Lindsay Ripley
Most people know the word “adrenaline” better than the word “epinephrine,” but the substance is one and the same. The first word is of Latin origin, the second Greek. Akin to Mars, representing the bloodlust and barbarism of war to the Romans, as Ares embodied it for the Greeks. Each word loosely means “near the kidney” in its respective language, referencing the chemical’s manufacturer, the adrenal gland—a little pea that sits atop the larger bean of the kidney. The gland’s purpose was a mystery until very recently in the span of human history.
We tend to use the Greek term in medical contexts: “Do you want the lidocaine with epi or without?”; “Sweetie, do you have your EpiPen with you?” “The patient’s blood pressure is still low. We should add a pressor; do you want vasopressin, norepinephrine, or epinephrine?”
The Latin word dominates when referencing the natural form secreted by our own glands. No one says “my epinephrine is pumping” to convey stress. The use of “adrenaline” in that capacity dates back to the 1920s—“a shot of adrenaline” was used as a metaphor for excitement or vigor. In the 1960s, the term gained popularity around high octane, thrill-seeking behavior.
I was born at 2 a.m. one month before my due date. Given my over eagerness, when my mom told my dad in bed the preceding evening that she thought the baby was coming, he said, “No honey, it’s too early,” and rolled over, his snores soon permeating the room. Later that night they were rushing down the hospital corridor as my scalp crowned. There wasn’t time for an epidural; instead, my mom cursed loudly through my mercifully brief delivery.
Amid the overnight sprint to the hospital, my father had asked his sister Sylvia, who was living with us at the time, to stay home with my three-year-old brother, Keith,. Still asleep, Sylvia had blearily consented. After waking in the morning, she got dressed and went to work as usual, not noticing anything amiss. Keith popped out of bed as only a small child does, selected a book from a haphazard stack in his room, and wandered the house seeking a willing reader. “Mommy? Daddy? Aunt Sylvia?”
Back at the hospital, Dad called Sylvia to assure her that all had gone well with my delivery. Though he usually moved at a glacial pace, he jumped off the couch in a panic when he learned that Sylvia was at work, totally unaware of the night’s events. My dad floored it home, adrenaline pumping, to find Keith sitting on the stairs bawling, clutching an unopened book with tiny white fingers.
When confronted with a scary or intense situation, the sympathetic nervous system and the fight or flight response activates. Some people don’t do either, hence the alternative term fight or flee or freeze response. I was fighting, my dad was fleeing, and my brother was freezing. Mom was still recovering from labor, her epinephrine spent. Keith claims I scarred him, though in the end my dad brought him to the hospital where his day quickly improved as nurses fawned over the “poor baby” and fed him cake.
The concept of networks of nerves spanning the body dates back to Galen in the 2nd century. Galen proposed that these networks allowed a sympathetic, or coordinated, bodily response. It wasn’t until the 19th century that scientists developed realistic theories of the sympathetic nervous system and its actions, which led to knowledge of the counteracting parasympathetic nervous system. Rest and digest. Two sides of the same coin.
The string of sympathetic nerves that travels from the brain to the spinal cord, then in a “chain of little brains” out to the body’s organs, causes blood vessels to constrict, the heart to pump faster, pupils to dilate, and digestion to pause. In short, changes to prepare the body for a heightened, quickened physical response. Eustachius had discovered the adrenal glands in 1563, but we did not link the two together.
In the late 1800s, various clinicians described a syndrome in which otherwise healthy people had recurrent paroxysms of headache, palpitations, sweating, anxiety—symptoms mimicking overactivity of the sympathetic nervous system. Autopsies in many of these patients revealed masses on the adrenal glands, labeled pheochromocytomas. Charles Mayo, a surgeon, set out in 1926 to treat an affected patient by severing her sympathetic nerves. Digging around in her abdomen to do so, he found a large tumor on her left adrenal gland. Mayo made a game time decision—instead of severing the nerves, he focused on excising this mass, becoming the first surgeon to remove a pheochromocytoma from a living patient. Her symptoms resolved.
