Overview

• Status: Completed
• Conditions: Critical Illness
• Intervention / Treatment: Other: Modular ketogenic feed; Other: Standard feed

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Bristol, United Kingdom, BS2 8HW
    • Bristol Royal Infirmary
  • London, United Kingdom, E1 1BB
    • Royal London Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Modular ketogenic enteral feed; Ketogenic enteral feed to be administered continuously for 10 days.	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
Active Comparator: Standard enteral feed; Standard enteral feed to be administered continuously 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of patient recruitment; number eligible from screening	Number of patients screened	15 months
Feasibility of patient recruitment; percentage eligible from screening	Percentage of patients eligible for recruitment	15 months
Feasibility of patient recruitment; number from consent process	Number of eligible patients able to be consented to join the study	15 months
Feasibility of patient recruitment: percentage from consent process	Percentage of eligible patients able to be consented to join the study	15 months
Feasibility of patient retention during the 10 day study period: number of participants	Number of participants retained for the 10 day study; reasons for withdrawal analysed by descriptive statistics	15 months
Feasibility of patient retention during the 10 day study period; percentage of participants	Percentage of participants retained for the 10 day study; reasons for withdrawal analysed by descriptive statistics	15 months
Feasibility of provision of ketogenic feed: staff-completed questionnaire	Non-validated questionnaire to be completed by ICU bedside nurses and critical care research nurses within 2 weeks of recruitment completing. 12 questions will ask about ease of reconstituting and using the feed and any side effects encountered. Each question will be scored on a scale of 0-10 with 0 the worst/lowest score and 10 the best/highest score. The results for each question will be presented individually using descriptive statistics as mean +/- standard deviation, with a text description adding any comments received.	15 months
Incidence of Adverse Events/Serious Adverse Events, gastric intolerance, glucose variation	Percentage of days event occurred out of total possible days (mean +/- 95% confidence interval): pulmonary aspiration; vomiting, diarrhea (Bristol Stool Score T5-T7), prokinetics use, gastric residual volume >300mls; adverse blood glucose levels of >10.1mmol/l and <3.9mmol/l; Daily insulin use.	15 months
Coefficient of Glucose Variation (scored as mean/standard deviation)	Coefficient of Glucose Variation (scored as mean/standard deviation)	15 months
Timescale for the development and establishment of ketosis during 10 days of intervention or control feed; beta-hydroxybutyrate	Plasma levels of beta-hydroxybutyrate: mmol/l	15 months
Timescale for the development and establishment of ketosis during 10 days of intervention or control feed; acetoacetate	Plasma levels of acetoacetate mmol/l	15 months
Timescale for the development and establishment of ketosis during 10 days of intervention or control feed; pyruvate	Plasma levels of pyruvate mmol/l	15 months
Timescale for the development and establishment of ketosis during 10 days of intervention or control feed, fat	Plasma levels of fat (ratio of Medium Chain to Long Chain Triglyceride)	15 months
Timescale for the development and establishment of ketosis during 10 days of intervention or control feed, glucose	Plasma levels of glucose mmol/l	15 months
Timescale for the development and establishment of ketosis during 10 days of intervention or control feed, lactate	Plasma levels of lactate mmol/l	15 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data: blood gases	Arterial Blood Gases, pH, PaO2 and PaCO2 in kPa	15 months
Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data; biochemistry	Bicarbonate, Base Excess, Lactate, other biochemistry data in mmol/l	15 months
Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data; haematology	Hematology data (Hb in g/l, White cell count and platelets in 10 to power of 9/l)	15 months
Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data; bedside physiology	Bedside Physiology (BP, HR, SOFA score, Fluid Balance)	15 months
Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data; nutritional data	Nutritional data (Protein g/kg/day and Energy kcal/kg/day	15 months
Feasibility of data collection into electronic database from medical notes and nursing sheets as assessed by completion of >80% of available data; Propofol	Propofol dose (mg/day)	15 months
Feasibility of performing quadriceps ultrasound scans: muscle mass	Ultrasound scans of rectus femoris part of quadriceps muscle as a measure of muscle mass	15 months
Feasibility of performing functional assessment at hospital discharge by Two- or Six-Minute Walk Test	Two minute or Six-Minute Walk Test (depending on patient capability) captures all the walking distance that a patient can demonstrate (in metres)	15 months
Feasibility of performing functional assessment at hospital discharge by Short Physical Performance Battery	Short Physical Performance Battery (scoring between 0-10; includes results of the gait speed, balance tests and chair stand)	15 months
Feasibility of performing functional assessment at hospital discharge by CPAx score	Chelsea Critical Care Physical Assessment Score (CPAx): scoring 0-5 in 10 domains	15 months
Feasibility of collecting metabolic data on ICU: indirect calorimetry	non-invasive metabolic data via indirect calorimetry on ICU	15 months
Feasibility of collecting follow-up data by telephone re quality of life: ED5Q survey	Use of ED5Q survey to determine health-related quality of life; scoring 1-5 in 5 domains, plus 1-100 in 1 domain	18 months
Feasibility of collecting follow-up data by telephone re job status: Questions on employment status	Questions on employment status (full-time: yes/no; part-time: yes/no)	18 months
Feasibility of collecting follow-up data from medical records: number of GP/nurse visits	Information on health care resource usage from number of GP/nurse visits during 12 months post-ICU and hospital discharge	18 months
Biochemical analysis of urine	To determine urinary concentrations of beta-hydroxybutyrate and total nitrogen (in mmol/l)	18 months
Biochemical analysis of plasma metabolites, beta-hydroxy butyrate, acetoacetate, leucine, and alanine (all measured in the same Arbitrary Units [AU]).	Investigation into beta-hydroxy butyrate, acetoacetate, leucine, and alanine (all measured in the same Arbitrary Units [AU]) by HPLC; NMR spectra will be phased, baseline corrected, zero filled and referenced prior to multivariate analysis. Multivariate techniques will include principal components analysis (PCA) and prediction and regression using partial least squared discriminant analysis (PLS-DA). Owing to the high variability expected in this data set, orthogonal projection to latent structures (OPLS) will be utilised to maximise the variation in the intervention under study. Given the high number of metabolites expected to be seen, statistical total correlation spectroscopy (STOCSY) will be utilised to detect endogenous responses.	18 months

