Neurotoxicity of sub-anesthetic doses of sevoflurane and dexmedetomidine co-administration in neonatal rats.

BACKGROUND

Preclinical studies suggest that exposures of infant animals to general anesthetics cause acute neurotoxicity and affect their neurobehavioral development representing a potential risk to human infants undergoing anesthesia. Alternative or mitigating strategies to counteract such adverse effects are desirable. Dexmedetomidine (DEX) is a clinically established sedative with potential neuroprotective properties. DEX ameliorates experimental brain injury as well as neurotoxicity caused by anesthetic doses of sevoflurane (SEVO) or other general anesthetics in infant animals. However, it is unknown whether DEX also is beneficial when given together with lower doses of these drugs. Here we tested the hypothesis that DEX co-administration with a sub-anesthetic dose of SEVO reduces responsiveness to external stimuli while also protecting against SEVO-induced brain cell apoptosis.

METHOD: Rats were exposed on postnatal day 7 for 6 h to SEVO 1.1, 1.8, or 2.5% and were given intraperitoneal injections of saline or DEX at different doses (1-25 μg/kg) three times during the exposure. Responsiveness to external stimuli, respiratory rates, and blood gases were assessed. Apoptosis was determined in cortical and subcortical brain areas by activated caspase-3 immunohistochemistry.

RESULTS

Rats exposed to SEVO 1.1% alone were sedated but still responsive to external stimuli whereas those exposed to SEVO 1.8% reached complete unresponsiveness. SEVO-induced brain cell apoptosis increased dose-dependently, with SEVO 1.1% causing a small increase in apoptosis above that in controls. Co-administration of DEX at 1 μg/kg did not alter the responsiveness to stimuli nor the apoptosis induced by SEVO 1.1%. In contrast, co-administration of DEX at 5 μg/kg or higher with SEVO 1.1% reduced responsiveness but potentiated apoptosis.

CONCLUSIONS

In the neonatal rat model, co-administration of a clinically relevant dose of DEX (1 μg/kg) with a sub-anesthetic dose of SEVO (1.1%) does not affect the neurotoxicity of the anesthetic while co-administration of higher doses of DEX with SEVO 1.1% potentiates it.