Scientists realized the adrenal gland played a significant role in the sympathetic nervous system. A barrier to understanding the function of the glands was that, excepting the sympathetic nerves providing input, they didn’t seem to be connected to anything. How could these isolated glands be causing effects in other parts of the body? It turns out that adrenaline, produced in the adrenal medulla and released in response to stimulation from the sympathetic nervous system, was the first discovered hormone—a chemical secreted directly into the blood that affects distant organs.
While the nerves of the sympathetic nervous system do directly innervate some sites where their actions take effect, perhaps their most important function is to stimulate the adrenals to secrete epinephrine, washing the body with excitement and regulating its overall response to arousing stimuli. Pheochromocytomas are tumors that make epinephrine.
I spent my first night outside the womb in the neonatal intensive care unit. My mom complains about how she couldn’t hold or even touch me. She could only put hands into the incubator through gloves built into its side, a layer between us, as if I were in quarantine for a highly transmittable disease. Or an alien—a creature of unknown origins and potentially dangerous. Something not fit for this world.
I was fine and was released home after a couple days. There weren’t any more health scares until my toddler years. One day someone innocently handed me a jar of peanut butter and a spoon without a second thought. I lugged my prize out to the back deck, plopped down in a sunny spot, and dug into the jar as large as my head. The sensation that hit me was new: the smell, the taste, the stickiness. But the distinction went further. Red welts popped up all over my body, my tongue and eyes swelled, and I struggled for breath. My already scarred brother, now five or six, watched in horror. Initially paralyzed as he had been back on those stairs when he thought he’d been abandoned, but quickly running, screaming for help.
I don’t know if I remember the moment, or if I can just viscerally feel that sensation from other times it has usurped my body. I am sucking air through a straw and don’t know how long I can keep it up. I am dizzy and my vision is fading; if I stand up, I will pass out. My whole body burns as if I’ve fallen into a pile of fire ants. My lips have blown up three sizes and my eyes are mere slits. Tears fill the only space they have left and stream down my face. My stomach is revolting, rejecting the poison, trying to expel it by any means possible. I do remember my nanny holding me upside down over the sink, frantically washing my mouth out from the faucet, shaking me, trying to get it all out.
This is anaphylaxis, a process triggered by an antigen that is perceived as foreign and harmful. Anaphylaxis affects the respiratory system: the bronchioles constrict and the airway narrows; the cardiovascular system: the blood vessels dilate, causing hypotension and decreased delivery of oxygen to the brain; the skin and mucous membranes: hives erupt diffusely, the eyelids, tongue, and lips swell; the GI system: abdominal cramping, vomiting, diarrhea. The airway compromise can be fatal. But there is an antidote: epinephrine.
As it does in a physiologic, sympathetic response, epinephrine attaches to different adrenergic receptors—there are two main subsets, alpha and beta—each triggering different downstream effects. It narrows the dilated blood vessels again, bringing the blood pressure up to a normal or high range. It tells the heart to beat stronger and faster, contributing further to a bump in blood pressure. By binding to another receptor in the smooth muscle of the lung, epinephrine causes bronchodilation—the shrunken airways open up. Both blood and air are again delivered to the body.
The first craze for using epinephrine was to decrease bleeding in surgical procedures, particularly in delicate but highly vascular areas like the nose and the eyes—the constriction of blood vessels means less bleeding. Formulations of epinephrine plus lidocaine (a local anesthetic) were created to numb up the skin in minor procedures; the vasoconstriction also means less lidocaine gets carried away from the injection site, decreasing its systemic effects and increasing its local ones. Had there been time, my mom would have gotten epinephrine as part of her epidural.
On a larger scale, obstetricians injected epinephrine into the hemorrhaging uterus damaged by the placenta tearing from its wall; gastroenterologists injected epinephrine into ulcers hemorrhaging into the intestines. Boxing cut men started applying epinephrine to the tips of cotton swabs they’d press on fighter’s faces between rounds to quell bleeding and avoid the ref calling the match. These uses remain common today.
