Exogenous Ketone Supplementation in ICU Delirium

Summary

Delirium is a common syndrome in intensive care unit (ICU) patients. Those experiencing delirium may suddenly feel confused, have trouble thinking clearly, struggle to pay attention, or see and hear things that are not real. Delirium is associated with worse long-term outcomes such as cognitive impairment, depression, and PTSD (post-traumatic stress disorder). This study examines whether an investigational medical-grade ketone supplement drink (ketone monoester \[brand name: Ultrapure Ketone Monoester\]) is safe and feasible to use in ICU patients, and to look for signals that it might reduce delirium or shorten its duration compared to a volume-, taste-, and calorie-matched placebo.

Timeline

Start

2026-06-09

Primary completion

2026-12-31

Completion

2027-12-31

Publications

• Background Smith R, Harrison F, Bastarache J, Williams Roberson S, Zaganjor E, Pandharipande P, Rice T, Ely W. Potential therapeutic benefit of exogenous ketone ester administration in delirium: a narrative review. Crit Care. 2025 Oct 7;29(1):424. doi: 10.1186/s13054-025-05680-5.
• Background Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN, Douglas IS, Malhotra A, Owens RL, Feinstein DJ, Khan B, Pisani MA, Hyzy RC, Schmidt GA, Schweickert WD, Hite RD, Bowton DL, Masica AL, Thompson JL, Chandrasekhar R, Pun BT, Strength C, Boehm LM, Jackson JC, Pandharipande PP, Brummel NE, Hughes CG, Patel MB, Stollings JL, Bernard GR, Dittus RS, Ely EW; MIND-USA Investigators. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. 2018 Dec 27;379(26):2506-2516. doi: 10.1056/NEJMoa1808217. Epub 2018 Oct 22.
• Background Saris CGJ, Timmers S. Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention. Front Nutr. 2022 Nov 15;9:947567. doi: 10.3389/fnut.2022.947567. eCollection 2022.
• Background Hou L, Yang J, Li S, Huang R, Zhang D, Zhao J, Wang Q. Glibenclamide attenuates 2,5-hexanedione-induced neurotoxicity in the spinal cord of rats through mitigation of NLRP3 inflammasome activation, neuroinflammation and oxidative stress. Toxicol Lett. 2020 Oct 1;331:152-158. doi: 10.1016/j.toxlet.2020.06.002. Epub 2020 Jun 6.
• Background Oh U, Woolbright E, Lehner-Gulotta D, Coleman R, Conaway M, Goldman MD, Brenton JN. Serum neurofilament light chain in relapsing multiple sclerosis patients on a ketogenic diet. Mult Scler Relat Disord. 2023 May;73:104670. doi: 10.1016/j.msard.2023.104670. Epub 2023 Mar 25.
• Background Bock M, Steffen F, Zipp F, Bittner S. Impact of Dietary Intervention on Serum Neurofilament Light Chain in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021 Nov 11;9(1):e1102. doi: 10.1212/NXI.0000000000001102. Print 2022 Jan.
• Background McDougall A, Bayley M, Munce SE. The ketogenic diet as a treatment for traumatic brain injury: a scoping review. Brain Inj. 2018;32(4):416-422. doi: 10.1080/02699052.2018.1429025. Epub 2018 Jan 23.
• Background Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015 Mar;21(3):263-9. doi: 10.1038/nm.3804. Epub 2015 Feb 16.
• Background Prins M, Greco T, Alexander D, Giza CC. The pathophysiology of traumatic brain injury at a glance. Dis Model Mech. 2013 Nov;6(6):1307-15. doi: 10.1242/dmm.011585. Epub 2013 Sep 12.
