Delirium is a prevalent neuropsychiatric syndrome characterized by an acute disturbance in attention, cognition, and consciousness. It is associated with increased mortality, prolonged hospitalization, and long-term cognitive impairment. Convergent mechanistic data implicate neuroinflammation, blood-brain barrier disruption, mitochondrial dysfunction, and failure of cerebral energy metabolism arising from microglial-neuronal substrate competition.

In response to systemic inflammation, microglia transition to a pro-inflammatory phenotype characterized by increased aerobic glycolysis to meet heightened energy and biosynthetic demands. This metabolic reprogramming depletes glucose availability for neurons, resulting in a neuronal energy deficit. The competition for nutrients exacerbates neuronal metabolic stress. We hypothesize that this neuronal energy deficit contributes to the cognitive and neurological symptoms characteristic of delirium.

Ketones, such as β-hydroxybutyrate, are the brain’s secondary source of energy when glucose is insufficient. After transport across the blood-brain barrier, β-hydroxybutyrate is metabolized to acetyl-CoA, thereby directly entering the tricarboxylic acid cycle, bypassing the glycolytic bottleneck, to produce adenosine triphosphate (ATP). In addition to serving as a substrate for ATP production, ketones support mitochondrial function, limit oxidative stress, and reduce neuroinflammation. Thus, ketones confer a two-fold therapeutic advantage in the setting of nutrient competition. Not only do they support neuronal oxidative phosphorylation, but they also promote anti-inflammatory microglial phenotypes, inhibit inflammasome activation, and support metabolic reprogramming. This dual effect further reduces microglial glucose demand, enhancing neuronal substrate availability.

Ketone monoester [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate], which transiently increases serum β-hydroxybutyrate concentrations, represents an investigational novel metabolic intervention for ICU delirium. This proposed study is a single-center, randomized, blinded, placebo-controlled Phase 1 clinical trial in 40 critically ill adults to evaluate the safety, feasibility, pharmacokinetics, and biologic effects of exogenous ketone supplementation in critically ill adults. Findings from KETONES-ICU will provide foundational data for future randomized clinical trials aimed at improving delirium, cognitive recovery, and survivorship after critical illness.

About me:

Ryan J. Smith, MD, JD, is a Clinical Fellow in the Division of Allergy, Pulmonary, and Critical Care Medicine at Vanderbilt University Medical Center. He graduated from Mayo Clinic School of Medicine and Loyola Law School, and completed his residency in internal medicine at Mayo Clinic before pursuing subspecialty training at Vanderbilt. Dr. Smith is interested in the intersection of critical illness, brain energy metabolism, neuroinflammation, and ICU delirium. His research focuses on how novel metabolic interventions, including exogenous ketones, may protect the vulnerable brain and support cognitive recovery after critical illness.