Bala Venkatesh Professor of Intensive Care Wesley & Princess...
Transcript of Bala Venkatesh Professor of Intensive Care Wesley & Princess...
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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
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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
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Traditional thinking
• One of harm
• Ketones are strong anions
• Clinicians- associate ketones with ketoacidosis
• Diabetic / Alcoholic /Starvation
• SGLT2 inhibitors- Euglycemic ketoacidosis
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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
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Where, how and how much ketones are produced?
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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
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Fate of circulating ketones
• Plasma concentrations
Fasting state 6 mM/L
Postprandial 0.1 mM/L
DKA 25 mM/L
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Circulating ketones
• Energy source for brain, skeletal muscle, myocardium and the kidney
• 20% excreted unchanged
• A number of physiological effects
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What happens when ketones reach the brain ?
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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.
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Relationship between plasma ketones and brain energy metabolism
J. Lipid Res . 2014. 55: 1818–1826.
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How does the brain utilize ketones?
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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
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History of ketone supplementation in clinical practice
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Pierre Marie – Epilepsy resulted from intestinal intoxication and cured by fasting
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Trials of ketone supplementation in
other chronic neurological states
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Trials of ketone supplementation in acute brain injury
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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
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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
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Adverse effects of ketones
• Enteral preparations –dehydration, hypoglycemia, decreased bone density, hepatic failure, dilated cardiomyopathy, nephrolithiasis
• Parenteral formulations
pH
Serum Na with 20% formulations
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An IV formulation of ketones
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One of the biggest obstacles to developing a parenteral formulation
was cost - $1000 /day
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What are the plasma concentrations of ketones in patients with acute
brain injury?
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Modulating plasma ketone profiles in acute brain injury:
feasibility and safety
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Trial of ketocal supplementation in ABI
Manuscript under review
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Other findings
• Well tolerated.
• No adverse effects on pH, bicarbonate and AG
• No adverse effects on ICP / CPP.
• No SAE
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Current international trials
Lancet Neurol 2018; 17: 84–93
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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