{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T09:17:19Z","timestamp":1768727839663,"version":"3.49.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Therapeutic ketosis is traditionally induced with dietary modification. However, owing to the time delay involved, this is not a practical approach for treatment of acute conditions such as traumatic brain injury. Intravenous administration of ketones would obviate this problem by rapidly inducing ketosis. This has been confirmed in a number of small animal and human studies. Currently no such commercially available product exists. The aim of this systematic review is to review the safety and efficacy of intravenous beta-hydroxybutyrate. The Web of Science, PubMed and EMBASE databases were searched, and a systematic review undertaken. Thirty-five studies were included. The total beta-hydroxybutyrate dose ranged from 30 to 101 g administered over multiple doses as a short infusion, with most studies using the racemic form. Such dosing achieves a beta-hydroxybutyrate concentration &amp;gt;1 mmol\/L within 15 min. Infusions were well tolerated with few adverse events. Blood glucose concentrations occasionally were reduced but remained within the normal reference range for all study participants. Few studies have examined the effect of intravenous beta-hydroxybutyrate in disease states. In patients with heart failure, intravenous beta-hydroxybutyrate increased cardiac output by up to 40%. No studies were conducted in patients with neurological disease. Intravenous beta-hydroxybutyrate has been shown to increase cerebral blood flow and reduce cerebral glucose oxidation. Moreover, beta-hydroxybutyrate reduces protein catabolism and attenuates the production of counter-regulatory hormones during induced hypoglycemia. An intravenous beta-hydroxybutyrate formulation is well tolerated and may provide an alternative treatment option worthy of further research in disease states.<\/jats:p>","DOI":"10.3389\/fmed.2021.740374","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T05:11:40Z","timestamp":1632201100000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["A Systematic Review of Intravenous \u03b2-Hydroxybutyrate Use in Humans \u2013 A Promising Future Therapy?"],"prefix":"10.3389","volume":"8","author":[{"given":"Hayden","family":"White","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron J.","family":"Heffernan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Worrall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Grunsfeld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matt","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1042\/bj0930652","article-title":"Regulation of glucose uptake by muscle. 8 effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscles","volume":"93","author":"Randle","year":"1964","journal-title":"Biochem J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/BF02263641","article-title":"Glucose metabolism in a child with 3-hydroxy-3-methylglutaryl-coenzyme a lyase deficiency","volume":"4","author":"Fran\u00e7ois","year":"1981","journal-title":"J Inherit Metab Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1093\/bja\/83.2.325","article-title":"Mitochondrial redox state in the critically ill","volume":"83","author":"Yassen","year":"1999","journal-title":"Br J Anaesth."},{"key":"B4","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1159\/000129229","article-title":"Superoxide production by liver macrophages in a septic rat model\u2013relation to arterial ketone body ratio","volume":"24","author":"Iimuro","year":"1992","journal-title":"Eur Surg Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1097\/00003246-200001000-00019","article-title":"Evolution of lactate\/pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock","volume":"28","author":"Levy","year":"2000","journal-title":"Crit Care Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1097\/00008877-200609000-00009","article-title":"Neuroprotective and disease-modifying effects of the ketogenic diet","volume":"17","author":"Gasior","year":"2006","journal-title":"Behav Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1007\/s11940-008-0043-8","article-title":"The ketogenic diet: uses in epilepsy and other neurologic illnesses","volume":"10","author":"Bara\u00f1ano","year":"2008","journal-title":"Curr Treat Options Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"59","DOI":"10.3389\/fphar.2012.00059","article-title":"The ketogenic diet as a treatment paradigm for diverse neurological disorders","volume":"3","author":"Stafstrom","year":"2012","journal-title":"Front Pharmacol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"474296","DOI":"10.1155\/2014\/474296","article-title":"Ketogenic diet in neuromuscular and neurodegenerative diseases","volume":"2014","author":"Paoli","year":"2014","journal-title":"Biomed Res Int."