The Association of Fructose Metabolism With Anesthesia/Surgery-Induced Lactate Production

BACKGROUND: In elderly individuals, excessive lactate levels in the brain may be associated with the development of cognitive impairment after surgery, including delayed neurocognitive recovery (dNCR). Since the origin of this increased lactate is unknown, here we assessed associations between metabolic pathways and postoperative dNCR. METHODS: This study included 43 patients (≥60 years old) who had surgery under general anesthesia. We also used a mouse model in which 20-month-old mice were exposed to sevoflurane to induce postoperative dNCR, while control mice were exposed to 40% oxygen. Mice in the control group and anesthesia/surgery group were injected with fructose or glucose intracerebroventricularly, or fructose metabolism inhibitor intraperitoneally. Barnes maze test and Y maze were used to measure cognitive function in mice. Metabolomics was used to measure metabolites in the serum of patients and the brains of mice after anesthesia/surgery. Isotope labeling and metabolic flux were used to analyze flow and distribution of specific metabolites in metabolic pathways. RESULTS: Among 43 patients, 17 developed dNCR. Metabolomics showed significantly decreased postoperative serum fructose 1-phosphate levels in dNCR compared to nondNCR patients (mean difference [×10 4 ] = –0.164 ± 0.070; P = .024). Similar results were found in the brains of mice (mean difference = –1.669 ± 0.555; * P = .014). Isotope labeling and metabolic flux experiments in mice showed fructose but not glucose entered glycolysis, increasing lactate levels in the brain after anesthesia/surgery ( P < .05). Administration of intraperitoneal fructose inhibitors to mice effectively inhibited increased lactate levels in the brain (mean difference =96.0 ± 4.36, P = .0237) and cognitive dysfunction after anesthesia/surgery (mean difference =69.0 ± 3.94, P = .0237). In a small subsample, we also found anesthesia/surgery increased interleukin-6 (IL-6) levels in the brains of mice (mean difference =88.3 ± 3.44, P = .0237) and that IL-6 may function upstream in fructose activation. CONCLUSIONS: These results suggest that anesthesia/surgery activates fructose metabolism, producing excessive lactate in the brain that is associated with postoperative cognitive impairment. Fructose metabolism is thus a potential therapeutic target for dNCR.