Three Little Steps
Do you know what type of poisoning affects three million people each year? What this poison has to do with chemical weapons? And what toxin is so potent it can kill lions in just a few steps? Listen to find out!
This is the Pick Your Poison podcast. I’m your host Dr. JP and I’m here to share my passion for poisons in this interactive show. Will our patients survive this podcast? It’s up to you and the choices you make. Today’s episode is called Three Little Steps.
Do you know what type of poisoning affects three million people each year? What this poison has to do with chemical weapons? And what toxin is so potent it can kill lions in just a few steps? Then stay tuned!
Today’s episode starts in a busy emergency room in New York City. Medics roll in with a thirty-two-year-old woman covered in vomit and feces. Her husband called 911 after arriving home from his job on the night shift to find the family ill. Their 3-month-old and 7-year-old were also covered in vomit and diarrhea. The children are in the Pediatric emergency department, next door. The nurses hook the woman up to the monitor and get her undressed.
“We gotta real Code Brown here,” one nurse says, peeling back the blanket and the patient’s pants. Code Brown, ER nurse slang for an explosion of fecal matter, literal or figurative. The patient’s legs are covered in feces all the way down to her feet. It’s caked between her toes.
The patient is awake but minimally answering your questions and staring off into space. It’s unclear if this is volitional or if her metal status is truly altered. The nurse points, directing your attention to the monitor. The patient’s heart rate is slow at 49 beats per minute. Her blood pressure also low at 99/54. Her temperature is 99 F (37C) with normal breathing and oxygen saturation.
Her examination is notable for profuse sweating. She’s already soaking through the gown the nurse just put on. Diaphoresis, the term for this, is not a clinical exam finding I love to see. If the patient has a high fever, fine, it’s expected. Without a fever, it’s very nonspecific, but usually indicates something bad like a heart attack, cardiac arrythmia, tuberculosis or other life-threatening issue. Her pupils are small. You hear crackling noises in her lungs when you listen with your stethoscope. She is able to move all extremities, though her muscle strength is weak.
A common cause of vomiting and diarrhea in the ER is a basic stomach virus, gastroenteritis. I’m sure you know from personal experience, its common in young children and all family members can get it at the same time. Easy, except the history seems odd. Copious vomiting and diarrhea, sure. Covered in stool? No. Not unless it’s an old person who can’t take care of themselves. And even if the mom didn’t feel good, most parents don’t leave their children in that condition. Also, the medics said the family was fine, without complaints, when dad left for work 10 hours ago.
Another red flag is her slow heart rate. If a patient with vomiting and diarrhea becomes dehydrated, they should have a fast heart rate. In episode one we talked about the toxicologic causes of bradycardia, mostly blood pressure medicines. While just about anything in overdose can cause some vomiting or diarrhea, antihypertensives don’t cause copious symptoms like this.
Just as you say to the nurse, “Something isn’t right,” the patient’s limbs start twitching uncontrollably. She loses consciousness and has a generalized, tonic-clonic seizure. In the past, a gram mal seizure. This is definitely not an anti-hypertensive overdose or a stomach virus.
You call for lorazepam, or Ativan, a benzodiazepine the first line treatment for seizures in the emergency department. Fortunately, the seizure stops after a minute. Unfortunately, the patient doesn’t wake up. Is this a post-ictal phase? After a seizure, it’s common for patients to be sleepy, confused or even agitated for several minutes or hours. This altered mental status isn’t unexpected, but it is complicating our evaluation. Has her condition drastically deteriorated, or will she gradually wake up in the next hour or so?
To help us figure it out, the nurse gets a fresh set of vitals. Her heart rate is in the 40s, lower than before. Again, concerning because seizures usually cause high heart rates. Her breathing is labored and even without your stethoscope you hear wheezing. That’s not from the seizure either. She’s drooling copiously. No matter how much the nurse suctions out her mouth, it doesn’t stop.
A picture forms in your mind as her constellation of symptoms come together. This is a classic toxidrome, signs and symptoms indicating a specific category of toxins. To sum up, she has a slow heart rate, bradycardia, vomiting and diarrhea, salivation, and muscle weakness.
All classic findings of the cholinergic toxidrome.
You probably remember from science class your nervous system is divided into two parts the sympathetic nervous system, responsible for the fight or flight response, and the parasympathetic nervous system, sometimes called rest and digest or feed and breed. The parasympathetic system counteracts the sympathetic response, keeping your body calm, relaxed and in balance.
