Table 3.
Ketone studies with metabolic outcomes.
| Year | Author (Ref) | Study | Population | No. participants | Formulation | Fasting | Intervention | Total average BHB dose | Insulin used | Findings overview | Concentration BHB | ADR |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1968 | Balasse and Ooms (25) | Placebo-controlled | Healthy | 8 BHB / 5 Controls | Racaemic Na-3-OHB | Unclear | 5 mmol/kg/h for 1.5 h | No | Ketonaemia up to 47.6 mg/100 mL resulted in a mild alkalosis (pH 7.39 to 7.48) with a 50% reduction in non-esterified fatty acids and a reduced blood glucose concentration from 84 mg/100 mL to 69 mg/100 mL, without a change in insulin concentration. | Mild headache, thirst | ||
| 1975 | Sherwin et al. (26) | Case-series | Obese + Healthy | 9 Healthy / 10 Obese | Racaemic Na-OHB 40% | 12 h, 3 day and 3–5 week fast | Loading dose twice continuous infusion dose over 20 min. Non-obese controls 3 mg/kg/min for 3 h, Obese dose 110 mg/m2/min for 6 h. | Healthy group: No change in insulin, pyruvate, lactate and glucagon. All patients exhibited a slight reduction in both glucose and alanine. | BHB 0.84 ± 0.09 mM after infusion. Basal obese BHB 0.12 ± 0.03 mM increasing to 0.94 ± 0.10 mM post-6 h infusion. Obese after 3-days starvation: baseline BHB 1.39 ± 0.22 mM doubled post infusion. Obese after 3-5 week fast baseline 5.72 ± 0.64 mM to peak 10.39 ± 0.91 mM. | Nil noted | ||
| 1976 | Wildenhoff (24) | Crossover | T1D + Healthy controls | 26 T1DM / 9 Controls | Racaemic Na-3-OHB 1 M | Fasting | 50 mmol over 4 min | Administered to T1DM, no doses specified. | Increased urinary excretion T1DM, normalized with insulin administration. Lower ketone elimination non-obese T2DM patients but not obese T2DM patients when compared with healthy controls. Treatment with glibenclamide or phenformin had a decreased the ketone elimination in the obese, but not non-obese T2DM patients compared with healthy controls. Decreased tissue ketone uptake in non-obese T2DM patients may mediate lower elimination. | Nil noted | ||
| 1976 | Sherwin et al. (27) | Crossover | T1DM + Healthy | 7 T1DM / 12 Healthy | Racaemic Na-BHB | Fasting | 6 mg/kg/min bolus over 20 min followed by 3 mg/kg/min over 3–4.5 h. | 1 participant 1mU/kg/min | Ketone clearance decreased by 42% in T1DM. Blood glucose concentration reduced by 25% in T1DM and marginally reduced in healthy controls. Alanine concentration reduced. | T1DM BHB 0.40 ± 0.08 mM to 1.67 ± 0.11 mM. T1DM AcAc 0.11 ± 0.02 mM to 0.41 ± 0.06 mM. Healthy BHB 0.12 ± 0.02 0.82 ± 0.06 mM. Healthy AcAc 0.04 ± 0.01 to 0.24 ± 0.01 mM. | Nil noted | |
| 1980 | Frølund et al. (28) | Crossover | Healthy | 6 | Racaemic Na-3-OHB | Fasting | 8 mg/kg loading dose followed by infusion 4 mg/kg/min for 90 min. 3 subjects also had 26 mg/kg loading dose followed by 13 mg/kg/min CI | Loading dose 24.20 g and maintenance dose 78.94 g | Insulin 0.15 units/kg to induce hypoglycaemia. | Ketone infusion did not change hypoglycaemic symptoms. Ketone administration did not change catecholamine or cortisol response to hypoglycaemia. | 0.1 mM to 0.45 mM at a 4 mg/kg/min BHB dose and 4.0 mM following a 13 mg/kg/min BHB dose. | Shivering and nausea in all patients receiving 13 mg/kg/min (high dose) Na-3-OHB following insulin injection. |
| 1983 | Miles et al. (29) | Crossover | Healthy | 6 | Racaemic Na-OHB 3 M, pH 7 | Fasting | 30 μmol/kg/min for 20 min followed by μmol/kg/min for 3 h. Doses based on D-enantiomer. | No | No decrease in proteolysis with reduced alanine and free fatty acids. | Total ketone body baseline 0.21 ± 0.04 mM to 2.33 ± 0.48 mM post infusion | Nil noted | |
| 1983 | Quabbe et al. (30) | Crossover | Healthy | 10 | Racaemic Na-3-OHB 7.5% | Fasting | 15 g/h for 3 h | Yes - induce hypoglycaemia | FFA suppressed during BHB infusion. Growth hormone increased. Glucagon increased by 10–20 pg/mL. Delayed rebound of FFA and GH following insulin-induced hypoglycaemia. | Nil noted | ||
