Desensitized
Want to know what class of drugs is dangerous enough to have been used by a serial killer nurse, but is also in cough drops? What antidote for the life-threatening overdoses caused these drugs is a common nutritional ingredient? 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. Our episode today is called Desensitized.
Want to know what class of drugs is dangerous enough to have been used by a serial killer nurse, but is also in cough drops? What antidote for the life-threatening overdoses caused these drugs is a common nutritional ingredient? Then stay tuned!
Today's episode starts in the hospital. It's a quiet day in the emergency department, you think, making a classic mistake. Superstitious ER doctors and nurses know better than to mention the Q word. Just as you think there might be time to both eat and go to the bathroom, a commotion erupts in room 4. The patient is a 65-year-old with a hip fracture due to a fall. It’s a straightforward case. I mean it, should be a straightforward case. What is happening?
You hear the resident’s voice calling for lorazepam, or Ativan, as a nurse tells you the patient is having a seizure. Inside the room, one nurse holds an oxygen mask over his face while another pushes lorazepam into the IV. The patient is having a generalized tonic-clonic seizure, meaning he’s unconscious with rhythmic contractions of his extremities. If you’ve listened to previous episodes, you know lorazepam is a benzodiazepine, a class of drugs with lots of uses, especially in toxicology. One important use is as an anti-epileptic or anti-seizure drug.
You ask the resident what happened. With a stunned expression, he says the patient complained of a funny taste in his mouth and said his tongue felt numb, then started seizing. Your heart drops to your toes. Anyone can have a seizure anytime, certainly, but the patient has no prior history of seizures so I wouldn’t put my money on this. The patient fell, breaking his hip, but didn’t hit his head, making a post-traumatic seizure unlikely. We’d check a head CT once the patient was stabilized, but again, in this case, not likely to give us the answer.
How did we get from a hip fracture to a seizure? What do we need to do next?
You push the ultrasound machine away and the resident, wearing a surgical gown, sterile gloves and still holding a long, thin needle, backups up giving you space at the bedside. Did I hear you ask for vital signs? Good question. Also, good luck. It’s difficult to measure vital signs during a seizure to put it mildly. Usually, patients have an elevated temperature due to the increased muscle activity. They’re tachycardic, meaning a rapid heart rate. It’s pretty much impossible to get a blood pressure. Probably the most important vital sign is an oxygen saturation. It’s also tough to measure, so we always administer supplemental oxygen.
The patient is still seizing. Benzodiazepines aren’t going to hurt him, but they aren’t going to help either. The patient needs an antidote. Let’s take a quick step back. If you fall and break your hip, obviously it’s painful and we will treat with opioids. By now everyone knows the side effects of opioids, like respiratory depression. In the hospital, especially in elderly patients, they also commonly cause delirium. So, while we don’t want the patient to be in pain, we know large doses of opioids can cause as much harm as good.
Another option for pain control is a nerve block, injecting numbing medicine, like lidocaine, around a nerve to desensitize a particular area. May people have had nerve blocks, at the dentist’s office or with epidural anesthesia, during labor or surgery. Lidocaine is in a class of drugs called local anesthetics. In contrast to general anesthetic gas given in the OR.
The reason the resident is holding a long needle? He was doing a fascia iliaca nerve block with bupivacaine, another local anesthetic, to block the nerves innervating the hip to reduce the patient’s pain.
Question one. The resident made an error. What was it?
A. He hit a nerve
B. he used the wrong medicine
C. he injected the local anesthetic into the wrong location
D. he caused an infection
Answer: C. All of these are potential complications of a nerve block. In this case, he injected into the wrong location. Hitting the nerve causes pain, not seizures. Any procedure can cause an infection, but it takes a day or two to develop. He used the right medicine, but in the wrong place. This is local anesthetic systemic toxicity, or LAST for short. Let’s talk about what happens and its amazing antidote.
Local anesthetics are used literally every single day in many, many different departments The emergency department, the operating room, dentist's offices, labor and delivery, just to name a few. In the ER I use lidocaine multiple times per shift to suture lacerations, and honestly, I don’t spend any time worrying about LAST. Occasionally someone has an allergic reaction, but that’s about it. There is a maximum dose of lidocaine, a question on the ER board exam, but it’s only an issue if a patient comes in for something the size of a shark bite. Am I being cavalier by not thinking about it more? No. The reason has to do with the resident’s mistake. Location.
Giving local anesthetics subcutaneously, in the skin and soft tissues, is safe. The ‘S’ in LAST stands for systemic, meaning it occurs with intravascular injection. Intravenous or intraarterial, allowing it to circulate systemically. This mistake is much easier to make with the deeper infiltration required for some nerve blocks.