• Background Xu Q, Zhang Y, Zhang X, Liu L, Zhou B, Mo R, Li Y, Li H, Li F, Tao Y, Liu Y, Xue C. Medium-chain triglycerides improved cognition and lipid metabolomics in mild to moderate Alzheimer's disease patients with APOE4-/-: A double-blind, randomized, placebo-controlled crossover trial. Clin Nutr. 2020 Jul;39(7):2092-2105. doi: 10.1016/j.clnu.2019.10.017. Epub 2019 Oct 22.
• Background Ota M, Matsuo J, Ishida I, Takano H, Yokoi Y, Hori H, Yoshida S, Ashida K, Nakamura K, Takahashi T, Kunugi H. Effects of a medium-chain triglyceride-based ketogenic formula on cognitive function in patients with mild-to-moderate Alzheimer's disease. Neurosci Lett. 2019 Jan 18;690:232-236. doi: 10.1016/j.neulet.2018.10.048. Epub 2018 Oct 24.
• Background Jensen NJ, Nilsson M, Ingerslev JS, Olsen DA, Fenger M, Svart M, Moller N, Zander M, Miskowiak KW, Rungby J. Effects of beta-hydroxybutyrate on cognition in patients with type 2 diabetes. Eur J Endocrinol. 2020 Feb;182(2):233-242. doi: 10.1530/EJE-19-0710.
• Background Fortier M, Castellano CA, Croteau E, Langlois F, Bocti C, St-Pierre V, Vandenberghe C, Bernier M, Roy M, Descoteaux M, Whittingstall K, Lepage M, Turcotte EE, Fulop T, Cunnane SC. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimers Dement. 2019 May;15(5):625-634. doi: 10.1016/j.jalz.2018.12.017. Epub 2019 Apr 23.
• Background Fortier M, Castellano CA, St-Pierre V, Myette-Cote E, Langlois F, Roy M, Morin MC, Bocti C, Fulop T, Godin JP, Delannoy C, Cuenoud B, Cunnane SC. A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT. Alzheimers Dement. 2021 Mar;17(3):543-552. doi: 10.1002/alz.12206. Epub 2020 Oct 26.
• Background Cunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E, Tremblay S, Castellano A, Pifferi F, Bocti C, Paquet N, Begdouri H, Bentourkia M, Turcotte E, Allard M, Barberger-Gateau P, Fulop T, Rapoport SI. Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition. 2011 Jan;27(1):3-20. doi: 10.1016/j.nut.2010.07.021. Epub 2010 Oct 29.
• Background Dienel GA. Brain Glucose Metabolism: Integration of Energetics with Function. Physiol Rev. 2019 Jan 1;99(1):949-1045. doi: 10.1152/physrev.00062.2017.
• Background Onyango IG, Dennis J, Khan SM. Mitochondrial Dysfunction in Alzheimer's Disease and the Rationale for Bioenergetics Based Therapies. Aging Dis. 2016 Mar 15;7(2):201-14. doi: 10.14336/AD.2015.1007. eCollection 2016 Mar.
• Background Aldana BI. Microglia-Specific Metabolic Changes in Neurodegeneration. J Mol Biol. 2019 Apr 19;431(9):1830-1842. doi: 10.1016/j.jmb.2019.03.006. Epub 2019 Mar 13.
• Background An Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O, Chia CW, Egan JM, Ferrucci L, Troncoso J, Levey AI, Lah J, Seyfried NT, Legido-Quigley C, O'Brien R, Thambisetty M. Evidence for brain glucose dysregulation in Alzheimer's disease. Alzheimers Dement. 2018 Mar;14(3):318-329. doi: 10.1016/j.jalz.2017.09.011. Epub 2017 Oct 19.
• Background Myette-Cote E, Soto-Mota A, Cunnane SC. Ketones: potential to achieve brain energy rescue and sustain cognitive health during ageing. Br J Nutr. 2022 Aug 14;128(3):407-423. doi: 10.1017/S0007114521003883. Epub 2021 Sep 28.
• Background Stagg DB, Gillingham JR, Nelson AB, Lengfeld JE, d'Avignon DA, Puchalska P, Crawford PA. Diminished ketone interconversion, hepatic TCA cycle flux, and glucose production in D-beta-hydroxybutyrate dehydrogenase hepatocyte-deficient mice. Mol Metab. 2021 Nov;53:101269. doi: 10.1016/j.molmet.2021.101269. Epub 2021 Jun 8.