| 1983 | Woods et al. (31) | Placebo controlled | Post-operative cholecystectomy | 17 BHB / 15 Controls | Racaemic Na-3-OHB | Fasting | 0.75 g/h for 3 days |
54 g | No | No difference post-operative mean daily urinary nitrogen losses. | Nil noted | |
| 1986 | Bratusch-Marrain et al. (32) | Crossover | Healthy | 9 | Racaemic-Na-OHB 4 M; pH 7.24 | Fasting | 30 μmol/kg/min for 20 min followed by 15 μmol/kg/min for 4 h | Yes - EG | Glucose appearance rate and metabolism were unchanged during and after BHB infusion. | 109 ± 31 μM to 496 ± 81 μM post-infusion | Nil noted | |
| 1986 | Christensen et al. (23) | Case-series | Healthy | 7 | Racaemic Na-BHB 50 g/L | Fasting | 0.5 g/kg over 1 h | 35.5 g | No | No change in urinary albumin excretion, GFR or blood pressure. Small increase beta-2-microglobuin excretion. | 0.05 ± 0.05 mM baseline to 1.96 ± 0.53 mM | Nil noted |
| 1986 | Desir et al. (33) | Crossover | Healthy | 7 | Racaemic-Na-BHB 40% | Fasting | 1 mmol/kg over 20 min followed by 0.01 mmolkg/min for 160 min. | No | Increased serum and urine pH, reduced potassium (4.18 ± 0.09 to 3.58 ± 0.06 mM), 35% increased urinary ammonia excretion. GFR unchanged. | 53 ± 9 μmol/L to ~200 μmol/L post-infusion | Nil noted | |
| 1987 | Fioretto et al. (22) | Crossover | T1DM + Healthy | 11 T1DM / 11 Controls | Racaemic 3-hydroxybutyric acid/Racaemic Na-3-OHB | Fasting | 40/30 μmol/kg/min for 2 h | 30 μmol/kg /min: 367.2 mmol (46.3 g) T1DM and 378 mmol (47.66 g) Healthy; 40 μmol/kg/ min: 489.6 mmol (61.73 g) T1DM and 504 mmol (63.55 g) Healthy |
Yes - EG | GFR increased T1DM. No change pH or bicarbonate. | Following infusion 40 μmol/kg/min healthy controls total ketone body concentration of 2.719 ± 0.163 mM and 3.089 ± 0.149 mM T1DM. Following infusion of 30 μmol/kg/min, total ketone body concentration of 0.95 ± 0.17 mM and 1.49 ± 0.27 mM in T1DM. | Nil noted |
| 1988 | Nair et al. (34) | Crossover | Healthy | 13 | Racaemic Na-BHB; pH 6.8–7.4 | Fasting | 12.5 μmol/kg/h | 452.63 mmol (57.07 g) | No | Decreased glucose and free fatty acids with unchanged c-peptide, glucagon, noradrenaline and adrenaline concentrations. Decreased leucine oxidation unrelated to a change in blood pH; thereby likely promoting protein synthesis. | <0.5 mM to ~2 mM post-infusion. | Nil noted |
| 1989 | Crowe et al. (35) | Case-series | Post-operative Total Hip Replacements | 6 | Racaemic-Na-BHB | Fasting | 6 mg/kg/min over 20 mins followed by 3 mg/kg/min for 2 h | No | Leucine concentrations and rate of appearance increased following BHB infusion. Insulin concentration not affected following BHB infusion. |
Pre-op 0.06 ± 0.01 to 0.69 ± 0.16 mM post-infusion. Post-op 0.04 ± 0.01 to 0.62 ± 0.12 mM post-infusion. | Nil noted | |
| 1990 | Moller et al. (36) | Cross-over | T1DM | 5 | Racaemic-Na-OHB; pH 6.5 | Fasting | 1.8 mmol/kg/h for 20 min and 0.9 mmol/kg/h for 100 min | Yes - EG | NEFA decreased in both hypo- and hyperglycaemia conditions. No change in NEFA clearance. | Pre-infusion: euglycaemia 127 (30-435) μmol/L and hyperglycaemia 137 (20-350) μmol/L. Post-infusion: euglycaemia 770 (520-955) μmol/L and hyperglycaemia 665 (450-910) μmol/L. | Nil noted | |
| 1991 | Amiel et al. (37) | Randomized placebo-controlled crossover | Healthy | 6 | Racaemic Na-OHB 6.24–7.38 g/100 mL | Fasting | 6 mg/kg/min for 20 min followed by 3 mg/kg/min. | 48.1 g | Yes - EG | Following hypoglycaemia, all hormone peak concentrations (noradrenaline, adrenaline, cortisol and growth hormone) were decreased in subjects receiving BHB compared with controls. |
61 ± 17 μmol/L to 580 ± 69 μmol/L post-infusion. | Nil noted |
| 1991 | Hiraide et al. (38) | Placebo-controlled | Blunt trauma | 11 BHB / 9 Controls | Racaemic Na-3-OHB 20% | Unclear | 25 μmol/kg/min for 3 h | 247.5 mmol (31.21 g) | No | Slight decrease in non-esterified fatty acids and alanine release. Mild alkalosis for both sodium lactate and BHB infusion. | Total ketone body 210.5 ± 176.0 μmol/L to 1519.2 ± 420.6 μmol/L. | Nil noted |
