Alternative Substrates in the Critically Ill Subject

Critical Illness Clinical Trial

— ASICS  

Official title:

Alternative Substrates in the Critically Ill Subject

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04101071
• Other study ID #: 266031
• Status: Completed
• Phase: N/A
• Start date: October 2, 2019
• Est. completion date: April 27, 2022

Study information

• Verified date: March 2022
• Source: Barts & The London NHS Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: April 27, 2022
• Est. primary completion date: April 27, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Critical Illness

Intervention

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
• 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

Locations

Country	Name	City	State
United Kingdom	Bristol Royal Infirmary	Bristol
United Kingdom	Royal London Hospital	London

Sponsors (3)

Lead Sponsor	Collaborator
Barts & The London NHS Trust	Bristol Royal Infirmary, Institute of Child Health

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility of patient recruitment; number eligible from screening	Number of patients screened	15 months
Primary	Feasibility of patient recruitment; percentage eligible from screening	Percentage of patients eligible for recruitment	15 months
Primary	Feasibility of patient recruitment; number from consent process	Number of eligible patients able to be consented to join the study	15 months
Primary	Feasibility of patient recruitment: percentage from consent process	Percentage of eligible patients able to be consented to join the study	15 months
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Coefficient of Glucose Variation (scored as mean/standard deviation)	Coefficient of Glucose Variation (scored as mean/standard deviation)	15 months
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Feasibility of collecting metabolic data on ICU: indirect calorimetry	non-invasive metabolic data via indirect calorimetry on ICU	15 months
Secondary	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
Secondary	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
Secondary	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
Secondary	Biochemical analysis of urine	To determine urinary concentrations of beta-hydroxybutyrate and total nitrogen (in mmol/l)	18 months
Secondary	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