Literature Spotlight: Exogenous Ketone Bodies & HIE

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LITERATURE SPOTLIGHT:  Exogenous Ketone Bodies as Promising Neuroprotective Agents for Developmental Brain Injury. 

When neuroprotection first became part of the NICU dialogue it was typically used to describe those interventions aimed at preventing brain injury and neuronal death.  Over the past decade, the term neuroprotection has evolved to describe all therapies and interventions that not just project the newborn brain from injury, but also to support the brain after an injury has occurred.  There are many investigtional and promising therapies as well as some interventions that have become the standard of care. 

For more than a decade now, Therapeutic Hypothermia has been considered the standard of care for term infants with HIE.  Meanwhile, there are dozens of investigational drug trials searching for stand-alone and adjunctive therapies for infants of all ages.  Epogen is in a Phase 3 Clinical Trial to supplment hypothermia, Melatonin is being considered to enhance neuronal repair after severe IVH, and stem cells are being concered for several different brain injuries across the spectrum of NICU population.   In addition to these, there are simple interventions such as midline head positioning, optimizing non-invasive respiratory care, eliminating infection and optimizing nutritional profiles to maximize growth and development of the brain.  One thing can be said for sure, the field of neuroprotection is broad and ever-evolving. 

The field of neuroprotection is broad and ever-evolving

An exciting new area of research is the focus of our Literature Spotlight this month.  Researchers have begun investigating the use of exogenous ketone bodies as neuroprotective agents for the injured newborn brain. 

Ketone bodies, particularly the use of strict ketogenic diets and administration of exogenous ketones have long been studied in the setting of adult brain injury as well as for intractable epilepsy in pediatric patients.   In addition to the medical use of the strict ketogenic diet for management of brain injury, the “keto diet” or “low-carb” diet trend has become extremely popular in the mainstream media for weight loss, but significant literature also exist for the use of a “ketogenic state” as an alternative or complimentary treatment for certain types of cancer,  to improve mental and athletic performance, and even more recently has been investigated by the NFL as a potential post-concussive therapy.   

So then, what is so special about the ketogenic diet and what does it have to do with babies?

But, did you know that neonates were made for ketosis? The normally developed neonate is in significant ketosis during the first week of life, with at least 10% of cerebral metabolic energy requirements being met through ketosis. Click To Tweet

In the body, we have two types of fuel sources – fats and carbohydrates.   Although carbohydrates provide quick energy, they do so with a high cost in terms of oxidative stress.  Fat on the other hand can be stored easily by the body, and therefore is more abundant, and is a cleaner and more efficient fuel source for the Kreb’s cycle (i.e. for making ATP to fuel the body and brain). 

Due to the abundance of carbohydrates in the American adult diet, the adult brain typically only relies on ketones (or fat stores) in times of physiologic stress such as fasting, or during significant and prolonged carbohydrate deficit.  On the other hand, the healthy neonatal brain relies on ketones as both an energy source and a preferred precursor for the creation of fatty acids and cholesterol, which are both essential components of the brain’s grey matter.  This reliance and preference begins in utero and ketones can even be found in the urine of newborns if tested.   

As I mentioned above, research has shown several benefits of exogenous ketone administration in adult brian injury including Alzheimer’s disease, stroke, Parkinson’s disease, and traumatic brain injury (TBI).  Additionally, ketone bodies have been shown to decrease oxidative stress, a critical contributor to cellular injury after HIE.

Ketones are made up of several specialized constituents, Beta Hydroxybutyrate (BHB) and acetoacetate (AcAc), which both have direct antioxidant effects and can act as scavengers, neutralizing hydroxyl free radicals released after injury to neuronal cells.  If you want to read more about these molecules, click here.

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Preclinical trials in animal models of neonatal HIE have shown that ensuring adequate levels of BHB and AcAc through administration of exogenous ketones may have promising benefits in the days and weeks following brain injury allowing for not just neuroprotection but even structural repair! 

Access the full article and read more about this exciting new field of research here:

Want to learn more about Neuroprotection as a pillar of Neuro Nurturing NICU care?  You can access Kathi’s FREE NeuroNICU QuickStart guide here:

REFERENCE:  Wood, T.R., Stubbs, B.J., and Juul, S.E. (2020). Exogenous Ketone Bodies as Promising Neuroprotective Agents for Developmental Brain Injury, Dev Neurosci, 40, pp. 451-462,

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