Bala Venkatesh

Professor of Intensive Care

Wesley & Princess Alexandra Hospitals

The George Institute for Global Health

University of Queensland & NSW

Ketones as a neuro-protective agent

Scope of this talk

• Brief review of physiology

• History of ketone use

• Ketones and the brain

• Neuroprotection – Animal data

• Neuroprotection – Human data

• Data on supplementation

• Commercial formulations

• Challenges for the intensivist

Traditional thinking

• One of harm

• Ketones are strong anions

• Clinicians- associate ketones with ketoacidosis

• Diabetic / Alcoholic /Starvation

• SGLT2 inhibitors- Euglycemic ketoacidosis

Current thinking

• Energy fuel for extrahepatic tissues like brain, heart, or skeletal muscle,

• Mammalian cell metabolism, homeostasis, and signaling

• Drivers of protein post-translational modification (PTM)

• Modulators of inflammation and oxidative stress

Where, how and how much ketones are produced?

Ketones – Basic physiology

• By-products of fat metabolism

• Three KB – Acetoacetate, beta-hydroxybutyrate and acetone

• Precursor- Acetyl CoA.

Extent of reaction depends on the pool of NAD BHB/AcAc ratio an index of the redox state of

the cell

Fate of circulating ketones

• Plasma concentrations

Fasting state 6 mM/L

Postprandial 0.1 mM/L

DKA 25 mM/L

Circulating ketones

• Energy source for brain, skeletal muscle, myocardium and the kidney

• 20% excreted unchanged

• A number of physiological effects

What happens when ketones reach the brain ?

Ketones and the brain

• Glucose – major fuel, <3% of total cerebral metabolism from ketones

• During starvation – ketones can provide 60-70% of energy needs

• Bulk of ketones in brain from plasma

• ? Local production by astrocytes.

Relationship between plasma ketones and brain energy metabolism

J. Lipid Res . 2014. 55: 1818–1826.

How does the brain utilize ketones?

Neuroprotective effects of ketones

• Mitochondrial biogenesis

• BHB more energy efficient than glucose – decrease glucose uptake, improve cellular ATP

• Decrease oxidant damage in the brain –reduce ROS, increase glutathione

• Anti-inflammatory

• Protect against glutamate mediated apoptosis and necrosis

• Improved CBF

History of ketone supplementation in clinical practice

Pierre Marie – Epilepsy resulted from intestinal intoxication and cured by fasting

Trials of ketone supplementation in

other chronic neurological states

Trials of ketone supplementation in acute brain injury

If ketones are beneficial, challenges of inducing ketosis in critically ill patients?

• Developing a method of inducing ketosis

• Determining plasma concentrations of ketones in patients with ABI

• Feasibility, safety and tolerability of enteral ketone supplementation and their effect on plasma ketone profiles

Methods of inducing ketosis in critically ill patients

• Prolonged fasting

• Caloric restriction – high fat, low carbohydrate diet

• Oral administration of BHB

• Parenteral administration of BHB

Adverse effects of ketones

• Enteral preparations –dehydration, hypoglycemia, decreased bone density, hepatic failure, dilated cardiomyopathy, nephrolithiasis

• Parenteral formulations

pH

Serum Na with 20% formulations

An IV formulation of ketones

One of the biggest obstacles to developing a parenteral formulation

was cost - $1000 /day

What are the plasma concentrations of ketones in patients with acute

brain injury?

Modulating plasma ketone profiles in acute brain injury:

feasibility and safety

Trial of ketocal supplementation in ABI

Manuscript under review

Other findings

• Well tolerated.

• No adverse effects on pH, bicarbonate and AG

• No adverse effects on ICP / CPP.

• No SAE

Current international trials

Lancet Neurol 2018; 17: 84–93

Conclusions

• Physiological basis for beneficial effects of ketones • Encouraging animal and phase I human data • in chronic neurological states • Animal data to suggest that ketones may be beneficial in

ABI – minimal human data • Data in humans suggest that plasma ketones are not raised

in ABI • Minimal elevations in plasma ketones after oral

supplementation • Optimal plasma /CSF concentration – unknown • No dose-response data available • IV formulations possible –but expensive