Shortly after the peanut butter debacle, the same thing happened with fried catfish. No one seemed to realize I also had severe allergies to antigens besides peanuts. We had gotten EpiPens by the time I ate fish, however, so I ended up with a puncture wound in the thigh. EpiPen is the brand name practically synonymous with epinephrine autoinjectors. The whole device is the length of a new pencil, but much thicker; grasping an EpiPen is similar to holding a dumbbell. When the tip hits a surface with sufficient force, a 1.5 cm needle emerges, delivering the epinephrine. I had to carry my EpiPen with me everywhere as a precaution. Other precautions included things like not cleaning the cafeteria tables after lunch like all the other kids and eating in the school nurse’s office when fish sticks were served.
I didn’t use my EpiPen again for over a decade. Then came the only time I’ve had to inject myself. I was a college student on summer vacation, staying with a well-to-do family in Madrid. The children ate separately from the adults, served by the nanny. Often the parents were out at an event until the morning hours. If they were home, they’d eat dinner at 9 or 10. More on the kids’ schedule, I joined the clan for dinner one night at a reasonable hour and took a bite of what I assumed was a chicken nugget. Wrong. It was a fish stick.
One chew. Two chews. I spit it out. Embarrassed at my idiocy and the vulnerability of my body, I quickly retreated to my basement suite.
I could feel my face swell. Self-control out the window, my nails tore at my flaming skin, forming superficial lacerations. I started to wheeze. I had not spat the bite out soon enough. Frantically, releasing my own adrenaline, just not enough of it, I rummaged through my never fully unpacked suitcase and found the stick I’d been coached to always have at hand. Cap off, I plopped the device on the white comforter next to me, pondering the next step.
I was scared to use it. A rush to the bathroom with diarrhea interrupted my weighing of pros and cons. I threw up in a trash can while I sat on the toilet. Spots appeared in my vision. As I tried to stand, I slipped onto the floor, barely conscious. The choice was obvious. I half crawled and half dragged myself over the tile back to the bedroom, reached up to grab the pen, and plunged epinephrine into the lateral portion of my already bare right thigh. Almost immediately, my throat opened, and my blood pressure normalized.
I read a ton of adventure books as a kid, and always wondered what would become of me if I were trapped on an island, like The Swiss Family Robinson, or Tom Hanks in Cast Away. I’d either die from eating fish or die from starvation—surely one can’t live on coconuts alone. Sometimes this fear, among other worries and anxieties, led to me staying home. I’d gone to Spain, but I didn’t tell anyone what happened. I quivered when I read a news story of a girl who had died from her throat closing after a bee sting, despite carrying two EpiPens and using them both. I can safely assume I’m allergic to bees, but I’ve never actually been stung. If I’m enjoying myself in a gorgeous botanical garden or strolling through a peaceful meadow and I near bees I get out. When planning a trip with a friend, I vetoed Thailand as a vacation destination citing my discomfort with the cuisine, which I pictured as a filet of fish topped with crumbled peanuts.
Psychologist Kenneth Carter wrote a book called Buzz!: Inside the Minds of Thrill-Seekers, Daredevils, and Adrenaline Junkies. In it he postulates there are two types of people: low sensation seekers and high sensation seekers. Carter labels himself the former and constantly references his fascination and puzzlement of the latter. Why would anyone find risky or unfamiliar experiences enjoyable? Two people can have totally different reactions to the same stimulus, one finding an experience exhilarating, the other plagued with anxiety.
It turns out these people we label as adrenaline addicts or even chaos junkies have lower levels of epinephrine release in response to stimuli. Are people who jump out of planes and off bridges seeking a level of arousal that others might attain simply by watching a horror movie from the safety of their own couch? A lot of thrill seekers claim to dislike being adrenaline-charged. One base jumper stated “I don’t like the way it feels. I don’t like being scared.” Rather, the point of these activities may be to attain a flow state, a hyper focus, a control of one’s emotions. Another labeled thrill seeker said of running with the bulls “It’s not a disregard for life, but an addiction to life and trying to intensify moments instead of dull them out.” Do these people who skirt death so flippantly have a greater appreciation for life?
