Purpose   The purpose of this study was to test the hypothesis that caffeine administration accelerates emergence from isoflurane anesthesia in healthy humans.


Methodology   This was a prospective, double-blind study. Eligible study subjects were healthy males, age 25 to 40 years. Preanesthetic screening, urine toxicology analysis, and electrocardiogram were performed. Those with obstructive sleep apnea, alcohol or drug abuse history, seizures, or head trauma were excluded. The eligible eight participants were subject to two general anesthetic sessions separated by a minimum of 2 weeks time. Subjects were randomized to the order they would receive normal saline or caffeine infusions.


Following a propofol induction, an LMA was inserted. Subjects breathed spontaneously while isoflurane was delivered at an end-tidal concentration of 1.2% for 60 minutes. Ten minutes prior to the discontinuation of isoflurane, the subjects received either an IV infusion of normal saline or 7.5 mg/Kg caffeine.


Test subjects emerged from anesthesia in a tranquil environment without physical stimuli. All subject had a vigorous gag response as the end tidal isoflurane levels diminished. Upon spontaneous eye opening, verbal commands were given to open their mouth for LMA withdrawal. Time to return of gag reflex, eye opening, and response to verbal commands were recorded. Minute ventilation was measured during emergence. Awakening was defined as the presence of a gag reflex . After awakening subjects indicated how “well” they felt on a visual analog scale and completed two psychomotor tests. These assessments were repeated every 15 minutes for 2 hours following isoflurane cessation.[Editor’s Note: for details about the tests used see notes following the comment.]


Result   There was a significant difference between the saline group and caffeine group in time to emergence, time to eye opening, end tidal isoflurane concentration on awakening, and psychomotor testing. There was a modest improvement in the divided attention task in subjects who received caffeine. There were no differences in HR or mean arterial pressure (MAP). Participants performed similarly in the “feels well” and memory test.


Time to awakening following saline was 16.5 minutes vs. 9.6 minutes following caffeine (P=0.002). This was a 42% reduction in time to awakening. Time to eye opening in the saline group was 17.6 minutes; whereas time to eye opening after caffeine was 11.1 minutes; a mean difference of 6.5 minutes. When test subjects received caffeine, they awakened from anesthesia at 0.33% end-tidal isoflurane compared to 0.21% when they received saline.


Figure 1: Mean Time to Awakening & Eye Opening

Notes: Awakening defined as first gag.


Table 1: End-tidal Isoflurane on Emergence






Conclusion   Subjects given IV caffeine before isoflurane was turned off awoke 6.9 minutes sooner and at a higher end-tidal isoflurane concentration. Additionally, psychomotor function recovered more quickly following IV caffeine infusion.




Initially, I was not impressed with this study and felt it offered little clinical insight. I felt that as anesthesia professionals we have nearly mastered the timing of anesthetic emergence. However, my view began to change as my week of clinical anesthesia progressed and I encountered some patients who awoke more slowly than I would have liked. I experienced a few delayed awakenings when relieving colleagues who used a technique different from my own. I also had a couple patients who were sensitive to anesthetic agents and were "slow to emerge." In these instances, caffeine administration would have been clinically beneficial.


An eight ounce brewed coffee contains 100 mg of caffeine while a 1.5 ounce espresso shot averages 60 mg. At 7.5mg/Kg, a 70 Kg patient would have received 525 mg caffeine. Four hundred mg of caffeine is the safe daily maximum for healthy adults.


We lack a novel reversal agent for general anesthesia and the post anesthesia stupor that periodically follows. This study revealed that after receiving IV caffeine, patients emerged nearly 7 minutes faster and were more coherent. The 42% reduction in time to emergence despite a higher end tidal isoflurane concentration could have tangible clinical impact. I was pleasantly surprised by the lack of tachycardia or hypertension following caffeine administration.


Lastly, an expeditious return of psychomotor and cognitive function should translate into a shorter length of stay in the PACU. Additionally, an expedited recovery should increase patient satisfaction. We encounter patients who are truly more sensitive to anesthetic agents causing them to experience prolonged emergence and recovery times. Caffeine administration could be the solution in such scenarios.