Methylphenidate actively induces emergence from general anesthesia

Abstract

Background: Although accumulating evidence suggests that arousal pathways in the brain play important roles in emergence from general anesthesia, the roles of monoaminergic arousal circuits are unclear. In this study, the authors tested the hypothesis that methylphenidate (an inhibitor of dopamine and norepinephrine transporters) induces emergence from isoflurane general anesthesia.

Methods: Using adult rats, the authors tested the effect of intravenous methylphenidate on time to emergence from isoflurane general anesthesia. They then performed experiments to test separately for methylphenidate-induced changes in arousal and changes in minute ventilation. A dose-response study was performed to test for methylphenidate-induced restoration of righting during continuous isoflurane general anesthesia. Surface electroencephalogram recordings were performed to observe neurophysiological changes. Plethysmography recordings and arterial blood gas analysis were performed to assess methylphenidate-induced changes in respiratory function. Intravenous droperidol was administered to test for inhibition of methylphenidate's actions.

Results: Methylphenidate decreased median time to emergence from 280 to 91 s. The median difference in time to emergence without methylphenidate compared with administration of methylphenidate was 200 [155-331] s (median, [95% CI]). During continuous inhalation of isoflurane, methylphenidate induced return of righting in a dose-dependent manner, induced a shift in electroencephalogram power from delta (less than 4 Hz) to theta (4-8 Hz), and induced an increase in minute ventilation. Administration of intravenous droperidol (0.5 mg/kg) before intravenous methylphenidate (5 mg/kg) largely inhibited methylphenidate-induced emergence behavior, electroencephalogram changes, and changes in minute ventilation.

Conclusions: Methylphenidate actively induces emergence from isoflurane general anesthesia by increasing arousal and respiratory drive, possibly through activation of dopaminergic and adrenergic arousal circuits. The authors' findings suggest that methylphenidate may be useful clinically as an agent to reverse general anesthetic-induced unconsciousness and respiratory depression at the end of surgery.

Fig. 1

Methylphenidate decreases time to emergence from isoflurane anesthesia. (A) Rats inhaled isoflurane (1.5%) for a total of 45 min, and received normal saline or methylphenidate (5 mg/kg IV, solid arrow) 5 min before removal from the anesthetizing chamber (dashed arrow). Time to emergence was defined as the time from termination of isoflurane 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 versus methylphenidate (5 mg/kg IV). The line represents the median. *** P < 0.0001.

Fig. 2

Methylphenidate induces emergence during continuous inhalation of isoflurane. (A) Rats inhaled isoflurane at a dose sufficient to maintain loss of righting for a total of 40 min, and received normal saline. Five minutes later, methylphenidate was administered IV. Isoflurane was continued at the same dose until return of righting occurred or 30 min elapsed. (B) Dose-dependence of methylphenidate-induced emergence. (C) Scatter plot of time to righting for rats that received 0.5 versus 5 mg/kg IV of methylphenidate. The line represents the median. (D) After pretreatment with droperidol (0.5 mg/kg IV) instead of normal saline, high-dose methylphenidate (5 mg/kg IV) did not induce return of righting in any of the six animals tested. *** posterior probability > 0.95, * P < 0.05.

Fig. 3

Methylphenidate-induced electroencephalogram changes during continuous inhalation of isoflurane are inhibited by droperidol. (A) Thirty-second epochs of electroencephalogram recordings from a single rat show the change from an active, theta-dominant pattern during the awake state to the delta-dominant pattern during inhalation of isoflurane (1.0%). The latter pattern is unchanged after the administration of normal saline. Administration of methylphenidate (5 mg/kg IV) induced a prompt 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 15 min. (B) Thirty-second epochs of raw electroencephalogram recordings from a different animal than (A) show the same patterns during the awake and anesthetized states. Administration of droperidol (0.5 mg/kg IV) induced no appreciable change in the electroencephalogram pattern. However, when methylphenidate (5 mg/kg IV) was administered 5 min after droperidol, the electroencephalogram did not return to the active, theta-dominant pattern observed during the awake state. Rather, the delta-dominant pattern persisted.

Fig. 4

Spectral analysis of electroencephalogram data reveals a shift in power induced by methylphenidate that is inhibited by droperidol. 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 inhaling isoflurane (1.0%) shows predominance of delta power (<4 Hz) before and after administration of normal saline. However, administration of methylphenidate (5 mg/kg IV) promptly induced a shift in power to an active theta-dominant pattern similar to that observed during the awake state. This animal began to move vigorously approximately 5 min after methylphenidate administration, generating significant motion artifacts. Therefore the experiment was promptly terminated. (C) A representative spectrogram computed from a rat that received droperidol (0.5 mg/kg IV) instead of normal saline shows that similar to the rat in (B), delta power is dominant during inhalation of isoflurane (1.0%), before and after administration of droperidol. However, after administration of droperidol, methylphenidate (5 mg/kg IV) did not induce a shift in electroencephalogram to the theta-dominant pattern characteristic of the awake state. In addition, this animal showed no purposeful movement after methylphenidate administration.

Fig. 5

Electroencephalogram power spectra and spectrograms computed for each of four animals reveal a shift in peak power from delta to theta after administration of methylphenidate that is inhibited by droperidol. The top panel shows the two-minute windows used to compute power spectra before methylphenidate administration (red, “PRE”), and after methylphenidate administration (blue, “POST”). (A) Spectrograms and power spectra computed from animals that received normal saline prior to methylphenidate (MPH). Power spectra show results of the Kolmogorov-Smirnov test for the 2-min periods before and after 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 0-10 Hz. (The fourth animal moved during the time window used for the analysis, and therefore motion artifact may account for the persistent high delta power observed after methylphenidate administration in this animal.) (B) Spectrograms and power spectra computed from animals that received droperidol prior to methylphenidate (MPH). After droperidol, methylphenidate only induced statistically significant decreases in delta power.

Fig. 6

Methylphenidate induces an increase in respiratory rate that is inhibited by droperidol. (A) Time series of respiratory rate (filled circles) and tidal volume (open squares) recorded from one animal during inhalation of isoflurane (1.5%). Normal saline and methylphenidate (5 mg/kg IV) were administered at the indicated times. Methylphenidate induced a prompt and sustained increase in respiratory rate from 103 to 154 breaths/min (p < 10^-16), while tidal volume remained essentially unchanged. (B) When a different animal was pretreated with droperidol (0.5 mg/kg IV) instead of normal saline, methylphenidate induced little change in respiratory rate or tidal volume.