},{"key":"B10","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1159\/000336404","article-title":"Nutrition and acne: therapeutic potential of ketogenic diets","volume":"25","author":"Paoli","year":"2012","journal-title":"Skin Pharmacol Physiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.1093\/eurheartj\/ehw125","article-title":"Dietary patterns and the risk of major adverse cardiovascular events in a global study of high-risk patients with stable coronary heart disease","volume":"37","author":"Stewart","year":"2016","journal-title":"Eur Heart J."},{"key":"B12","doi-asserted-by":"publisher","first-page":"H701","DOI":"10.1152\/ajpheart.1993.264.3.H701","article-title":"Competition between palmitate and ketone bodies as fuels for the heart: study with positron emission tomography","volume":"264","author":"Vanoverschelde","year":"1993","journal-title":"Am J Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e005066","DOI":"10.1161\/JAHA.116.005066","article-title":"Ketone body infusion with 3-hydroxybutyrate reduces myocardial glucose uptake and increases blood flow in humans: a positron emission tomography study","volume":"27","author":"Gormsen","year":"2017","journal-title":"J Am Heart Assoc."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1161\/CIRCULATIONAHA.118.036459","article-title":"Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients","volume":"139","author":"Nielsen","year":"2019","journal-title":"Circulation."},{"key":"B15","doi-asserted-by":"publisher","first-page":"E746","DOI":"10.1152\/ajpendo.1996.270.5.E746","article-title":"Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia","volume":"270","author":"Hasselbalch","year":"1996","journal-title":"Am J Physiol Endocrinol Metab."},{"key":"B16","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1046\/j.1471-4159.2001.00575.x","article-title":"Measurement of \u03b2-hydroxybutyrate in acute hyperketonemia in human brain","volume":"79","author":"Pan","year":"2001","journal-title":"J Neurochem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1097\/00004647-200207000-00014","article-title":"[2,4-13C2]-\u03b2-hydroxybutyrate metabolism in human brain","volume":"22","author":"Pan","year":"2002","journal-title":"J Cereb Blood Flow Metab."},{"key":"B18","doi-asserted-by":"publisher","first-page":"E20","DOI":"10.1152\/ajpendo.00294.2001","article-title":"Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients","volume":"283","author":"Blomqvist","year":"2002","journal-title":"Am J Physiol Endocrinol Metab."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e0190556","DOI":"10.1371\/journal.pone.0190556","article-title":"Regional cerebral effects of ketone body infusion with 3-hydroxybutyrate in humans: reduced glucose uptake, unchanged oxygen consumption and increased blood flow by positron emission tomography. A randomized, controlled trial","volume":"13","author":"Svart","year":"2018","journal-title":"PLoS ONE."},{"key":"B20","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1530\/EJE-19-0710","article-title":"Effects of \u03b2-hydroxybutyrate on cognition in patients with type 2 diabetes","volume":"182","author":"Jensen","year":"2020","journal-title":"Eur J Endocrinol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1210\/jc.2014-2608","article-title":"Systemic, cerebral and skeletal muscle ketone body and energy metabolism during acute hyper-D-\u00df-hydroxybutyratemia in post-absorptive healthy males","volume":"100","author":"Mikkelsen","year":"2015","journal-title":"J Clin Endocrinol Metab."},{"key":"B22","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1210\/jcem-65-2-331","article-title":"Glomerular filtration rate is increased in man by the infusion of both D,L-3-hydroxybutyric acid and sodium D,L-3-hydroxybutyrate","volume":"65","author":"Fioretto","year":"1987","journal-title":"J Clin Endocrinol Metab."},{"key":"B23","doi-asserted-by":"publisher","first-page":"239","DOI":"10.3109\/00365518609083665","article-title":"Effect of 3-hydroxybutyrate infusion on urinary protein excretion in healthy man","volume":"46","author":"Christensen","year":"1986","journal-title":"Scand J Clin Lab Invest."},{"key":"B24","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1111\/j.0954-6820.1976.tb08200.x","article-title":"Blood ketone body disappearance rate in diabetics and normals after rapid infusion of dl-3-hydroxybutyrate. Studies before and after diabetic treatment","volume":"200","author":"Wildenhoff","year":"1976","journal-title":"Acta Med Scand."},{"key":"B25","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/BF01219433","article-title":"Changes in the concentrations of glucose, free fatty acids, insulin and ketone bodies in the blood during sodium beta-hydroxybutyrate infusions in man","volume":"4","author":"Balasse","year":"1968","journal-title":"Diabetologia."