Potential therapeutic benefit of exogenous ketone ester administration in delirium: a narrative review

Abstract

Delirium is a prevalent neuropsychiatric syndrome during critical illness and is associated with prolonged hospitalization, increased mortality, and post-ICU cognitive decline. It is hypothesized to result from systemic inflammation, disrupted neurotransmission, and failure of cerebral energy metabolism. This narrative review highlights the key role of altered neurometabolism and neuroinflammation, which occurs due to peripheral inflammation, compromised blood-brain barrier integrity, and increased microglial glycolysis. These changes limit neuronal glucose uptake, leading to a brain energy crisis and consequently amplifying oxidative and inflammatory stress. We focus on studies of ICU delirium in the setting of acute critical illness with an emphasis on sepsis-associated encephalopathy, where mechanistic data derived from murine models are most robust. Ketones bypass the glycolytic bottleneck and enter the tricarboxylic acid cycle directly, activating signaling pathways that enhance mitochondrial biogenesis, bolster antioxidant defenses, modulate neurotransmission, and reduce inflammation. In models of neurodegenerative diseases and traumatic brain injury, ketosis restores cerebral metabolism, reduces neuroinflammation, and enhances cognitive function. Additionally, preliminary human studies have demonstrated cognitive benefits and patient tolerance of ketone supplementation. Although data in the critically ill are limited, pilot studies suggest that enteral ketone supplementation can safely achieve therapeutic serum concentrations without worsening acidosis or hemodynamic instability. We hypothesize that exogenous ketone ester supplementation may support brain energy production by providing an alternative substrate for energy production, reducing microglial substrate competition, and mitigating the neuronal stress that precipitates delirium. In conclusion, exogenous ketone esters are a biologically plausible, rapidly acting metabolic intervention that warrants rigorous clinical evaluation as a novel strategy to prevent or treat delirium in those who are critically ill. However, randomized controlled trials are essential for verifying safety, determining optimal dosing, and assessing clinical effectiveness in the intensive care setting.

Keywords: Beta-hydroxybutyrate; Critical illness; Delirium; Exogenous ketone ester; Intensive care unit; Neuroinflammation; Neurometabolism.

Fig. 1

Conceptual Depiction of the Pathophysiology of Delirium. Delirium is hypothesized to result from altered glucose metabolism, which occurs as a downstream consequence of peripheral inflammation, leading to a degradation of blood-brain barrier integrity. This results in the activation of resident microglial cells that further amplify the inflammatory response and support their metabolism through exuberant glycolysis, resulting in decreased glucose availability for neurons. Consequently, this creates a cerebral energy deficit, which contributes to delirium. Created with Biorender

Fig. 2

Distribution of GLUTs and MCTs by Cell Type. GLUT and MCT are responsible for transporting glucose and ketones from the blood into the brain, respectively. GLUT1 is found on the blood-brain barrier endothelium, microglial cells, and astrocytes. GLUT2 and GLUT7 are found on astrocytes. GLUT3 and GLUT4 are found on neurons. MCTs are found on all cell types. GLUT: glucose transporter; MCT: monocarboxylate acid transporter. Created with Biorender

Fig. 3

Ketones are the Preferred Neuronal Energy Substrate when Glucose is Not Available. When glucose levels are insufficient for CNS metabolism, such as during sepsis, serum ketone concentrations rise and serve as an alternative energy substrate for ATP production in neurons. Ketones enter neurons through MCTs and directly enter the tricarboxylic acid cycle without the energy input that glycolysis requires. Beta-hydroxybutyrate dehydrogenase (BHD) catalyzes the conversion of β-hydroxybutyrate to acetoacetate while reducing NAD + to NADH. Succinyl-CoA:3-oxoacid CoA transferase (SCOT) forms acetoacetyl-CoA, which thiolase cleaves to produce two molecules of acetyl-CoA that then enter the tricarboxylic acid cycle for eventual ATP production. ATP: adenosine triphosphate; GLUT: glucose transporter; MCT: monocarboxylate acid transporter; NAD+: reduced nicotinamide adenine dinucleotide; NADH: oxidized nicotinamide adenine dinucleotide; PDC: pyruvate dehydrogenase complex. Created with Biorender

Fig. 4

Brain Energy Gap in Delirium. Patients with preexisting cognitive impairment, such as mild cognitive impairment or Alzheimer’s dementia, have a baseline brain energy gap due to decreased cerebral glucose metabolism. This 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, contributing to the worsening of preexisting cognitive impairment. Created with Biorender

Fig. 5

Overview of the Mechanism by Which Exogenous Ketones Restore Brain Energy Balance in Delirium. Under normal conditions, glucose efficiently crosses the intact blood-brain barrier through glucose transporters, allowing for sufficient neuronal ATP production via mitochondrial oxidative phosphorylation. During systemic inflammation, blood-brain barrier integrity is compromised, allowing inflammatory cytokines to activate microglia. Once activated, microglia undergo metabolic reprogramming characterized by increased glycolysis, which decreases neuronal glucose availability. Concurrent mitochondrial dysfunction impairs oxidative phosphorylation, resulting in decreased ATP production and increased oxidative stress. We hypothesize that the result of this brain energy deficit is delirium. Exogenous ketones cross the blood-brain barrier and enter neurons via monocarboxylate transporters. Ketones bypass glycolysis and contribute to energy production via oxidative phosphorylation, thereby replenishing neuronal ATP stores, reducing oxidative stress, and alleviating the brain energy deficit. ATP: adenosine triphosphate; GLUT: glucose transporter; MCT: monocarboxylate acid transporter. Created with Biorender