• Background Falkenhain K, Daraei A, Forbes SC, Little JP. Effects of Exogenous Ketone Supplementation on Blood Glucose: A Systematic Review and Meta-analysis. Adv Nutr. 2022 Oct 2;13(5):1697-1714. doi: 10.1093/advances/nmac036.
• Background Newman JC, Verdin E. beta-Hydroxybutyrate: A Signaling Metabolite. Annu Rev Nutr. 2017 Aug 21;37:51-76. doi: 10.1146/annurev-nutr-071816-064916.
• Background Myette-Cote E, Caldwell HG, Ainslie PN, Clarke K, Little JP. A ketone monoester drink reduces the glycemic response to an oral glucose challenge in individuals with obesity: a randomized trial. Am J Clin Nutr. 2019 Dec 1;110(6):1491-1501. doi: 10.1093/ajcn/nqz232.
• Background Lowder J, Fallah S, Venditti C, Musa-Veloso K, Kotlov V. An open-label, acute clinical trial in adults to assess ketone levels, gastrointestinal tolerability, and sleepiness following consumption of (R)-1,3-butanediol (Avela). Front Physiol. 2023 Jun 28;14:1195702. doi: 10.3389/fphys.2023.1195702. eCollection 2023.
• Background Mah E, Blonquist TM, Kaden VN, Beckman D, Boileau AC, Anthony JC, Stubbs BJ. A randomized, open-label, parallel pilot study investigating metabolic product kinetics of the novel ketone ester, bis-hexanoyl (R)-1,3-butanediol, over one week of ingestion in healthy adults. Front Physiol. 2023 Jun 22;14:1196535. doi: 10.3389/fphys.2023.1196535. eCollection 2023.
• Background Bolyard ML, Graziano CM, Fontaine KR, Sayer RD, Fisher G, Plaisance EP. Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. Nutrients. 2023 Nov 22;15(23):4876. doi: 10.3390/nu15234876.
• Background Stubbs BJ, Cox PJ, Kirk T, Evans RD, Clarke K. Gastrointestinal Effects of Exogenous Ketone Drinks are Infrequent, Mild, and Vary According to Ketone Compound and Dose. Int J Sport Nutr Exerc Metab. 2019 Nov 1;29(6):596-603. doi: 10.1123/ijsnem.2019-0014.
• Background McNelly A, Langan A, Bear DE, Page A, Martin T, Seidu F, Santos F, Rooney K, Liang K, Heales SJ, Baldwin T, Alldritt I, Crossland H, Atherton PJ, Wilkinson D, Montgomery H, Prowle J, Pearse R, Eaton S, Puthucheary ZA. A pilot study of alternative substrates in the critically Ill subject using a ketogenic feed. Nat Commun. 2023 Dec 15;14(1):8345. doi: 10.1038/s41467-023-42659-8.
• Background Mikkelsen KH, Seifert T, Secher NH, Grondal T, van Hall G. Systemic, cerebral and skeletal muscle ketone body and energy metabolism during acute hyper-D-beta-hydroxybutyratemia in post-absorptive healthy males. J Clin Endocrinol Metab. 2015 Feb;100(2):636-43. doi: 10.1210/jc.2014-2608. Epub 2014 Nov 21.
• Background Cunnane SC, Courchesne-Loyer A, St-Pierre V, Vandenberghe C, Pierotti T, Fortier M, Croteau E, Castellano CA. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. Ann N Y Acad Sci. 2016 Mar;1367(1):12-20. doi: 10.1111/nyas.12999. Epub 2016 Jan 14.
• Background Courchesne-Loyer A, Croteau E, Castellano CA, St-Pierre V, Hennebelle M, Cunnane SC. Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study. J Cereb Blood Flow Metab. 2017 Jul;37(7):2485-2493. doi: 10.1177/0271678X16669366. Epub 2016 Jan 1.
• Background Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016 Aug 9;24(2):256-68. doi: 10.1016/j.cmet.2016.07.010. Epub 2016 Jul 27.