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1172\/JCI108057","article-title":"Effect of ketone infusions on amino acid and nitrogen metabolism in man","volume":"55","author":"Sherwin","year":"1975","journal-title":"J Clin Invest."},{"key":"B27","doi-asserted-by":"publisher","first-page":"776","DOI":"10.2337\/diab.25.9.776","article-title":"Effect of diabetes mellitus and insulin on the turnover and metabolic response to ketones in man","volume":"25","author":"Sherwin","year":"1976","journal-title":"Diabetes."},{"key":"B28","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1210\/jcem-50-3-557","article-title":"Effect of ketone body infusion on plasma catecholamine and substrate concentrations during acute hypoglycemia in man","volume":"50","author":"Fr\u00f8lund","year":"1980","journal-title":"J Clin Endocrinol Metab."},{"key":"B29","doi-asserted-by":"publisher","first-page":"197","DOI":"10.2337\/diab.32.3.197","article-title":"Failure of infused \u03b2-hydroxybutyrate to decrease proteolysis in man","volume":"32","author":"Miles","year":"1983","journal-title":"Diabetes."},{"key":"B30","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1210\/jcem-57-3-613","article-title":"Influence of ketone body infusion on plasma growth hormone and glucagon in man","volume":"57","author":"Quabbe","year":"1983","journal-title":"J Clin Endocrinol Metab."},{"key":"B31","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/s0140-6736(83)91560-x","article-title":"Effect of intravenous 3-hydroxybutyrate on postoperative nitrogen balance","volume":"37","author":"Woods","year":"1983","journal-title":"Hum Nutr Clin Nutr."},{"key":"B32","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1055\/s-2007-1012266","article-title":"Failure of hyperketonemia to alter basal and insulin-mediated glucose metabolism in man","volume":"18","author":"Bratusch-Marrain","year":"1986","journal-title":"Horm Metab Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1016\/0026-0495(86)90241-6","article-title":"Effect of hyperketonemia on renal ammonia excretion in man","volume":"35","author":"Desir","year":"1986","journal-title":"Metab Clin Exp."},{"key":"B34","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1172\/JCI113570","article-title":"Effect of \u03b2-hydroxybutyrate on whole-body leucine kinetics and fractional mixed skeletal muscle protein synthesis in humans","volume":"82","author":"Nair","year":"1988","journal-title":"J Clin Inves."},{"key":"B35","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/0022-4804(89)90141-8","article-title":"Does hyperketonemia affect protein or glucose kinetics in postabsorptive or traumatized man?","volume":"47","author":"Crowe","year":"1989","journal-title":"J Surg Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1530\/acta.0.1230629","article-title":"Lack of effects of hyperglycemia on the disposal of 3-hydroxybutyrate in insulin-dependent diabetic patients","volume":"123","author":"M\u00f8ller","year":"1990","journal-title":"Acta Endocrinol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1042\/cs0810189","article-title":"Ketone infusion lowers hormonal responses to hypoglycaemia: evidence for acute cerebral utilization of a non-glucose fuel","volume":"81","author":"Amiel","year":"1991","journal-title":"Clin Sci."},{"key":"B38","first-page":"176","article-title":"Effect of 3-hydroxybutyrate on posttraumatic metabolism in man","volume":"109","author":"Hiraide","year":"1991","journal-title":"Surgery."},{"key":"B39","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1080\/00365519109104571","article-title":"The independent effect of ketone bodies on forearm glucose metabolism in normal man","volume":"51","author":"Walker","year":"1991","journal-title":"Scand J Clin Lab Invest."},{"key":"B40","doi-asserted-by":"publisher","first-page":"E268","DOI":"10.1152\/ajpendo.1992.262.3.E268","article-title":"Effects of D-beta-hydroxybutyrate and long- and medium-chain triglycerides on leucine metabolism in humans","volume":"262","author":"Beaufr\u00e8re","year":"1992","journal-title":"Am J Physiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1093\/ajcn\/58.5.608","article-title":"Effects of infused sodium acetate, sodium lactate, and sodium beta-hydroxybutyrate on energy expenditure and substrate oxidation rates in lean humans","volume":"58","author":"Chiol\u00e9ro","year":"1993","journal-title":"Am J Clin Nutr."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1097\/00003246-199407000-00007","article-title":"Metabolic effects of a D-beta-hydroxybutyrate infusion in septic patients: inhibition of lipolysis and glucose production but not leucine oxidation","volume":"22","author":"Beylot","year":"1994","journal-title":"Crit Care Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.2337\/diab.43.11.1311","article-title":"Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans","volume":"43","author":"Veneman","year":"1994","journal-title":"Diabetes."