According to Optimal Arousal Theory, we all seek a sweet spot where we are neither bored and lethargic, nor stressed and panicking. A Goldilocks Zone in the center of a bell curve, either extreme of which feels unpleasant and likely leads to poor performance. Exactly where that spot is and how to get there is different for everyone. Without an instruction manual for oneself, finding that spot is a matter of trial and error. Carter says the world needs both high and low sensation seekers, and that these people need each other. Low sensation seekers are the anchor for the ship that needs to stay still; high sensation seekers are the tugboat for the barge that needs to be coaxed along.
I learned a lot about myself during my internal medicine residency, essentially three years of being shuffled around between hospitals and clinics, different subspecialties, with decreasing levels of supervision over time. I didn’t want to be an intensive care doctor—the constant pressure and high stress, having to insert a central line into a giant vein in the neck or a tube into the airway in critically ill patients freaked me out. When I had to stay overnight in the hospital, I lay awake on top of the sheets in the call room, sweating through my scrubs and waiting for my pager to go off to let me know that someone was dying. I pounded coffee the mornings after my sleepless nights to keep up that arousal that made me miserable, but that I needed to wrap up patient care before I could leave. The anxiety didn’t stop at the hospital’s doors; at home I’d often wake to hallucinations of my pager shrilly wailing.
I also knew from practicing as a primary care doctor a few days a month, seeing relatively well and often hypochondriacally inclined patients in clinic, that I didn’t want that either. One patient after another. All day. Everyday. Prescribing blood pressure medications and talking about diet and mood. I’d be bored out of my mind.
After residency I chose to work as a hospitalist, a general doctor who cares only for hospitalized patients. Those who are sick enough to be in the hospital, not so sick that they require intensive care. Optimally ill? That sympathetic response, the epinephrine, is necessary for more than just aggressive or frightened responses. It’s important for small arousals, a series of which most people “need” each day. Unless epinephrine and the sympathetic response activate when we stand up, squeezing the vessels down on a fixed volume of blood, gravity will overpower us. The blood will pool in our legs, draining the life force from those vital organs at higher altitude. We will become dizzy, fall, pass out. Even lying down, being sedentary, for too long can trigger this. Thank God there are doctors unlike me who enjoy the extremes.
In addition to pheochromocytomas, those tumors that secrete epinephrine, all kinds of masses can grow on the adrenal glands. Most are meaningless. They do nothing but sit there, perhaps enlarging sluggishly, never reaching notable size nor causing an adverse effect. A minority are functioning masses, secreting hormones; this can be epinephrine, or it can be other products of the adrenals: cortisol or aldosterone. And a small but important percentage of adrenal tumors represent malignancy. A cancer that can spread and kill.
On autopsy, pathologists find a mass on the adrenal gland in 5-10% of patients. As our methods for performing non-invasive imaging have leapt forward exponentially over the past decades, we are detecting more and more of these in living patients. The adrenal glands have become the characteristic home of the annoying, the vexing, the troublesome incidentaloma, a term coined in 1982 to describe this surging diagnostic conundrum. Not long after, in 1986, a New England Journal of Medicine article first used the term “cascade effect” in reference to evolving medical technology and its downstream effects.
Physicians can identify pheochromocytomas, as well as other hormonally active adrenal masses, by testing blood and urine for certain metabolites. The only way to know for sure if a mass is cancer is to cut it out, stain slices of it, and peer at them under a microscope. Chasing every mass will end in a lot of unnecessary surgeries. Even if we just perform blood tests on every patient, the healthcare system will incur a lot of unnecessary costs, the patient will be sapped of time and resources, and we may find other abnormalities of little or undetermined significance that snowball into further testing. Like giving a mouse a cookie.
What if we hadn’t done the scan that revealed the mass in the first place? Studies have shown that patients with incidentalomas have a decreased quality of life. Perhaps due to a constant low level of induced anxiety. All of this—whether to do an initial test, whether to order additional testing to follow up an unexpected abnormality—is a series of risk-benefit analyses in search of the optimal testing threshold. Physicians need to be able to tolerate a certain amount of risk and uncertainty. I find unanticipated masses, nodules, anatomical variations all the time that don’t warrant further testing in the hospital. Many do warrant testing in clinic, follow up in six months or a year, a visit to a subspecialist. I can’t guarantee this will happen; I have to let my patients out into the world.
