Caffeine Accelerates Emergence From Isoflurane Anesthesia in Humans

A Randomized, Double-blind, Crossover Study

Robert Fong, M.D., Ph.D.; Lingzhi Wang, M.D.; James P. Zacny, Ph.D.; Suhail Khokhar, M.P.H.; Jeffrey L. Apfelbaum, M.D.; Aaron P. Fox, Ph.D.; Zheng Xie, M.D., Ph.D.


Anesthesiology. 2018;129(5):912-920. 

In This Article

Abstract and Introduction


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.


ALTHOUGH pharmacologic reversal agents exist for many categories of drugs routinely used by anesthetists including opioids, benzodiazepines, and paralytics, there are currently no drugs available to reverse the coma-like state induced by general anesthetics.[1] Identification of such drugs would be of considerable utility in clinical practice. Patients recover from anesthesia with varying time courses, dependent upon a number of factors that are beyond the clinician's control, including but not limited to genetics, comorbidities, and age.[2] After emergence, cognitive and psychomotor compromise can persist for minutes to hours as evidenced by delayed reaction time, memory impairment, and problems with motor coordination. Prolonged recovery delays return to baseline, safe functioning, and independence and engenders significant costs in the form of extended stays in postanesthesia recovery units. Seniors represent a particularly vulnerable population in this regard because recovery time after anesthesia can be markedly prolonged from hours to days in some cases.[3]

There have been ongoing efforts to reverse the effects of anesthesia in animals, most of which involved intracerebral injection of various agents including a cyclic adenosine monophosphate (cAMP) analog,[4] an antibody directed against potassium channels,[5] a cholinesterase inhibitor and muscarinic agonist,[6] and nicotine.[7] Although compelling, these studies are of limited clinical utility because they involve injecting drugs directly into the brain. More recently, aminophylline has shown promise in accelerating emergence from anesthesia.[8–10] Finally, Solt et al.[2,11] have shown that methylphenidate accelerated emergence from anesthesia in rats, implicating D1 dopamine receptor activation as the mechanistic basis of their observed effect.[12,13] Of note, activation of D1 receptors is known to produce downstream elevation of [cAMP]i.[14,15]

Previously, we demonstrated that a series of drugs that elevate [cAMP]i could dramatically accelerate emergence from anesthesia when administered intravenously in rats.[16] Of the three drugs tested, caffeine was most effective. Here we hypothesize that caffeine is able to accelerate emergence from anesthesia in humans and may represent a useful adjunct to modern anesthesiology.