Background: Besides effect of general anesthesia, sevoflurane also induces hyperactivity during induction and recovery, especially in young children. Lack of satisfied animal model impedes the investigation of causes of the hyperactivity as well as its prevention. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker might produce sedative effect. This study developed a novel mice model of hyperactive behaviors and further explored effects of HCN channel blocker on sevoflurane-induced hyperactivity.
Methods: C57BL/6 mice were used in the present study. Maximal speed, mean speed, total movement distance and resting percentage of mice were quantitatively measured by behavioral tracking software. Age-dependence of this model was also analyzed. HCN channel blocker ZD7288 at doses of 6.25 and 12.5 μg/kg were intraperitoneal injected to prevent sevoflurane-induced hyperactivity.
Results: In the behavioral model, sevoflurane could induce significant hyperactivity in mice under 1% sevoflurane inhalation and in recovery period, characterized as increased movement speed and total distance. The sevoflurane-induced hyperactivity was more significant in young mice than adult (P<0.01). Pre-administration of ZD7288 could significantly prevent sevoflurane-induced hyperactivity.
Conclusions: The mice behavioral model developed in this study could characterize sevoflurane-induced hyperactivity in induction and recovery period as well as age-dependence. In addition, by this animal model, HCN channel blocker ZD7288 could prevent sevoflurane-induced hyperactivity. Thus, HCN channel might be the underlying therapeutic target for sevoflurane-induced agitation in general anesthesia.
Citation: Peng Liang, Xu-Bin Huang, Feng-Shan Li, Han Huang, Jing-Xuan Qiu, Da-Qing Liao, et al. Hyperpolarization-activated cyclic nucleotide-gated channel blocker ZD7288 prevents sevoflurane-induced hyperactivity in a novel mice behavioral model. J Anesth Perioper Med 2017; 4: 205-12. doi: 10.24015/JAPM.2017.0011
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Inhaled anesthetics have been widely used in clinic for more than 170 years; however, the mechanisms are not fully understood yet. Sevoflurane is one of the most commonly used inhaled anesthetic in clinic, particularly in pediatric anesthesia for its low respiratory irritation and short-lasting action. Unfortunately, like other general anesthetics, sevoflurane, could also cause some side effects. Exciting behavior is a common side effect during sevoflurane induction and recovery, including epileptiform electroencephalographic activity and seizure like movements (1-8). Some patients are also observed convulsions without epileptogenic EEG during sevoflurane induction (9). Convulsions percentage has been reported with an incidence of 5% during sevoflurane anesthesia (10). These hyper-excitatory side effects are of tremendous concern because potentially delayed neurologic and cognitive defects might be induced in neonates and infants (11).
Previous studies have reported the increased rates of emergence agitation after sevoflurane anesthesia in pediatric patients (12). Emergence agitation is defined as a dissociative state with altered cognitive perception, excitation, restless, agitation, hyperactivities and increased muscular tension during the early post-anesthetic period, which may be associated with physical injury as well as negative post-operative behaviors in children (12). The incidence of emergence agitation induced by sevoflurane greatly varies among studies and the highest incidence is up to 80% (12). Such events pose a risk for injury as well as decreased parental satisfaction, especially in the ambulatory and office-based setting.
There are many clinical studies about sevoflurane-induced emergence agitation, but the causes of sevoflurane-induced agitation are still unclear, especially the molecular causes. No satisfied animal model is one of the main reasons to impede the linkage between clinical observations and molecular mechanisms. Therefore, the therapy for agitation prevention and novel anti-agitation drug development are quite limited because of the poor understands. At this moment, the common therapy for emergence agitation is sedative drugs, such as midazolam, propofol and opioids in clinical setting (13-16). However, combined with other general anesthetics in PACU could significantly increase general anesthetic risk and result in respiratory depression and prolonged recovery.
By previous studies, Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel might be the target of general anesthetics. Intravenous general anesthetics including ketamine, inhaled anesthetics like isoflurane and sevoflurane have been found to interact with HCN channels (17, 18). Therefore, we hypothesized that HCN channel blocker could produce light sedative effect, which might attenuate sevoflurane-induced emergence agitation.
In this study, we developed a mice behavioral model to test its relevance to sevoflurane-induced exciting behaviors and further investigate prevention of HCN channel blocker ZD7288 on sevoflurane-induced exciting behaviors.