Cholinergic poisoning is excessive stimulation of the parasympathetic nervous system. Too much resting and digesting if you will. It’s called cholinergic because acetylcholine is the neurotransmitter responsible for turning on the parasympathetic system. So, too much acetylcholine equals overstimulation, resulting in this classic toxidrome.
The pneumonic medical students use to remember the symptoms is SLUDGE. S for salivation, L for lacrimation or tearing, U for urination, D for defecation or diarrhea, E for emesis or vomiting. The second part of the pneumonic is called the Killer Bs. Killer because these are what will kill you. Bradycardia, bronchoconstriction or bronchospasm, and bronchorrhea. Bronchospasm is what causes asthma and COPD, the airways constrict and impair breathing. Bronchorrhea is fluid flooding the lungs. Almost all the causes of cholinergic toxicity are drugs and toxins.
The monitor beeps loudly as the patient starts gasping for air. There’s no time to consider what she’s been exposed to. Her airway is no longer intact and she requires immediate intervention. The wheezing is bronchoconstriction, the crackles you heard initially is fluid from bronchorrhea. To begin with, she needs a breathing tube and ventilator. But unlike our last episode, that isn’t enough to keep her from dying. She needs an antidote. Right now.
Question 1. What is the antidote for cholinergic toxicity?
A. Naloxone (Narcan)
B. diphenhydramine (Benadryl)
C. albuterol (a breathing treatment)
D. atropine
Answer: D. atropine
Naloxone reverses opioid poisonings, not useful here. Benadryl has anticholinergic properties, so in theory it could combat some of the effects of a cholinergic drug however making this patient sleepier isn’t going to save her life. Albuterol in asthma inhalers might help, but again, not lifesaving here. She needs atropine a very strong anticholinergic drug to stop the excessive cholinergic symptoms killing her. There’s a second antidote to consider, but it’s somewhat controversial, let’s hold on it a few minutes.
Though cholinergic toxicity isn’t common in the US, we do use atropine routinely for slow heart rates. For example, an elderly person with heart disease can be treated with atropine until they get more definitive intervention like a pacemaker. The typical dose of atropine is one, maybe two milligrams.
For cholinergic toxicity, there isn’t a standard dose. You have to give enough to combat and reverse the poison. How do you know how much they were exposed to? You don’t. The goal is to reverse the symptoms. There are lots of different protocols, the one I like is a doubling protocol. For example, start with one milligram of atropine and double the dose every five minutes. So 1mg to 2mg to 4mg to 8mg etc. The goal of therapy: atropinization.
What exactly does that mean? Keep treating until you see the side effects of atropine. When this happens, you know the poison is being successfully counteracted. Specifically, drying up secretions. In other words, no drooling or sweating, and dry armpits.
I have to pause for a medical training aside. I had the good fortune to train under one of the fathers of toxicology. On my first day of fellowship, I was warned he’d occasionally grab the hands of a fellow and put them into a patient’s armpit to evaluate if it was wet or dry. Anytime he was around, I always wore gloves, just in case, afraid of finding my bare hand in a sweaty armpit.
You tell the nurse to call the pharmacy, we’re going to need a lot of atropine. After multiple doses, the patients’ pupils are less constricted, her heart rate is normal, she stops wheezing. You check her armpits— with gloves— and they are dry. Success. She’s atropinized. The next step is a drip at the atropine dose that worked. We haven’t forgotten about the second antidote, but some considerations depend on what she’s been poisoned with, so let's talk about that first.
Question number 2. What are the causes of cholinergic poisoning?
A. Chemical weapons
B. Mushrooms
C. Medicines
D. Pesticides
E. All of the above
Answer: E. All of the above
Pesticides, including insecticides and rodenticides, medicines, chemical weapons, and mushrooms. Our patient wasn’t exposed to a chemical weapon in the middle of NYC, otherwise her entire building, block or borough would be sick. Also not a lot of mushrooms growing in NYC, so unlikely. Chemical weapons and mushrooms, are fascinating topics. Stay tuned for future episodes.
Physostigmine (brand name Antilirium) is a cholinergic drug. I’m mentioning it because it’s an important antidote, used to treat anticholinergic toxicity like a Benadryl overdose and because it has a fascinating history, not because it’s is a likely source of the patients’ symptoms. Physostigmine comes from the Calabar bean, native to West Africa and was used as a trial bean. What’s a trial bean? Ancient justice dating back to Hammurabic code was trial by ordeal. If you survived the ordeal, sometimes fire or water, the gods supported your innocence, if you died, obviously you were guilty. In Nigeria, the Calabar bean was used for this purpose. Those who didn’t bite the bean survived. Those who did, died of cholinergic toxicity. We do see cholinergic side effects from medicines, but it's extremely rare to see poisoning.
