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Physician anesthesiologist at Stanford at Associated Anesthesiologists Medical Group

Richard Novak, MD is a Stanford physician board certified in anesthesiology and internal medicine.Dr. Novak is an Adjunct Clinical Professor in the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University, the Medical Director at Waverley Surgery Center in Palo Alto, California, and a member of the Associated Anesthesiologists Medical Group in Palo Alto, California.
emailrjnov@yahoo.com

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Data exists that intravenous caffeine may be effective in assisting the awakening of patients following general anesthesia. Will future anesthesiologists routinely use caffeine to wake patients after surgery? Will a shot of IV espresso be the stimulus for you to return to consciousness after your general anesthetic? Perhaps.

Caffeine is the most popular and commonly used psychoactive drug in the world.In 2014 85% of American adults consumed some form of caffeine daily, 164 mg/person/day on the average.¹A cup of coffee contains from 80 to 120 mg of caffeine.A 12-ounce cola contains from 30 to 50 mg. Currently intravenous caffeine is marketed as a three milliliter ampule that contains only 20 mg/ml of caffeine, or 60 mg total. Multiple commercial energy drinks include significantly higher doses of caffeine per the chart below.

The safety of caffeine has been well established, and the energy drink market is expected to reach 83.4 billion dollars by 2024.

The market share for leading energy drink brands is shown below.

Intravenous caffeine post-surgery is not a new idea. When I first went into the private practice of anesthesia in 1986, gray-haired anesthesiologists at our community hospital in Fremont, California occasionally injected 100 mg of caffeine into a patient’s IV after a surgery if the patient was slow to wake. “It helps a lot!” my fellow anesthesiologists reported. I tried it on several of my patients who had prolonged awakening after general anesthesia. It seemed to speed the time to eye opening, but I had no metrics or data to evaluate whether this was a bona fide finding. Now we have more information.

The Department of Anesthesia and Critical Care at my alma mater the University of Chicago School of Medicine published two landmark papers on IV caffeine and anesthesia awakening. The first studies were conducted on rats.²Researchers placed rats in a gas-tight anesthesia box where the animals were exposed to 3% isoflurane until they became unconscious. The rats were then removed from the box, 2% isoflurane was delivered to them via an anesthesia nose cone, an intravenous line was inserted into their tails, and the rats were returned to the anesthesia box. After a total of 45 minutes of exposure to isoflurane, either IV caffeine 25 mg/kg or a placebo was injected into the IV. Anesthesia was terminated 5 minutes later and the rats were placed on their backs on a table. The recovery time was the time from when the animals were removed from the anesthesia box until they stood with four paws on the table. Rats who received IV caffeine doses awakened more quickly (in as quick as only 40% of the time) compared to those who received placebo.

In a second experiment they exposed rats to propofol anesthesia. The researchers placed the rats in a gas-tight anesthesia box where they were exposed to 3% isoflurane until they became unconscious. The rats were then removed from the box, an intravenous line was inserted into their tails, and they were allowed to wake up. A bolus of 4 mg/kg propofol was injected into the IV along with either 25 mg/kg caffeine or a placebo. Those treated with caffeine woke within an average of 6 minutes compared to 9.8 minutes for controls. There were no vital signs differences between the groups treated with caffeine or placebo in either rat experiment.

The Chicago researchers followed the rat studies with a randomized controlled study on human volunteers.³Eight healthy males each underwent two general anesthetics, one with IV caffeine and one without. The induction was with IV propofol, a laryngeal mask airway (LMA) was placed, and anesthesia was continued with isoflurane for one hour. Ten minutes before the termination of each anesthetic, the subjects were randomized to receive either IV caffeine 15 mg/kg or a saline placebo. (Note that this dose approximates 1000 mg of caffeine for a 70 kg adult, a large dose.) The recovery time was charted as the time from when the isoflurane was discontinued until the time the patient first gagged on the LMA. The average recovery time in the caffeine group was 9.6 minutes versus 16.5 minutes in the control group (P=0.002), a 42% reduction in time. Once again, there were no vital signs differences between the subjects treated with caffeine or with placebo.

Why does caffeine accelerate awakening from anesthesia? The Chicago researchers cited two mechanisms: caffeine acts by inhibiting phosphodiesterase to elevate intracellular cAMP, and it also antagonizes adenosine receptors A₁and A_2A. Caffeine reversibly blocks the action of adenosine on its receptors and consequently prevents the onset of drowsiness induced by adenosine.

Currently the only medical uses for caffeine are to treat neonatal apnea and to treat migraine or postdural puncture spinal headaches. Despite the fact that caffeine is considered safe,caffeine overdose can result in a central nervous system overstimulation called caffeine intoxication which typically occurs only after ingestion of large amounts of caffeine, (e.g. more than 400–500 mg at a time).⁴This is only half the dose that Chicago researchers administered in their human study. Symptoms of caffeine intoxication include restlessness, anxiety, a rambling flow of thought and speech, irritability, and irregular or rapid heartbeat.⁵Massive overdoses of caffeine can result in death. The LD₅₀(lethal dose in 50% of cases) of caffeine in humans is estimated to be 150–200 mg per kilogram of body mass (i.e. 100-130 cups of coffee for a 70 kilogram adult).⁶

It’s too soon for caffeine use to become routine in the operating room. The Chicago researchers did not envision caffeine as a routine reversal agent for all general anesthetics. Anesthesiologists are skilled at weaning their patients from anesthetics for timely wakeups after the conclusion of most surgeries, but there are always outliers who are slow to wake. For these patients, a dose of IV caffeine may be helpful without introducing any increased risk. The Chicago researchers wrote, “the judicious use of caffeine could provide a tool to accelerate emergence in those individuals who manifest unanticipated prolonged emergence times and populations, such as the elderly, that are prone to prolonged emergence and recovery. . . . Further work is needed, and will follow, to extend these findings to other anesthetics including common IV agents like propofol, as well as demonstrating that these results are reproducible in patient populations, including females, older individuals, and those with chronic medical conditions undergoing operative procedures who receive multiple classes of pharmacologic agents in the course of a normal anesthetic.”

We may see intravenous caffeine following general anesthesia in the future for selected patients. Those private anesthesiologists I worked with in 1986 may have been correct when they injected IV caffeine into their sleepy patients after surgery and judged that “It helps a lot!”

References:

Mitchell DC, et al (January 2014). “Beverage caffeine intakes in the U.S”. Food and Chemical Toxicology. 63: 136–42.
Wang Q, et al. Caffeine accelerates recovery from general anesthesia, J Neurophysiol, 2014 Mar;111(6), 1331-1340.
Fong R, et al. Caffeine accelerates emergence from isoflurane anesthesia in humans, Anesthesiology. 2018 Nov;129(5):912-920.
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders (4th ed.). American Psychiatric Association. ISBN 978-0-89042-062-1.
“Caffeine (Systemic)”. MedlinePlus. 25 May 2000.
Holmgren P, Nordén-Pettersson L, Ahlner J (January 2004). “Caffeine fatalities–four case reports”. Forensic Science International. 139 (1): 71–3.