Exogenous Ketone Supplementation in ICU Delirium

Delirium is a prevalent neuropsychiatric syndrome characterized by an acute disturbance in attention, cognition, and consciousness. It is associated with significant morbidity, mortality, and healthcare expenditures. Recent research has provided evidence supporting the connection between brain metabolism and delirium. During states of increased systemic inflammation, such as sepsis or trauma, the brain experiences a mismatch between energy supply and demand, which is commonly associated with delirium, especially in those with preexisting cognitive impairment. In critically ill patients, mitochondrial dysfunction occurs in the setting of systemic inflammation, contributing to increased blood-brain barrier permeability and neuroinflammation. The downstream consequence of this is microglial activation, which amplifies the inflammatory response through the release of pro-inflammatory cytokines. The resultant mitochondrial dysfunction leads to impaired oxidative phosphorylation, decreased adenosine triphosphate (ATP) production, and increased reactive oxygen species production. In response to systemic inflammation, microglia transition to a pro-inflammatory phenotype characterized by increased aerobic glycolysis. This metabolic reprogramming depletes glucose availability for neurons and exacerbates the cerebral energy deficit. Emerging evidence suggests that activated microglia compete with neurons for metabolic substrates during inflammation. Activated microglia exhibit metabolic flexibility, shifting toward increased glycolysis to meet their heightened energy and biosynthetic demands. This competition for nutrients exacerbates the neuronal energy deficit and increases metabolic stress. The investigators hypothesize that this brain 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 not available. After transport across the blood-brain barrier, β-hydroxybutyrate is metabolized to acetyl-CoA (acetyl coenzyme A), thereby directly entering the tricarboxylic acid cycle, bypassing the glycolytic bottleneck, to produce ATP. In addition to serving as a substrate for ATP production, ketones support mitochondrial function, limit oxidative stress, and reduce neuroinflammation. Ketones confer a two-fold therapeutic advantage in the setting of nutrient competition. Not only do they support neuronal oxidative phosphorylation by bypassing impaired glycolysis, 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. The investigators propose a prospective, randomized, placebo-controlled pilot study of exogenous ketone ester supplement administration in 40 critically ill patients to assess the safety and feasibility of this novel intervention and to generate preliminary data on its efficacy in reducing ICU delirium, as measured by delirium and coma free days (DCFDs). Exogenous ketones have been shown to support brain energetics and reduce neuroinflammation, directly targeting pathways implicated in the development of delirium. By reducing the duration of delirium or preventing its onset, this research has the potential to improve long-term cognitive outcomes for ICU survivors. The investigators propose enrolling adult patients at the time of ICU admission, with randomization to either an enteral ketone ester treatment group or a taste, volume, and calorie-matched dextrose-containing placebo. The study drug or placebo will be administered at the time of enrollment, within 24 hours of ICU admission, and every six hours thereafter for up to 7 days until ICU discharge, or death, whichever occurs first. Ketone administration will be continued after the diagnosis of delirium. In accordance with prior studies, the initial dose of β-hydroxybutyrate will be 25 g; however, subsequent doses will be titrated to maintain serum β-hydroxybutyrate levels between 1.5 and 3.5 mM, with protocolized monitoring of vital signs, serum pH, glucose levels, and adverse gastrointestinal effects. Delirium will be assessed using the Confusion Assessment Method for the ICU (CAM-ICU) delirium screening tool twice daily for a period of 7 days. This pilot study will assess the feasibility, safety, and tolerability of oral exogenous ketone supplementation in critically ill patients. The goal is to demonstrate that ketone administration is well-tolerated, with no significant safety concerns, consistent with prior evidence that oral ketones can be administered safely, even in vulnerable patient populations. Successful completion of this aim will establish a safety profile for ketone use in the ICU, which is essential before adopting this novel therapy for critically ill patients. The investigators hypothesize that patients receiving ketones will have more DCFDs compared to those receiving a placebo. The investigators will also perform an exploratory analysis of the biological impact of ketone therapy by examining biomarkers associated with delirium and ketone metabolism through serial measurement of serum levels of peripheral inflammatory mediators, metabolic stress assays, β-hydroxybutyrate levels, and markers of central nervous system (CNS) injury. Ketones offer a promising novel therapeutic option for delirium. By targeting the underlying neurometabolic and neuroinflammatory changes associated with delirium, they support energy production, decrease oxidative stress, and modulate inflammation. Patients with preexisting cognitive impairment, such as those with mild cognitive impairment or Alzheimer's dementia, exhibit a baseline brain energy gap due to impaired cerebral glucose metabolism. This chronic energy deficit increases the vulnerability of the aging brain to delirium. Furthermore, the neurometabolic consequences of delirium in those with preexisting cognitive impairment exacerbate the brain energy gap, accelerating cognitive decline. The safety, tolerability, and rapid induction of ketosis following oral administration of ketone esters, in addition to the aforementioned beneficial effects, suggest this may be a therapy that could be initiated upon ICU admission as a potential preventative measure in those patients at risk. Ketones have the potential to transform delirium management and improve patient care; however, this clinical trial is required to evaluate the safety and efficacy of oral ketone ester supplementation in reducing the incidence, severity, and duration of delirium in critically ill patients.