I’ve seen Tarantino’s Pulp Fiction probably a dozen times. The film is number two of Tarantino’s planned ten films for his career (he’s now finished nine), notorious for fascination with blood and gore. Pulp Fiction is also the break into the resurgence of John Travolta’s career. Travolta plays Vincent Vega, an enforcer for a drug kingpin. Vincent is always cool as a cucumber, barely blinking an eye when he’s shot at five times, or when he accidentally blows the head off a guy sitting in the backseat of his car. He manages instead to focus on the important things in life, such as how to order a quarter pounder with cheese from McDonald’s in Europe given they use the metric system, or if a milkshake can really be worth five dollars.
The only time Vincent gets riled up, shows some real fear and emotion, is when he finds his boss’s wife unconscious and foaming at the mouth. Uma Thurman’s character Mia has OD’ed from greedily snorting Vincent’s heroin that she mistook for cocaine. Vincent can’t let Mia die. After all, his boss has a reputation for throwing people who displease him out of windows. Vincent freaks out, calls his drug dealer Lance for help, then speeds his red Malibu convertible fully onto Lance’s front lawn, crashing into the trash bins. Lance, who has been interrupted eating a generic version of Fruity Pebbles and watching a black and white movie, emerges in his tattered robe and reluctantly helps drag Mia into the house. There is screaming. There is panic. “Get the shot!” Lance yells at his wife. “Fuck you!” she retorts. She must use that phrase on him a dozen times a day.
Eventually the gang gets it together and manages to find the vial of adrenaline, fill the syringe, and get past arguments of “I ain’t giving her the shot!”. Vincent Vega stabs Mia Wallace directly in the heart, through a target he’s drawn in red marker. I learned the shot was filmed in reverse—Tarantino didn’t think Travolta would be able to stab Thurman full force and make it look real. So he filmed Travolta pulling the needle rapidly away from Thurman’s breast then flipped it. After Travolta stabs (or unstabs?) Thurman, she pops up, gasps for air, and flails about like a mad woman. Her vitality has been regained; she needs a while to recover from the rush.
Let’s indulge Hollywood and ignore the medical fact that adrenaline is not the treatment for heroin overdose. Plus, you would never stab someone directly in the heart, as any perforation in the myocardium would cause a leak. What the scene gets right is that people are stabbed with epinephrine needles, as I did to myself, and the drug can revive the dead. Or at least we cling to it as though it does.
The first miracle act that epinephrine performed was to restart the heart of a dog that had been stopped 15 minutes earlier. In 1901, the LA Times advertised that “adrenaline can be made to revivify the heart of the dead child.” There was a rash of administering it to famous people, Thomas Edison and FDR included, around the time of death to stave off one’s maker. Usually unsuccessfully. Today, epinephrine is the go-to drug in Code Blue situations—trying to revive a patient in cardiopulmonary arrest, i.e. dead. No matter why the heart has stopped—a fatal arrhythmia, a lack of oxygen, a serious derangement in the blood’s acid or electrolyte levels—a milligram of epinephrine is administered every 3-5 minutes. Until the heart restarts, or the code and the time of death are called.
The last time I ran a code was in my third year of residency at Harborview, the county hospital where I trained. Just after 8 am, I was walking around the fifth floor with my two interns, reviewing test results and seeing patients before going to 9 am conference/donut-and-coffee-time. The hems of my scrub pants were still damp from the Seattle rain outside. As our trio was about to enter a patient room, the overhead speaker made the clicking sound it always made before coming on, followed by several infuriating seconds of static. I paused midstep and cocked my head to the side, waiting for the announcement. “Code Blue. Main hospital. Third floor. Room 217. Code Blue…”
I shot my interns a look intended to say “You know what this means. Go on without me” then took three strides to the stairwell across the hall. As I descended the two flights, one of multiple pagers clipped to my waist went off. The code pager. I emerged from the stairwell to find nearly a dozen people gathered in and around room 217. There were nurses, techs, a respiratory therapist. Lots of essential things were happening, but there was no coordinated effort.