This leaves us with, by far, the most common cause of cholinergic toxicity, pesticides. There are approximately 3 million exposures worldwide annually, resulting in approximately 300,000 deaths per year. Cholinergic pesticides are divided into two classes. The first is organophosphates, your classic pesticides. Nerve gases like VX and sarin are also organophosphates. The second group are carbamates.
The reason for the distinction is their effect within the body. We’ve established cholinergic poisoning is an excess of the neurotransmitter acetylcholine. What causes the increase? The toxin binds to the enzyme responsible for the breakdown of acetylcholine, called acetylcholinesterase. When an enzyme breaking down a substance doesn’t work, the substance accumulates in dangerous amounts. The difference between the categories is that carbamates bind reversibly and organophosphates (OPs for short) bind irreversibly. This irreversible binding is called aging and occurs at different times with different OPs. Soman gas ages within two minutes, some insecticides take longer than 48 hours to age.
At this point, our patient’s most likely source of poisoning is a pesticide. Back to antidote number two, oximes, a controversial topic. In the US this means pralidoxime, nicknamed 2-PAM. I don’t want to get in the weeds with an extensive discussion of some very dry medical literature. Briefly, oximes were designed in the ‘50s to reverse the binding of organophosphates to the acetylcholinesterase enzyme. Sounds perfect right? Unfortunately, the efficacy data in real life, outside the lab, isn’t clear, and studies are conflicting. To further confuse the issue, 2-PAM shouldn’t help with carbamates, since they bind irreversibility, yet some studies show a benefit with certain carbamates.
The general expert consensus in agreement with the World Health Organization recommends administering an oxime. All agree oximes work best the earlier they are given. After 48 hours, they have minimal efficacy. In the ER, we usually have no idea what the exposure was. As usual with toxicology testing, it’s limited and will take days to weeks to come back. Bottom line, if 2-PAM is available, I’d strongly consider giving it.
What about lab testing? The cholinergic toxidrome is enough to make the diagnosis, but everyone loves a confirmatory test. You can test for specific compounds, like specific pesticides. These will take days to weeks to come back. You can measure cholinesterase levels via several methods, no doubt the ICU team will do so. Interpreting these levels is difficult because normal human cholinesterase levels vary widely, and also, different organophosphates affect cholinesterase levels differently. That said, trends can be helpful to the inpatient team.
Back to our patient, now stable on the atropine drip. You call the critical care team to admit her to the ICU. As you hang up the phone, someone calls you. It’s the pediatric ER doctor from across the hall. She wants your help with atropine dosing. While resuscitating our patient, you’d forgotten about her sick children. Walking across the hall, you wonder how the patient was exposed to a pesticide. New York City isn’t exactly an agricultural center.
The two children have the same symptoms as the patient. They’re both intubated. The breathing tube in the 3-month-old is tiny, the size of a drinking straw. The Peds ER doctor tells you the seven-year-old was awake on arrival and told the staff her mom gave her a drink before bedtime. The mother mixed black pellets in water, then filled two glasses and one baby bottle with the concoction. The little girl said it tasted horrible and the baby was crying. The mother – your patient—forced her to finish the drink then emptied her own glass.
You have a nauseous feeling your stomach like you might vomit yourself. There is something in pellet form, illegal, but not hard to find in New York City if you know where to look. It causes these exact symptoms. You tell the pediatric ER doctor. She calls the police to report a murder suicide attempt.
What poisoned these patients? How were they exposed to a pesticide in a New York City apartment? It’s aldicarb, a carbamate rodenticide – rat poison. It’s called Tres Pacitos, meaning three little steps in Spanish, so lethal it kills mice and rats in three steps. It’s often illegally imported from the Dominican Republic. It’s also called The Cat Be Unemployed. In South Africa it’s called two step, and works so quickly it’s been used by burglars to poison dogs.
The question of what poisoned these patients, we can now answer. The question of why? We’ll never know.
An hour later, your shift ends. You go up to the ICU. In the elevator, you can’t avoid thinking about the fact that your patient tried to murder her two children. A real Code Brown.