Collaborators and Investigators

• Sponsor: Barts & The London NHS Trust
• Collaborators: Bristol Royal Infirmary; Institute of Child Health
• Investigators: Principal Investigator: Angela McNelly, PhD, Royal London Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2019
• Primary Completion (Actual): April 27, 2022
• Study Completion (Actual): April 27, 2022

Study Registration Dates

• First Submitted: June 26, 2019
• First Submitted That Met QC Criteria: September 23, 2019
• First Posted (Actual): September 24, 2019

Study Record Updates

• Last Update Posted (Actual): August 1, 2022
• Last Update Submitted That Met QC Criteria: July 29, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Critical care; enteral feeding; nasogastric; ketogenic feed; feasibility
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness
• Other Study ID Numbers: 266031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

(i) Where practicable, publicly funded research data should be made available for access, subject to such conditions as are necessary to ensure compliance with legal, data protection, ethical, confidentiality, intellectual property protection, and security/funder obligations.

(ii) The rights of researchers to the exclusive use of research data that they generate as part of a well-defined research project will be protected up until the point of publication or public availability.

(iii) Data arising from this research involving human subjects will be anonymised so that it will not be possible to identify any individuals. Where it appears inappropriate to make such data accessible, e.g. it might lead to identification of research subjects or because seeking consent would reduce the rate of participation in the research, the data will remain confidential.

(iv) For research collaborations, any open access arrangements can only take place with the agreement of all research partners.

• IPD Sharing Time Frame: Data will be available once the primary publication is available. It will be available for a period of 10 years.
• IPD Sharing Access Criteria: Access is available for anyone who is able to provide a reasonable case for their access to the data.
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No