I was the first senior resident to arrive; the responsibility of running the code was mine. My heart thumped in my ears. My eyes flitted around to take in the scene. One deep breath in and out; as any good resident knows, the first thing you do at a code is take your own pulse. What’s the worst that can happen? Technically the guy’s already dead. Yet my own pulse was racing.
Beta blockers are the common term for antagonists of the beta-adrenergic receptors in the heart. Clinically, their main purpose is in patients with heart failure, to decrease the amount of work that goes into pumping, granting the ailing heart a longer life span. Beta-blockers are an open secret among musicians and snipers, who use them to slow down their heart rates and keep their hands from shaking in high pressure situations. Others pop them for public speaking. While epinephrine itself is a common banned drug in sports due to its ability to activate the body, beta blockers are also banned for athletes for whom they might provide an advantage, like archers and biathletes. I wanted a beta blocker in that moment to counteract my rush of adrenaline and slow down my heart, whose pounding fueled my anxiety and drained my confidence.
While I had too much epinephrine pumping through my veins, putting me outside my optimal performance zone and certainly out of my comfort zone, maybe the same substance would help the patient. In a subset of situations, it has shown some ability to restart the heart. But this is rare. Additionally, research has failed to show any improvement in neurologic outcomes in these patients who have missed out on vital minutes of oxygen delivery to their brains. The American Heart Association’s statement underlying the rationale for administering epinephrine in resuscitation efforts boils down to one line: “It is reasonable.” Which sounds like another way of saying, “Well, crap, I don’t know, why not?”
With a deep breath, I pushed through the crowd to get into the patient’s room, introduced myself as the Code Leader, and gathered what information I could. The dead man had been found unresponsive on morning rounds. He was in his seventies, with a sick heart. He was thin, slightly disheveled, and his only movement was that caused by the compressions on his chest that had already begun. While I summarized the case and gave orders, the nurses and techs performed CPR, my co-residents arrived and placed a central line, put an ultrasound probe over his heart to get a look at what we were dealing with. The anesthesiologist intubated the patient and the respiratory therapist delivered breaths by manually squeezing a bag.
We gave epi two or three times. Then the nurse with her finger on the patient’s groin felt the femoral pulse she was looking for. Another nurse checked a blood pressure. Adequate. The man, now alive again, proved it further by turning his head and groaning. Things had certainly changed since he’d last been conscious. Nurses whisked him upstairs to the ICU. Later that morning another Code Blue rang out over the speakers. New room. Same patient. Same result. The third attempt at resuscitating him after I’d gone home that night was unsuccessful. Probably for the best; I hope he found that sweet spot of arousal, his Goldilocks Zone, while he was alive.
Lately I’ve thought about what a kid said to me in carpool one day on our way to ballet practice after elementary school: “Why don’t you just eat a peanut and then EpiPen yourself?” I couldn’t think of an answer but deemed the question imbecilic. What a stupid idea! One answer that occurs to me now is that I have no desire to eat a peanut. So why take any risk? I’m not even interested in volunteering for peanut allergy desensitization, a growing but still fairly new practice. But for some reason I really want to try sushi. And smoked salmon. And lobster bisque, crab nachos, caviar. I have a running list in my mind of all the foods I would try a bite of in quick succession before stabbing myself with the EpiPen. Of course, I’d have a back-up syringe and a doctor friend at hand. I call the concept Seafood Day. Can I afford to take that risk?
Can I afford not to? Near the middle of the runtime of Pulp Fiction, though near the end of its events in chronological order, Vincent—who has survived being shot at five times, prevented his boss’s wife from dying, escaped the law when he shoots a guy’s head off in broad daylight on the street, and foiled armed robbers at a diner—is shot and killed. Shot and killed with his own gun that he left on the counter, as he emerges from a bathroom in his typical languid fashion.
Lindsay Ripley, M.D., is a physician in internal medicine at a county hospital in Texas. Her publications have appeared in D magazine, Journal of Graduate Medical Education, The Smart Set, and multiple medical blogs. Dr. Ripley currently is pursuing an MFA in creative nonfiction at Antioch University in Los Angeles.