},{"key":"B44","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1093\/ajcn\/nqy170","article-title":"Effects of 3-hydroxybutyrate and free fatty acids on muscle protein kinetics and signaling during LPS-induced inflammation in humans: anticatabolic impact of ketone bodies","volume":"108","author":"Thomsen","year":"2018","journal-title":"Am J Clin Nutr."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e152","DOI":"10.2337\/dc18-1421","article-title":"Ketone body infusion increases circulating erythropoietin and bone marrow glucose uptake","volume":"41","author":"Lauritsen","year":"2018","journal-title":"Diabetes Care"},{"key":"B46","doi-asserted-by":"publisher","first-page":"75","DOI":"10.2337\/diab.38.1.75","article-title":"Kidney hemodynamics after ketone body and amino acid infusion in normal and IDDM subjects","volume":"38","author":"Nosadini","year":"1989","journal-title":"Diabetes."},{"key":"B47","doi-asserted-by":"publisher","first-page":"2606","DOI":"10.1172\/JCI107453","article-title":"Rapid intravenous sodium acetoacetate infusion in man metabolic and kinetic responses","volume":"52","author":"Owen","year":"1973","journal-title":"J Clin Invest"},{"key":"B48","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1210\/jcem-67-2-245","article-title":"Effect of exercise on the disposal of infused ketone bodies in humans","volume":"67","author":"Fery","year":"1988","journal-title":"J Clin Endocrinol Metab."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1111\/j.0013-9580.2004.10004.x","article-title":"Early- and late-onset complications of the ketogenic diet for intractable epilepsy","volume":"45","author":"Kang","year":"2004","journal-title":"Epilepsia."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e9639","DOI":"10.7759\/cureus.9639","article-title":"Advantages and disadvantages of the ketogenic diet: a review article","volume":"12","author":"Batch","year":"2020","journal-title":"Cureus."},{"key":"B51","doi-asserted-by":"publisher","first-page":"962","DOI":"10.3390\/nu11050962","article-title":"Low-carb and ketogenic diets in type 1 and type 2 diabetes","volume":"11","author":"Bolla","year":"2019","journal-title":"Nutrients."},{"key":"B52","doi-asserted-by":"publisher","first-page":"e10199","DOI":"10.7759\/cureus.10199","article-title":"Euglycemic Diabetic Ketoacidosis Precipitated by a Keto Diet: Importance of Dietary History in Diagnosis","volume":"12","author":"Shaikh","year":"2020","journal-title":"Cureus."},{"key":"B53","doi-asserted-by":"publisher","first-page":"6620832","DOI":"10.1155\/2021\/6620832","article-title":"Ketogenic diet-induced diabetic ketoacidosis in a young adult with unrecognized type 1 diabetes","volume":"2021","author":"Charoensri","year":"2021","journal-title":"Case Rep Endocrinol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1111\/j.1528-1167.2010.02543.x","article-title":"Type 1 diabetes and epilepsy: efficacy and safety of the ketogenic diet","volume":"51","author":"Dressler","year":"2010","journal-title":"Epilepsia."},{"key":"B55","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1111\/j.1527-3458.2005.tb00265.x","article-title":"KTX. 0101: a potential metabolic approach to cytoprotection in major surgery and neurological disorders","volume":"11","author":"Smith","year":"2005","journal-title":"CNS Drug Rev."},{"key":"B56","first-page":"149","article-title":"Veech rl ketoacids? Good medicine?","volume":"114","author":"Cahill","year":"2003","journal-title":"Trans Am Clin Climatol Assoc."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1111\/j.1528-1167.2008.01870.x","article-title":"A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy","volume":"50","author":"Neal","year":"2009","journal-title":"Epilepsia."},{"key":"B58","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.yrtph.2012.04.008","article-title":"Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects","volume":"63","author":"Clarke","year":"2012","journal-title":"Regul Toxicol Pharmacol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"E660","DOI":"10.1152\/ajpendo.1995.268.4.E660","article-title":"Metabolism of (R,S)-1,3-butanediol acetoacetate esters, potential parenteral and enteral nutrients in conscious pigs","volume":"268","author":"Desrochers","year":"1995","journal-title":"Am J Physiol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.740374\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T05:11:47Z","timestamp":1632201107000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.740374\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,21]]},"references-count":59,"alternative-id":["10.3389\/fmed.2021.740374"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.740374","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,21]]},"article-number":"740374"}}