A Systematic Review of Intravenous β-Hydroxybutyrate Use in Humans – A Promising Future Therapy?

Abstract

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 >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.

Ketone Body β-Hydroxybutyrate Prevents Myocardial Oxidative Stress in Septic Cardiomyopathy

“…Fortunately, the disruption of structure and the disorder of function in the septic hearts could be prevented by KE preconditioning. In the normal physiological conditions, the cardiac contractive function is highly energy consuming and depends much on mitochondrial OXPHOS for ATP generation [ 37 , 38 ]. Well-organized cristae and large mitochondrial matrices are indispensable for supercomplex formation and are closely associated with electron transfer efficiency [ 39 , 40 ].…”

Efficacy and safety of ketone ester infusion to prevent muscle weakness in a mouse model of sepsis-induced critical illness

“…Of note, in healthy conditions plasma glucose and free fatty acids typically decrease upon administration of exogenous ketones 34 , 35 , an effect that was not that clearly visible in this setting of critical illness. However, also during health, these effects are often short lasting, with both glucose and fatty acids recurring to normal levels within hours 36 , 37 and even unaffected levels with prolonged administration of exogenous ketone esters in rodents and humans 12 , 38 , 39 . Furthermore, critical illness by itself already strongly affects glucose and lipid homeostasis 40 , 41 , which might have interfered with the normal actions of 3HB.…”

“…Only d -3HB plasma was determined by enzymatic analysis, which limits the conclusions on pharmacokinetics of the ester enantiomers and their metabolites. A strength of our study is the used delivery route—where numerous studies with orally administered ketone esters in rodents and humans in different settings and disease models are available, information on the parenteral administration of ketones and ketone esters is scarce 37 . We here studied subcutaneous bolus injections and intravenous continuous infusion in the context of critical illness and found a clear safety benefit with the latter method.…”

Beta-Hydroxybutyrate: A Dual Function Molecular and Immunological Barrier Function Regulator

“…As a kind of indispensable spare metabolic fuel source, ketone bodies, including beta-hydroxybutyrate (BHB), acetone (Ac), and acetoacetate (AcAc), are accepted to play important roles in all realms of life and attract much attention by many researchers ( 1 – 5 ). Factors such as fasting, prolonged exercise, and feeding a ketogenic diet will increase the endogenous hepatic ketogenesis, which significantly raises the total concentration of ketone bodies in circulating blood and tissues.…”

“…For example, oral administration of exogenous BHB supplements, such as D-β-hydroxybutyrate monoester and ketone ester (KE), has become an efficient avenue to elevate circulating BHB concentration ( 12 ). Intravenous BHB is also a new approach to boosting the circulation of BHB because it obviates the time delay of circulating BHB elevation induced by oral BHB supplements administration ( 1 , 13 ).…”