Effects of Ketosis on Muscle Kinetics and Signaling During Critical Illness. (KETO-ICU)

Background:

Patients with critical illness in the intensive care unit (ICU) experience marked skeletal muscle weakness, muscle atrophy and disability in physical function, commonly termed ICU-acquired weakness (ICU-AW). The pathophysiology of ICU-AW is complex, but a key feature of skeletal muscle wasting is disturbed protein metabolism reflected in both increased rate of muscle protein degradation and reduced synthesis. Treatment with 3-OHB seems a promising new anticatabolic treatment in patients with critical illness, preventing ICU-AW. To date, no data exist on the clinical and functional effects of ketone body modulation in patients with critical illness.

Objective:

The aim to investigate the effect of exogenous 3-OHB administration on muscle protein kinetics and lipolysis in patients with critical illness, aiming towards preventing ICU-AW.

Design:

A randomized double-blind isocaloric placebo-controlled cross-over study in 10 mechanically ventilated patients with critical illness in the ICU.

Methods:

Evaluation of whole-body and focal leg protein kinetics using labeled phenylalanine and tyrosine tracers. Assessment of free fatty acid (FFA) turnover using a labeled palmitate tracer. Femoral arterial blood flow (assessed with pulsed-wave Doppler ultrasound) is evaluated once per study period. Blood- and urinary samples are collected routinely throughout the study day. Whenever feasible, muscle and fat biopsies will be taken for analysis of protein and adipocyte metabolic signaling and mitochondrial function.

Perspectives: This investigation may grant essential knowledge on ketosis in critical illness. This may lead to larger clinical trials, and hopefully a new and better treatment strategy aimed at preserving muscle mass and function during and improving recovery after critical illness.

Study Overview

• Status: Not yet recruiting
• Conditions: Critical Illness; Intensive Care Unit Acquired Weakness
• Intervention / Treatment: Dietary supplement: KetoneAid KE4 Pro Monoester; Dietary supplement: Maltodextrin and fat-based placebo

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kristoffer Berg-Hansen, MD; Phone Number: 60540700; Email: krbhan@gmail.com
• Study Contact Backup: Name: Niels Møller, Prof.; Email: niels.moeller@clin.au.dk

Study Locations

• Denmark
  • Aarhus, Denmark, DK-8200
    • Aarhus University Hospital
    • Contact: Kristoffer Berg-Hansen, MD; Email: krisbe@rm.dk
    • Contact: Niels Møller, Prof.; Email: niels.moeller@clin.au.dk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Invasive mechanical ventilation via a cuffed endotracheal or tracheotomy tube.
• Expected survival of ICU admission.
• Adults (≥18 years).
• Multi-organ failure (Sequential Organ Failure Assessment Score [SOFA] score ≥2 in 2 or more domains).

Exclusion Criteria:

• Moribund or expected withholding treatment within 48 hours as judged by the investigator.
• Palliative goals of care.
• Contraindication for enteral nutrition.
• Pregnancy.
• Known severe musculoskeletal or neurological disability.
• Diabetic ketoacidosis.
• Phenylketonuria.
• BMI ≤17 or deemed malnourished as judged by the investigator.
• BMI >40.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketone monoester (3-OHB); Weight-adjusted dose of 3-OHB Monoester (KetoneAID KE4, Virginia, US). Bolus of 300 mg/kg followed by a 2-hour continuous enteral infusion with a dosing of 100 mg/kg/hour (maximal total dose 50 grams). There is a 1-hour lag between the bolus and the continuous infusion.	Dietary supplement: KetoneAid KE4 Pro Monoester; A dietary supplement containing ketone monoester.
Placebo Comparator: Placebo Treatment; Maltodextrin- and fatbased placebo in isocaloric, isovolemic dose to the experimental arm.	Dietary supplement: Maltodextrin and fat-based placebo; Dosis isocaloric to the KetoneAid Arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Net leg phenylalanine release	As measured by rate of phenylalanine appearance in relation with the rate of disappearance.	3 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in rate of appearance of phenylalanine over the leg.		3 hours.
Change in rate of disappearance of phenylalanine over the leg.		3 hours.
Whole body palmitate flux	As measured by rate of appearance of a palmitate-tracer	3 hours.
Change in arterial pH.		3 hours.
Changes in inflammatory cytokines (IL-1, IL-6, IL-18, TNFa)		3 hours.
Changes in intramyocellular protein metabolic signalling pathways.	The Akt-, mTor-, and ubiquitin-proteasome pathways.	3 hours.

Collaborators and Investigators

• Sponsor: Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2023
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: September 17, 2021
• First Submitted That Met QC Criteria: September 29, 2021
• First Posted (Actual): October 12, 2021

Study Record Updates

• Last Update Posted (Actual): November 4, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness
• Other Study ID Numbers: KETO-ICU 1-10-72-231-21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No