Impaired glucose utilization in the brain of patients with delirium following hip fracture

Abstract

Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there are limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (standard deviation 10 years), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anaesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate and β-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, β-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. The level of 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium.

Keywords: 3-hydroxyisobutyrate; acetoacetate; branched-chain amino acids; lactate; β-hydroxybutyrate.

Figure 1

Box and whisker plots of CSF metabolites according to delirium status. The line in the middle of the boxes indicates the median, the upper and lower edges of the boxes indicate the 25th and 75th percentiles (lower and upper quartiles). The whiskers indicate the most extreme values within the 1.5 interquartile range of the upper or lower quartile; n = 406.

Figure 2

Metabolite concentrations and the odds of delirium. Logistic regression with delirium as the outcome adjusted for age, sex, cognitive impairment (IQCODE ≥3.44), American Society of Anesthesiologists (ASA) score (III-IV versus I-II), glomerular filtration rate (eGFR) and diabetes. The 95% confidence intervals that do not cross the vertical dashed line at 1.00 represent statistically significant findings. The analysis contains serum samples (except for glucose, which was measured in plasma) (n = 213) and CSF samples (n = 406).