Hyperammonemia heightens anesthetic sensitivity in male rats with acute hepatic encephalopathy via affecting brain areas represented by the cerebellum.

BACKGROUND

Precise anesthesia is essential to ensure perioperative safety in patients with hepatic encephalopathy (HE) due to severe liver injuries. Hyperammonemia has been implicated as a possible trigger for HE. However, anesthetic sensitivity in HE and the role of hyperammonemia, in the context of anesthetic sensitivity of HE both remain uncertain.

METHODS

We injected male Sprague Dawley rats with thioacetamide (TAA) to induce acute HE. The time to lose and recover the righting reflex induced by either the inhalation anesthetic isoflurane or the intraperitoneal anesthetic propofol, as well as the 50% effective dosage (ED) of propofol, were recorded to assess anesthetic sensitivity. Furthermore, we investigated the effect of blood ammonia on anesthetic sensitivity of ammonium acetate-induced hyperammonemia. Functional magnetic resonance imaging (fMRI) was used in tandem with the aforementioned models to identify brain areas that participate in the observed changes in behavior. Statistical significance was determined using student's t-test, Mann-Whitney test, one-way ANOVA and Kruskal-Wallis analysis, where appropriate.

RESULTS

Rats with TAA-induced acute HE took significantly reduced latency to lose the righting reflex and significantly prolonged recovery time under both isoflurane and propofol anesthesia. Additionally, the rats with TAA-induced acute HE displayed a reduction in the ED for propofol compared to the vehicle group (2.016 [1.787, 2,277] vs. 46.121 [38.853, 51.163] mg/kg). In the two hyperammonemia groups, only the higher concentration group displayed a reduction in isoflurane induction time (53.63 ± 5.418 vs. 105.8 ± 10.49 s, n = 8, p < 0.001) and prolonged awakening time (308.4 ± 31.76 vs. 166.9 ± 15.65 s, n = 8, p < 0.01), and the ED for propofol was reduced (38.848 [33.781, 45.983] vs. 45.643 [41.08, 50.694] mg/kg). The fMRI of HE exhibited neural activity fluctuations in multiple brain areas, while the increased neuronal excitability of the cortex of cerebellum was the main alteration in rats with hyperammonemia.

CONCLUSION

Our results indicate that hyperammonemia increases sensitivity to anesthetic drugs in HE. Neuroimaging evidence suggests the brain areas represents by the cerebellum may constitute to hyperammonemia-associated anesthetic hypersensitivity.