How does it make you feel? Doesn’t matter, regardless of what happened, our job is to take care of her. These conflicts contribute to burnout and moral injury. We tried to get some rest and relaxation on a tropical island to help with burnout during our last episode, the Hazardous Holiday. Spoiler alert things didn’t go well.
Walking into the ICU, you see the team rounding, so you share what you know about aldicarb. It’s relatively easy to obtain from behind the counter at a bodega if you speak Spanish. It’s popular with customers because it works better and faster than legally available rat poison. For more on potent rat poison, listen to episode 2 to hear about Rough on Rats.
Aldicarb is in the World Health Organization’s highest toxicity category for pesticides, toxic for humans and the environment. It’s tightly regulated, but still legal in the US for use on certain crops. It’s been banned in Europe for years. The US has had several outbreaks due to contaminated food, specifically cucumbers and melons. In South Africa, poisoning has occurred due to contaminated wine.
A unusual case of accidental poisoning occurred in 1998 in Louisiana. After a work lunch, guests developed vomiting and diarrhea, along with sweating, twitching and blurry vision. The Health Department discovered the cause was a homemade cabbage salad. The employee made the dish by mixing prepackaged cabbage with vinegar and pepper. The pepper was from a can labeled black pepper he found in the truck of a deceased relative. The health department tested the contents of this container, discovering it was actually aldicarb. The deceased owner was a crawfish farmer who’d used aldicarb to prevent the destruction of his nets by wild dogs and raccoons.
This surprising story, illustrates what some have called the Snapple bottle effect. Transferring substances from a properly labeled bottle to an unlabeled container like an empty Snapple bottle, coke bottle, or just a plain old plastic cup, has caused thousands, if not millions of unintentional exposures. Inevitably someone else picks up the bottle or the cup and takes a sip, unwittingly exposing themselves to the cleaning products, pesticide, engine fluid or other toxin.
The ICU resident notes the patient had a history of post-partum depression after the birth of the 7-year-old, wondering if this might be the reason, she poisoned herself and the children. He asks about her prognosis.
Mortality rates range between 2-25% after pesticide exposure, reflecting lethality of different pesticides, as well as drastic disparities in care. In the US and Western Europe, mortality rates are low. This is for two reasons, first due to widespread access to modern medical care. Second, strict regulation of pesticides and complete bans of the most lethal. Medically speaking our patient will probably recover. Psychologically, the prognosis is grim.
A random, but interesting fact. If a patient dies of aldicarb poisoning their organs can, and have been, safely transplanted. The question of organ transplantation after brain death from poisoning is often posed to toxicologists. Why? Because people who die from poisoning are often younger and otherwise healthy, unlike those who die from say heart disease or diabetes.
Carbamates are potent poisons. Carbofuran, banned in the US and Europe, is so potent it can kill even lions in a few steps. Farmers in Kenya used livestock carcasses sprinkled with the pesticide to kill lions. The dead lions were found right next to the poisoned carcasses.
Question 3 is today’s Pop Culture Consult.
What antidote did Nicholas Cage’s character in the movie The Rock inject into his heart? Bonus for extra credit-- what was the gas he was exposed to?
A. Physostigmine
B. Naloxone
C. 2-PAM
D. Atropine
Answer: D atropine.
He injected it after exposure to VX gas, an organophosphate chemical weapon. Right antidote, wrong method of delivery. Just for the record we never inject anything into the heart. All of your blood circulates through your heart, so whatever you give intravenously will get there in a few heartbeats. Also, if you put a needle in your heart you now have a hole in your heart and probably in your lung, too. At that point it doesn’t matter if the poison is lethal or antidote works, the hole will probably kill you before anything else.
Our patient wakes up, surviving the exposure, as do her children. They don’t suffer any long-term physical consequences. The resident was right, she’s diagnosed with postpartum depression. She’s also arraigned on attempted murder charges. This is a fictional case, as are all our cases, to protect the innocent. But it is based on real poisonings that have occurred periodically.
Question number four, the last in this episode. A chemical plant manufacturing aldicarb was the site of one of the worst occupational poisonings in history. At least two thousand people died immediately and as many as sixteen thousand people died as a result of exposure to this toxin in a chemical accident at the Union Carbide plant in Bhopal India. What was the toxin?
A. Fentanyl
B. Cyanide
C. Hydrogen sulfide
D. Carbon monoxide
Post your answers on our Twitter feed @pickpoison1. I’ll post the answer in the next 24 hours. Remember, never try anything on this podcast at home or anywhere else.
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