Active emergence from propofol general anesthesia is induced by methylphenidate

Abstract

Background: A recent study showed that methylphenidate induces emergence from isoflurane general anesthesia. Isoflurane and propofol are general anesthetics that may have distinct molecular mechanisms of action. The objective of this study was to test the hypothesis that methylphenidate actively induces emergence from propofol general anesthesia.

Methods: Using adult rats, the effect of methylphenidate on time to emergence after a single bolus of propofol was determined. The ability of methylphenidate to restore righting during a continuous target-controlled infusion (TCI) of propofol was also tested. In a separate group of rats, a TCI of propofol was established and spectral analysis was performed on electroencephalogram recordings taken before and after methylphenidate administration.

Results: Methylphenidate decreased median time to emergence after a single dose of propofol from 735 s (95% CI: 598-897 s, n = 6) to 448 s (95% CI: 371-495 s, n = 6). The difference was statistically significant (P = 0.0051). During continuous propofol anesthesia with a median final target plasma concentration of 4.0 μg/ml (95% CI: 3.2-4.6, n = 6), none of the rats exhibited purposeful movements after injection of normal saline. After methylphenidate, however, all six rats promptly exhibited arousal and had restoration of righting with a median time of 82 s (95% CI: 30-166 s). Spectral analysis of electroencephalogram data demonstrated a shift in peak power from δ (less than 4 Hz) to θ (4-8 Hz) and β (12-30 Hz) after administration of methylphenidate, indicating arousal in 4/4 rats.

Conclusions: Methylphenidate decreases time to emergence after a single dose of propofol, and induces emergence during continuous propofol anesthesia in rats. Further study is warranted to test the hypothesis that methylphenidate induces emergence from propofol general anesthesia in humans.

Fig. 1

Methylphenidate decreases time to emergence from propofol anesthesia. (A) Rats received a bolus of propofol (8 mg/kg IV), and 45 seconds later, received methylphenidate (5 mg/kg IV) or normal saline (vehicle). Time to emergence was defined as the time from administration of propofol to return of righting (i.e. all four paws touching the floor). (B) Scatter plot of time to emergence for rats that received normal saline vs. methylphenidate (5 mg/kg IV). The lines represent the medians. ** P<0.01.

Fig. 2

Methylphenidate induces emergence during a continuous target controlled infusion of propofol. (A) The final target plasma concentration of propofol was established at 0.5 μg/ml above the highest dose at which purposeful movements were observed, and maintained for 15 minutes before normal saline (vehicle) was injected. Five minutes later, methylphenidate (5 mg/kg IV) was administered. The propofol infusion was continued at the same dose. (B) None of the rats exhibited an arousal response during the 5 minutes after normal saline administration (n=6). However, methylphenidate induced a profound arousal response and restored the righting reflex within 4 minutes in all rats (n=6), despite continuous propofol general anesthesia. ***posterior probability > 0.95.

Fig. 3

Methylphenidate induces electroencephalogram changes during a continuous target controlled infusion of propofol. Thirty-second epochs of electroencephalogram recordings from a single rat show the change from an active, theta-dominant pattern during the awake state to a delta-dominant pattern during the continuous target controlled infusion of propofol. The latter pattern was unchanged after the administration of normal saline, but after administration of methylphenidate (MPH, 5 mg/kg IV) there was a shift in the electroencephalogram back to an active theta-dominant pattern similar to that observed during the awake state. This pattern persisted for more than 10 minutes.

Fig. 4

Spectral analysis of electroencephalogram data reveals a shift in power induced by methylphenidate during a continuous target controlled infusion of propofol. Warm colors (e.g. red) represent higher power at a given frequency, while cool colors (e.g. blue) represent lower power. (A) A representative spectrogram computed from a rat in the awake state shows predominance of theta power (4–8 Hz). (B) A representative spectrogram computed from a rat during propofol general anesthesia shows predominance of delta power (<4 Hz) before and after administration of normal saline. However, administration of methylphenidate (MPH, 5 mg/kg IV) promptly reduced delta power, and increased theta (4–8 Hz) and beta power (12–30 Hz), providing evidence for a new arousal state distinct from the baseline awake state.

Fig. 5

Electroencephalogram power spectra and spectrograms computed for each of 4 animals reveal a consistent shift in peak power from delta to theta and beta after administration of methylphenidate during continuous propofol general anesthesia. (A) A schematic showing the two-minute windows used to compute power spectra before methylphenidate administration (blue, “PRE”), and after methylphenidate administration (red, “POST”). (B) Spectrograms computed from 4 different animals that received methylphenidate at the time point indicated by the vertical dashed line. (C) Power spectra computed from the same animals with results of the Kolmogorov-Smirnov test for the two-minute periods before (blue) and after (red) methylphenidate administration. At a 0.05 significance level (with Bonferonni correction) the Kolmogorov-Smirnov test rejects the null hypothesis at all frequencies except those marked with white squares. Statistically significant changes occurred at most frequencies between 0–30 Hz. (D) Power spectra computed from the same animals with results of the Kolmogorov-Smirnov test, comparing a two-minute period from the baseline awake state in the absence of any drugs (green) to the two-minute period after methylphenidate administration during continuous propofol general anesthesia (red). Statistically significant changes occurred at most frequencies between 0–30 Hz.