• Background Soto-Mota A, Vansant H, Evans RD, Clarke K. Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Regul Toxicol Pharmacol. 2019 Dec;109:104506. doi: 10.1016/j.yrtph.2019.104506. Epub 2019 Oct 23.
• Background Avgerinos KI, Mullins RJ, Egan JM, Kapogiannis D. Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults >/= 55 Years Old. A Study Protocol for a Double-Blinded Randomized Controlled Clinical Trial. J Prev Alzheimers Dis. 2022;9(1):54-66. doi: 10.14283/jpad.2022.3.
• Background Kapogiannis D, Avgerinos KI. Brain glucose and ketone utilization in brain aging and neurodegenerative diseases. Int Rev Neurobiol. 2020;154:79-110. doi: 10.1016/bs.irn.2020.03.015. Epub 2020 Jul 10.
• Background Hohn S, Dozieres-Puyravel B, Auvin S. History of dietary treatment from Wilder's hypothesis to the first open studies in the 1920s. Epilepsy Behav. 2019 Dec;101(Pt A):106588. doi: 10.1016/j.yebeh.2019.106588. Epub 2019 Oct 30.
• Background Khan BA, Perkins AJ, Gao S, Hui SL, Campbell NL, Farber MO, Chlan LL, Boustani MA. The Confusion Assessment Method for the ICU-7 Delirium Severity Scale: A Novel Delirium Severity Instrument for Use in the ICU. Crit Care Med. 2017 May;45(5):851-857. doi: 10.1097/CCM.0000000000002368.
• Background Clarke K, Tchabanenko K, Pawlosky R, Carter E, Todd King M, Musa-Veloso K, Ho M, Roberts A, Robertson J, Vanitallie TB, Veech RL. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012 Aug;63(3):401-8. doi: 10.1016/j.yrtph.2012.04.008. Epub 2012 May 3.
• Background White H, Venkatesh B, Jones M, Kruger PS, Walsham J, Fuentes H. Inducing ketogenesis via an enteral formulation in patients with acute brain injury:a phase II study. Neurol Res. 2020 Apr;42(4):275-285. doi: 10.1080/01616412.2019.1709743. Epub 2020 Feb 26.
• Background Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, Speroff T, Gautam S, Bernard GR, Inouye SK. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001 Jul;29(7):1370-9. doi: 10.1097/00003246-200107000-00012.
• Background Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, Stirling M, Clarke K. On the Metabolism of Exogenous Ketones in Humans. Front Physiol. 2017 Oct 30;8:848. doi: 10.3389/fphys.2017.00848. eCollection 2017.
• Background Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, Vasilevskis EE, Shintani AK, Moons KG, Geevarghese SK, Canonico A, Hopkins RO, Bernard GR, Dittus RS, Ely EW; BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med. 2013 Oct 3;369(14):1306-16. doi: 10.1056/NEJMoa1301372.
• Background Cunnane SC, Courchesne-Loyer A, Vandenberghe C, St-Pierre V, Fortier M, Hennebelle M, Croteau E, Bocti C, Fulop T, Castellano CA. Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer's Disease. Front Mol Neurosci. 2016 Jul 8;9:53. doi: 10.3389/fnmol.2016.00053. eCollection 2016.
• Background Morris G, Puri BK, Maes M, Olive L, Berk M, Carvalho AF. The role of microglia in neuroprogressive disorders: mechanisms and possible neurotherapeutic effects of induced ketosis. Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109858. doi: 10.1016/j.pnpbp.2020.109858. Epub 2020 Jan 7.
• Background Jang J, Kim SR, Lee JE, Lee S, Son HJ, Choe W, Yoon KS, Kim SS, Yeo EJ, Kang I. Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases. Int J Mol Sci. 2023 Dec 21;25(1):124. doi: 10.3390/ijms25010124.
