Bioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone bodies may form an alternative substrate source, but the feasibility and safety of inducing a ketogenic state in physiologically unstable patients is not known. Twenty-nine mechanically ventilated adults with multi-organ failure were randomised into a two-centre safety and feasibility trial of ketogenic versus standard enteral feeding. Ketogenic feeding was feasible, safe, well tolerated and resulted in ketosis. Patients receiving ketogenic feeding had fewer hypoglycaemic events (0% vs. 1.58%), required less exogenous insulin (0.0 IU (IQR 0-16) vs.78 IU (IQR 0-412) but had slightly more daily episodes of diarrhoea (53.5% vs. 42.9%) over the trial period. Untargeted metabophenotyping revealed altered Cahill cycle flux and bioenergetic states, suggesting an advantageous metabolic profile. Ketogenic feeding is feasible and may be a novel intervention for addressing bioenergetic failure in critically ill patients.

DEB has received speaker fees, conference attendance support or advisory board fees from Baxter, Cardinal Health and Avanos. ZP has received honoraria for consultancy from GlaxoSmithKline, Lyric Pharmaceuticals, Faraday Pharmaceuticals and Fresenius-Kabi and speaker fees from Orion and Nestle. HM holds patents relating to intravenous hydration and to regulation of metabolic efficiency using renin-angiotensin system antagonists. SE and SJH hold patents with Vitaflo International Ltd for compositions different from that used in this study, for managing drug resistant epilepsy and disorders associated with mitochondrial dysfunction, and also are in receipt of grant funding from Vitaflo International Ltd (not connected with this study). A patent has been submitted for the ketogenic feed regime used in this study (ZAP, AM, AL, DB). Vitaflo International Ltd were involved in initial discussions about the study and provided the K.Quik component for the ketogenic feed gratis. Neither Vitaflo International Ltd nor Nestle Health Sciences contributed to study design, study implementation, data analysis or interpretation. Other authors have no conflicts of interest to declare.

NCT04101071

This study was funded by NIHR Research for Patient Benefit (PB-PG-0317-20006: GBP249,560; plus GBP10,549 additional COVID-related funding); Education grant from Nestle Health Science (GBP25000).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of National Research Ethics Service Wales 5 Bangor gave ethical approval for this work (REC reference 19/WA/0209; IRAS project ID 266031).

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The data that support the findings of this study are available for research purposes on reasonable request from the corresponding author [ZAP]. The data are not publicly available since this was not included in research participant consent.