| 1991 | Walker et al. (39) | Randomized crossover | Healthy | 7 | Racaemic Na-3-OHB 3 M; pH 7.2 | Fasting | 15 μmol/kg/min over 4 h | Yes - EG | Slight decrease and increase in glucose and lactate respectively. BHB did not inhibit insulin stimulated glucose uptake. | Total ketone body levels from 70 ± 4 to 450 ± 30 μM post-infusion. | Nil noted | |
| 1992 | Beaufrere et al. (40) | Placebo controlled | Healthy | 6 BHB / 4 Controls | Dextro-BHB 0.33 g/L; pH 6.8 | Fasting | 540 μmol/kg/h for 5 h | No | 73% reduction FFA. Unchanged cortisol, insulin and C-peptide concentrations. No significant change leucine oxidation. | Total ketone body from 180 ± 60 to 1647 ± 275 μM | Nil noted | |
| 1993 | Chiolero et al. (41) | Crossover | Healthy | 6 | Racaemic-Na-OHB | Fasting | 20 μmol/kg/min for 3 h | No | FFA decreased. Increased bicarbonate concentration. Oxygen consumption increased 5.5%. Carbohydrate oxidation inhibited 25%. | 0.02 ± 0.01 mM to 0.94 ± 0.07 mM post-infusion. | Nil noted | |
| 1994 | Beylot et al. (42) | Controlled | Sepsis patients in ICU + Healthy | 12 Sepsis/6 Healthy | Dextro-OHB, pH 6.8 | Unclear | 15 μmol/kg/min over 4 h | No | No change in pH. Slight decrease in free fatty acids, glycerol and endogenous glucose production. Mild insulin increase and leucine oxidation. | Nil noted | ||
| 1994 | Veneman et al. (43) | Randomized, crossover | Healthy | 13 | Racaemic-Na-BHB | Fasting | 40 μmol/kg/min for 20 min followed by 20 μmol/kg/min | Yes - EG | BHB infusion decreased counterregulatory hormone response to hypoglycaemia with 57% reduction in epinephrine and 28% reduction in cortisol. Reduced neuroglycopenic symptoms with BHB infusion. | 10 ± 5 μmol/L to 1.9 mmol/L | Nil noted | |
| 1997 | Wildenhoff (24) | Case-series | T1DM + Healthy | 7 T1DM/8 Healthy | Racaemic-Na-BHB; 1 M | Fasting | 50 mmol followed by 0 to 2.5 mmol/min | No | Linear relationship showing increased total urinary ketone body excretion and reabsorption rate with increasing urinary filtration rate in both healthy controls and T1DM patients. | 0.015 to 2.91 mM post-infusion. | Nil noted | |
| 2015 | Mikkelsen et al. (21) | Case-series | Healthy | 6 | Dextro-OHB | Fasting | 4.7 μmol/kg/min for 1 h then 9.4 μmol/kg/min for 1 h then 18.8 μmol/kg/min thereafter for 50 min. | 159.89 mmol (20.16 g) | No | 14% reduction glucose appearance and 37% decrease lipolytic rate. Insulin and glucagon concentrations unchanged. Cerebral OHB uptake kinetics linear, whereas skeletal muscle kinetics saturable. | Peak 1.7 mM | Nil noted |
| 2018 | Thomsen et al. (44) | Double blinded placebo-controlled crossover | Healthy | 10 | Racaemic Na-3-OHB 7.5% | Fasting | 0.18 g/kg/h 3-OHB | 101.05 g | Yes - EG | Net decrease protein loss. No effect on cytokine production. | BHB basal 115 (95% CI 20-210) to 3449 (1249-5652) mM. BHB clamp 12 (95% CI 2-22) to 3280 (95% CI 1184-5375) mM. | Nil noted |
| 2020 | Lauritzen et al. (45) | Randomized placebo-controlled crossover | Healthy | 9 | Racaemic-Na-OHB | Fasting | 0.22 g/kg/h for 4 h | No | Insulin, glucagon and Fibroblast growth factor-21 concentrations unchanged. | 0.0 ± 0.0 mM to 5.5 ± 0.4 mM | Nil noted |
ADR, adverse drug reaction; BHB, beta-hydroxybutyrate; CI, continuous infusion; CO, cardiac output; EG, euglycaemic clamp; FFA, free fatty acids; NEFA, non-esterified fatty acids; GFR, glomerular filtration rate; GH, growth hormone; HFrEF, heart failure with reduced ejection fraction; HR, heart rate; NYHA New York Heart Association; SVR, systemic vascular resistance; T1DM, type 1 or insulin-dependent Diabetes mellitus; T2DM, type 2 or non-insulin-dependent Diabetes mellitus; VT, ventricular tachycardia.
Data presented as mean ± standard error.