Table 2.

A summary of the current state of knowledge of ketone therapy in TBI treatment, including known effects, limitations, and unknowns.

Known effects	Summary
Metabolically efficient	Ketone body metabolism mechanisms are energetically favorable under the pathological conditions of a TBI and help reduce cerebral energy deficits.
Reduce oxidative stress	Ketone bodies reduce oxidative stress by inhibiting the production of reactive oxygen species, preventing lipid peroxidation and protein oxidation, and increasing levels of antioxidant proteins.
Regulate inflammation	Ketone bodies help regulate inflammatory processes that contribute to neurodegeneration and cerebral edema through the mTOR signaling pathway and NLRP3 inflammasome.
Improve blood flow	Ketone bodies improve cerebral blood flow through reduced mTOR expression and increased nitric oxide synthase expression.
Limit cell death	Ketone bodies can limit necrotic and apoptotic cell death by closing the MPTP protein complex and restoring mitochondrial function.
Limitations and unknowns	Summary
Age	Pediatric animal models show a faster and more sustained increase in plasma ketone levels compared to adults. Ketone bodies may not be able to address ongoing secondary injury processes in adults as effectively.
Sex	Aspects of mitochondrial function in human and animal studies are sex-dependent under normal physiological conditions. It is unknown how sex-dependent differences in TBI-induced mitochondrial dysfunction affect pathological responses.
	Baseline ketone body levels are higher and rise significantly more following the administration of exogenous ketones in female TBI animal models. Further research is needed to understand why ketone metabolism differs between sexes and how those differences impact TBI pathophysiology.
Timing and duration of ketone supplementation	Improvements in metabolic function following exogenous ketone administration may be dependent upon whether the patient is in a hypermetabolic or hypometabolic state.
	The effects of long-term ketosis in TBI recovery are unknown.
Experimental models	Animal models of TBI feature a homogenous type of injury with variables such as age, sex, genetic background, and injury parameters being well controlled. This may not accurately replicate the heterogenic nature of human TBI.
Ketone levels	The optimal level of cerebral ketones and the most effective method of ketone supplementation to achieve such levels are unknown.
Metabolic monitoring	Minimally invasive and accurate ways to monitor ketone metabolism in both intensive care and outpatient settings are needed.