Caffeine Accelerates Emergence from Isoflurane Anesthesia in Humans

Abstract

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background There are currently no drugs clinically available to reverse general anesthesia. We previously reported that caffeine is able to accelerate emergence from anesthesia in rodents. This study was carried out to test the hypothesis that caffeine accelerates emergence from anesthesia in humans. Methods We conducted a single-center, randomized, double-blind crossover study with eight healthy males. Each subject was anesthetized twice with 1.2% isoflurane for 1 h. During the final 10 min of each session, participants received an IV infusion of either caffeine citrate (15 mg/kg, equivalent to 7.5 mg/kg of caffeine base) or saline placebo. The primary outcome was the average difference in time to emergence after isoflurane discontinuation between caffeine and saline sessions. Secondary outcomes included the end-tidal isoflurane concentration at emergence, vital signs, and Bispectral Index values measured throughout anesthesia and emergence. Additional endpoints related to data gathered from postanesthesia psychomotor testing. Results All randomized participants were included in the analysis. The mean time to emergence with saline was 16.5 ± 3.9 (SD) min compared to 9.6 ± 5.1 (SD) min with caffeine (P = 0.002), a difference of 6.9 min (99% CI, 1.8 to 12), a 42% reduction. Participants emerged at a higher expired isoflurane concentration, manifested more rapid return to baseline Bispectral Index values, and were able to participate in psychomotor testing sooner when receiving caffeine. There were no statistically significant differences in vital signs with caffeine administration and caffeine-related adverse events. Conclusions Intravenous caffeine is able to accelerate emergence from isoflurane anesthesia in healthy males without any apparent adverse effects.

Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

“…Based on these results, we can hypothesize that adenosinergic system may modulate the influence of exogenous ketone supplement-generated ketosis on the onset of isoflurane-induced immobility by inhibition of sleep active neurons (possibly through A1Rs), which processes lead to delay in the anesthetic effects of isoflurane. Moreover, modulatory effects of adenosine receptor antagonists and an A1R agonist on isoflurane-induced anesthetic effects and on emergence from anesthesia [29,47,48] were also demonstrated. Thus, it is possible that exogenous ketone supplement-induced ketosis not only delay the onset of isoflurane induced anesthesia (immobility), but also modulate the time required for recovery from anesthesia.…”

“…Adenosine agonists induced sleep/electroencephalographic slow-wave activity, but adenosine receptor antagonists (e.g., a non-selective antagonist of adenosine receptors caffeine) reversed effects of adenosine on the sleep [46]. Moreover, adenosine accumulates under, for example, sleep deprivation and may have a role in the anesthetic action of isoflurane [27,39]: theophylline (a non-selective antagonist of adenosine receptors) reversed the cerebral effects of isoflurane in dogs (e.g., EEG has been changed from a sleep pattern to an awake pattern) [29] and caffeine accelerated emergence from isoflurane-evoked anesthesia in humans [47]. Moreover, enhanced activity of A1Rs (e.g., by an A1R agonist N-sulfophenyl adenosine) may cause increase in anesthesia recovery time [48] and isoflurane may activate A1Rs [49].…”

Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

“…There was a positive correlation between latency to immobility and blood βHB levels when all data point (b; R 2 = 0.2933) or the group means (c; R 2 = 0.5553) were considered. Abbreviations: KE, ketone ester; KEKS, mix of KE and KS in a 1:1 ratio; KEMCT, mix of KE and medium chain triglyceride (MCT) oil in a 1:1 ratio; KS, ketone salt; KSMCT, mix of KS and MCT oil in a 1:1 ratio; SD, standard diet/control; *p < 0.05; ***p < 0.001; ****p < 0.0001 effects of isoflurane in dogs (e.g., EEG has been changed from a sleep pattern to an awake pattern) [30] and caffeine accelerated emergence from isoflurane-evoked anesthesia in humans [52]. Moreover, enhanced activity of A1Rs (e.g., by an A1R agonist N-sulfophenyl adenosine) may cause increase in anesthesia recovery time [53] and isoflurane may activate A1Rs [54].…”

“…3). Moreover, adenosine receptors may also modulate anesthesia recovery time [52,53]. Thus, it is possible that exogenous ketone supplements not only delay the onset of isoflurane-induced anesthesia (immobility) [23] (Fig.…”

Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

“…Adenosine agonists induced sleep/electroencephalographic slow-wave activity, but adenosine receptor antagonists (e.g., a non-selective antagonist of adenosine receptors caffeine) reversed effects of adenosine on the sleep [51]. Moreover, adenosine accumulates under, for example, sleep deprivation and may have a role in the anesthetic action of isoflurane [28,44]: theophylline (a non-selective antagonist of adenosine receptors) reversed the cerebral effects of isoflurane in dogs (e.g., EEG has been changed from a sleep pattern to an awake pattern) [30] and caffeine accelerated emergence from isoflurane-evoked anesthesia in humans [52]. Moreover, enhanced activity of A1Rs (e.g., by an A1R agonist N-sulfophenyl adenosine) may cause increase in anesthesia recovery time [53] and isoflurane may activate A1Rs [54].…”