Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats.

BACKGROUND: Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic's long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats. METHODS: Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus. RESULTS: Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities. CONCLUSIONS: This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions.

Lipid metabolism disturbances and AMPK activation in prolonged propofol-sedated rabbits under mechanical ventilation.

AIM: To explore the mechanisms underlying the propofol infusion syndrome (PRIS), a potentially fatal complication during prolonged propofol infusion. METHODS: Male rabbits under mechanical ventilation through endotracheal intubation were divided into 3 groups (n=6 for each) that were sedated with 1% propofol (Group P), isoflurane (Group I) or isoflurane while receiving 10% intralipid (Group II), respectively. Blood biochemical parameters were collected at 0, 6, 12, 18, 24 and 30-36 h after the initiation of treatments. The hearts were removed out immediately after the experiments, and the level of tumor necrosis factor (TNF)-α in the hearts were studied using immunohistochemistry. AMP-activated protein kinase (AMPK) and phospho-AMPK in the hearts were assessed using Western blotting. RESULTS: The mortality rate was 50% in Group P, and 0% in Groups I and II. The serum lipids and liver function indices in Group P were significantly increased, but moderately increased in Group II. Significant decreases in these indices were found in Groups I. All the groups showed dramatically increased release of creatine kinase (CK). Intense positive staining of TNF-α was found in all the heart samples in Group P, but only weak and neglectful staining was found in the hearts from Group II and Group I, respectively. AMPK phosphorylation was significantly increased in the hearts of Group P. CONCLUSION: Continuous infusion of large dose of propofol in rabbits undergoing prolonged mechanical ventilation causes hyperlipidemia, liver dysfunction, increased CK levels, AMPK activation and myocardial injury. The imbalance between energy demand and utilization may contribute to PRIS.