Editors' ChoiceAnesthesiology

Awakenings

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Science Translational Medicine  23 May 2012:
Vol. 4, Issue 135, pp. 135ec90
DOI: 10.1126/scitranslmed.3004312

The untimely death of pop icon Michael Jackson highlighted the potentially lethal effects of the intravenous anesthetic propofol. Although this case was surely unique, the use of propofol during medical procedures carries the potential risk of excessive sedation. Such consequences may be difficult to manage if the provider is not an anesthesiologist. But what if the physician’s toolbox contained a second drug that overcame the effects of propofol on the brain? Now, Chemali et al. demonstrate that methylphenidate—an amphetamine commonly used to treat attention deficit disorder—can reverse the anesthetic effects of propofol in rodents.

Chemali and colleagues studied both bolus doses and continuous infusions of propofol in rats using the loss of righting reflex—which keeps animals on their paws rather than their backs—as a surrogate for unconsciousness. After general anesthesia was induced, methylphenidate or saline (control) was administered, and the return of righting reflex was measured. Relative to the control animals, methylphenidate-treated rodents displayed a faster recovery time from bolus doses of propofol (commonly given in the operating room), as well as nearly immediate signs of arousal during continuous infusions of propofol (commonly given during sedation in the intensive care unit or medical procedure rooms). Electroencephalography revealed a dramatic shift from slow wave to higher-frequency activity upon administration of methylphenidate.

These results are consistent with an earlier study by the same research team showing reversal of the inhaled anesthetic isoflurane by methylphenidate, a phenomenon potentially mediated by increases in the neurotransmitter dopamine. The consistent reversal of two molecularly distinct anesthetics by methylphenidate suggests that the mechanism of action may not be pharmacological antagonism of anesthetic actions, but rather a “cognitive ignition” for dopaminergic arousal systems in the brainstem. Traditionally, anesthesiologists have rapidly induced the state of general anesthesia, but have only passively waited for anesthetic recovery. The findings by Chemali et al. may herald the beginning of active recovery procedures that rapidly reverse general anesthesia or excessive sedation. Although there are no comparable human studies to date, methylphenidate is approved for use in patients, reducing the regulatory hurdles to a new role in the reversal of anesthesia-induced unconsciousness.

J. J. Chemali et al., Active emergence from propofol general anesthesia is induced by methylphenidate. Anesthesiology 116, 998–1005, (2012). [Abstract]

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