By Alexander E. Merkler, MD, MS
Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College
Post-operative delirium is a major health problem that occurs in about half of older patients who undergo surgery with general anesthesia. This prospective study from Norway of patients undergoing emergency hip repair surgery demonstrated from spinal fluid analysis that patients with delirium have abnormalities in brain glucose uptake and metabolism and have an early shift to ketosis in the spinal fluid.
Titlestad I, Wayne LO, Caplan GA, et al. Impaired glucose utilization in the brain of patients with delirium following hip fracture. Brain 2024;147:215-223.
Post-operative delirium is extremely common and affects up to almost half of the more than 16 million older Americans undergoing surgery each year. Post-operative delirium is associated with heightened length of stay and increased mortality. Improving our understanding of the pathophysiology underlying delirium may help us to discover novel pathways that lead to targeted therapies.
In this cohort study, the authors evaluated whether metabolites related to energy metabolism in the serum and cerebrospinal fluid (CSF) of patients with hip fracture were associated with delirium. The authors enrolled 406 patients (mean age 81 years) who were admitted for surgical repair of a hip fracture. Among these patients, 185 (46%) had dementia. CSF was collected at the onset of spinal anesthesia and serum samples were drawn concomitantly in 213 patients. CSF was evaluated for glucose, lactate, branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate, and B-hydroxybutyrate. Delirium was clinically assessed daily both pre-operatively and until the fifth post-operative day. Analyses were adjusted for age, sex, glomerular filtration rate, body mass index, dementia, diabetes, and American Society of Anesthesiologists physical status classification. In total, 224 (55%) patients developed delirium (pre- or post-operatively). Ketone body concentration (acetoacetate and B-hydroxybutyrate) and branched-chain amino acids (leucine and valine) were significantly elevated in the CSF but not in the serum among patients with delirium. The level of 3-hydroxyisobutyric acid was elevated in both the CSF and serum. There were no differences in glucose concentrations in patients with and without delirium.
Overall, the study found that patients with delirium had elevated CSF levels of ketones, branched-chain amino acids, and 3-hydroxyisobutyric acid despite normal CSF and serum glucose concentrations. The results of this study may suggest impaired glucose utilization may occur in the brain during delirium, where there may be a shift to ketone body metabolism. The authors acknowledged limitations, including the lack of information regarding eating habits (including fasting) and lack of formal evaluations for dementia. In addition, the lack of a multitude of unmeasured confounders, which may lead to delirium, were not addressed. Also, only patients hospitalized for hip fracture were included in this study. More importantly, it remains uncertain whether the proposed alteration in cerebral utilization is the cause or the result of delirium. Is the impaired glucose metabolism causing delirium, or, rather, merely a marker of its occurrence? Further investigation is needed to understand the significance of these results.
COMMENTARY
This study represents an important step in our understanding of the pathophysiology of delirium. Post-operative delirium is a major health concern, and future research is necessary to evaluate the causes and potential targets related to cerebral glucose utilization with the hope that we can prevent delirium. Are there strategies that might improve glucose utilization in these patients in whom there is a high prevalence (46%) of dementia?
