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Physostigmine and Methylphenidate Induce Distinct Arousal States During Isoflurane General Anesthesia in Rats

Kenny, Jonathan D.; Chemali, Jessica J. BS; Cotten, Joseph F. MD, PhD; Van Dort, Christa J. PhD; Kim, Seong-Eun PhD; Ba, Demba PhD; Taylor, Norman E. MD, PhD; Brown, Emery N. MD, PhD; Solt, Ken MD

doi: 10.1213/ANE.0000000000001234
Neuroscience and Neuroanesthesiology: Original Laboratory Research Report

BACKGROUND: Although emergence from general anesthesia is clinically treated as a passive process driven by the pharmacokinetics of drug clearance, agents that hasten recovery from general anesthesia may be useful for treating delayed emergence, emergence delirium, and postoperative cognitive dysfunction. Activation of central monoaminergic neurotransmission with methylphenidate has been shown to induce reanimation (active emergence) from general anesthesia. Cholinergic neurons in the brainstem and basal forebrain are also known to promote arousal. The objective of this study was to test the hypothesis that physostigmine, a centrally acting cholinesterase inhibitor, induces reanimation from isoflurane anesthesia in adult rats.

METHODS: The dose-dependent effects of physostigmine on time to emergence from a standardized isoflurane general anesthetic were tested. It was then determined whether physostigmine restores righting during continuous isoflurane anesthesia. In a separate group of rats with implanted extradural electrodes, physostigmine was administered during continuous inhalation of 1.0% isoflurane, and the electroencephalogram changes were recorded. Finally, 2.0% isoflurane was used to induce burst suppression, and the effects of physostigmine and methylphenidate on burst suppression probability (BSP) were tested.

RESULTS: Physostigmine delayed time to emergence from isoflurane anesthesia at doses ≥0.2 mg/kg (n = 9). During continuous isoflurane anesthesia (0.9% ± 0.1%), physostigmine did not restore righting (n = 9). Blocking the peripheral side effects of physostigmine with the coadministration of glycopyrrolate (a muscarinic antagonist that does not cross the blood–brain barrier) produced similar results (n = 9 each). However, during inhalation of 1.0% isoflurane, physostigmine shifted peak electroencephalogram power from δ (<4 Hz) to θ (4–8 Hz) in 6 of 6 rats. During continuous 2.0% isoflurane anesthesia, physostigmine induced large, statistically significant decreases in BSP in 6 of 6 rats, whereas methylphenidate did not.

CONCLUSIONS: Unlike methylphenidate, physostigmine does not accelerate time to emergence from isoflurane anesthesia and does not restore righting during continuous isoflurane anesthesia. However, physostigmine consistently decreases BSP during deep isoflurane anesthesia, whereas methylphenidate does not. These findings suggest that activation of cholinergic neurotransmission during isoflurane anesthesia produces arousal states that are distinct from those induced by monoaminergic activation.

Published ahead of print March 17, 2016.

From the *Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts.

Published ahead of print March 17, 2016.

Demba Ba, PhD, is currently affiliated with the Department of Electrical Engineering, Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts.

Accepted for publication January 13, 2016.

Funding: This work was supported by National Institutes of Health grant numbers TR01-GM104948, DP1-OD003646, and K08-GM094394.

Conflict of Interest: See Disclosures at the end of the article.

This report was previously presented, in part, at the Association of University Anesthesiologists in Philadelphia, PA, on May 12, 2011.

JD Kenny and JJ Chemali were co-first authors.

Reprints will not be available from the authors.

Address correspondence to Ken Solt, MD, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit St, GRB-444, Boston, MA 02114. Address e-mail to

© 2016 International Anesthesia Research Society