• Background Yang H, Shan W, Zhu F, Wu J, Wang Q. Ketone Bodies in Neurological Diseases: Focus on Neuroprotection and Underlying Mechanisms. Front Neurol. 2019 Jun 12;10:585. doi: 10.3389/fneur.2019.00585. eCollection 2019.
• Background Gomora-Garcia JC, Montiel T, Huttenrauch M, Salcido-Gomez A, Garcia-Velazquez L, Ramiro-Cortes Y, Gomora JC, Castro-Obregon S, Massieu L. Effect of the Ketone Body, D-beta-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy-Lysosomal Pathway. Cells. 2023 Feb 2;12(3):486. doi: 10.3390/cells12030486.
• Background Gnorich J, Reifschneider A, Wind K, Zatcepin A, Kunte ST, Beumers P, Bartos LM, Wiedemann T, Grosch M, Xiang X, Fard MK, Ruch F, Werner G, Koehler M, Slemann L, Hummel S, Briel N, Blume T, Shi Y, Biechele G, Beyer L, Eckenweber F, Scheifele M, Bartenstein P, Albert NL, Herms J, Tahirovic S, Haass C, Capell A, Ziegler S, Brendel M. Depletion and activation of microglia impact metabolic connectivity of the mouse brain. J Neuroinflammation. 2023 Feb 24;20(1):47. doi: 10.1186/s12974-023-02735-8.
• Background Afridi R, Kim JH, Rahman MH, Suk K. Metabolic Regulation of Glial Phenotypes: Implications in Neuron-Glia Interactions and Neurological Disorders. Front Cell Neurosci. 2020 Feb 11;14:20. doi: 10.3389/fncel.2020.00020. eCollection 2020.
• Background Bernier LP, York EM, Kamyabi A, Choi HB, Weilinger NL, MacVicar BA. Microglial metabolic flexibility supports immune surveillance of the brain parenchyma. Nat Commun. 2020 Mar 25;11(1):1559. doi: 10.1038/s41467-020-15267-z.
• Background Cunnane SC, Trushina E, Morland C, Prigione A, Casadesus G, Andrews ZB, Beal MF, Bergersen LH, Brinton RD, de la Monte S, Eckert A, Harvey J, Jeggo R, Jhamandas JH, Kann O, la Cour CM, Martin WF, Mithieux G, Moreira PI, Murphy MP, Nave KA, Nuriel T, Oliet SHR, Saudou F, Mattson MP, Swerdlow RH, Millan MJ. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discov. 2020 Sep;19(9):609-633. doi: 10.1038/s41573-020-0072-x. Epub 2020 Jul 24.
• Background Fu C, Weng S, Liu D, Guo R, Chen M, Shi B, Weng J. Review on the Role of Mitochondrial Dysfunction in Septic Encephalopathy. Cell Biochem Biophys. 2025 Mar;83(1):135-145. doi: 10.1007/s12013-024-01493-5. Epub 2024 Aug 30.
• Background Preau S, Vodovar D, Jung B, Lancel S, Zafrani L, Flatres A, Oualha M, Voiriot G, Jouan Y, Joffre J, Uhel F, De Prost N, Silva S, Azabou E, Radermacher P. Energetic dysfunction in sepsis: a narrative review. Ann Intensive Care. 2021 Jul 3;11(1):104. doi: 10.1186/s13613-021-00893-7.
• Background Zhang J, Chen S, Hu X, Huang L, Loh P, Yuan X, Liu Z, Lian J, Geng L, Chen Z, Guo Y, Chen B. The role of the peripheral system dysfunction in the pathogenesis of sepsis-associated encephalopathy. Front Microbiol. 2024 Jan 17;15:1337994. doi: 10.3389/fmicb.2024.1337994. eCollection 2024.
• Background Kealy J, Murray C, Griffin EW, Lopez-Rodriguez AB, Healy D, Tortorelli LS, Lowry JP, Watne LO, Cunningham C. Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium. J Neurosci. 2020 Jul 15;40(29):5681-5696. doi: 10.1523/JNEUROSCI.2876-19.2020. Epub 2020 Jun 8.
• Background Wilson JE, Mart MF, Cunningham C, Shehabi Y, Girard TD, MacLullich AMJ, Slooter AJC, Ely EW. Delirium. Nat Rev Dis Primers. 2020 Nov 12;6(1):90. doi: 10.1038/s41572-020-00223-4.

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