The goal of a nerve block is to infuse the medicine around the nerve, inducing numbness. If injected into the right place, in the soft tissues surrounding the nerves, the procedure is safe. The data shows it reduces the amount of opioids administered and patients have shorter hospitals stays, reflecting amongst other things, less delirium.
The major risk with nerve blocks, is injecting the anesthetic into the wrong place, meaning intravascularly, into a vein or artery. The danger is minimal when injecting into a cut, but much higher with deeper structures, near major blood vessels. In this area of the hip are the femoral artery and the femoral vein. Our resident was doing the procedure, as recommended, under ultrasound guidance to reduce the risk. Nevertheless, mistakes happen for multiple reasons including inexperience and anatomical anomalies, not every patient’s anatomy is textbook. There are few constants in medicine, but you can always count on Murphy's Law. If something can go wrong, it will. Later the case will be reviewed to see what went wrong and what can be done to minimize future errors. Now, we need to do something. Stat.
Question 2. The patient is having a seizure. What's next in the progression of local anesthetic toxicity?
A. Coma
B. Brain death
C. Cardiac arrest
D. Liver failure
Answer: C. Cardiac arrest.
LAST starts with dizziness and numbness, then seizures then progresses to cardiac arrest and rapidly, death. In 2006, an antidote was discovered. Prior treatment included benzodiazepines for seizures, antidysrhythmics for arrhythmias, and CPR and advance life support for cardiac arrest. Often, these measures didn’t work.
Some of you might be wondering why we use, or used to use lidocaine to treat arrythmias, if it’s a local anesthetic and can like the others cause, LAST. Once again, this is a case of the dose determining the poison. Lidocaine is the most widely used of the local anesthetics because it has the best safety profile. The antidysrhythmic dose is safe, higher doses of lidocaine are required to cause LAST. Bupivacaine, the medicine the resident was using, is infamous for its cardiac toxicity. Why did he use it? It’s often used for nerve blocks because its long lasting.
Local anesthetics work by opening sodium channels in nerves, essentially locking them into an open position. This keeps the nerve from depolarizing, or firing, meaning the nerve cell is unable to send messages to your brain. Therefore, you can’t feel any pain in the blocked area.
They also work in the heart, the reason why lidocaine is an antiarrhythmic. Different effects occur, some of which are dose dependent, with essentially, the same result. The medicines bind to ion channels in the heart, affecting nerve conduction. Frequently, conduction stops, resulting in asystole. A heart that can’t beat. It can also result in lethal arrythmias, like ventricular fibrillation which we’ve discussed before. Local anesthetics cause smooth muscle relaxation resulting in low blood pressure.
Bupivacaine was known for having both the highest potential for cardiac toxicity as well as being the most difficult to treat. Despite its deadliness, toxicity occurs very rarely. In one large series of 11, 080 patients receiving nerve blocks, only 15 had systemic toxicity. Ob/gyn data showed higher mortality rates, for this reason bupivacaine is no longer used in epidurals.
The monitor stops beeping. Good news, the patient stopped seizing. Bad news he’s now in asystole and cardiac arrest, with a flat line sliding across the monitor.
Question# 3. What is the antidote for LAST?
A. Epinephrine
B. Narcan
C. Methylene Blue
D. Lipid emulsion therapy (Intralipid)
Answer: D. Lipid emulsion therapy. Injecting fat. Intralipid is the brand name for 20% soybean oil. Sterilized, medical grade, of course but that’s it. You order 100mg of lipid emulsion, hold your breath, and hope it works. If it doesn't you killed your otherwise healthy patient during an elective procedure. The nurses continue CPR and you administer standard drugs like epinephrine.
After 20 seconds, a blip crosses the monitor. One heartbeat. Then another and finally, a few seconds later, a normal heart rhythm. His pulse is back. You wipe the sweat off your forehead and put your hands in your pockets so no one can see how badly they’re shaking.
How does intravenous fat work as an antidote? This is a quote from the man who discovered it, anesthesiologist Guy Weinberg. “It seems implausible that an injection of a simple, off-the-shelf, intravenous nutritional solution could be acutely life-saving for a patient with severe drug overdose.”
The answer isn’t completely understood, probably it acts via several mechanisms. One way, we used to call the lipid sink. Its like soap for the patient’s blood vessels. Soap is mostly fat, and works by sequestering dirt inside small vesicles. Lipid works the same way, binding up drugs to keep them from reaching end organs like the heart or the brain. This is now considered more of a lipid subway, with lipids removing the anesthetic from the blood or heart and redistributing it to less toxic areas like muscles for storage or the liver to break it down and metabolize it. Other theories include optimizing biochemical pathways to increase energy, ATP, inside cardiac cells and improving contractility and cardiac output.
The antidote’s story starts in 1998 when Guy Weinberg was researching bupivacaine and it’s cardiotoxicity. He noted animals pretreated with a lipid infusion had less toxicity than animals that weren't. He continued this research, but wasn’t until 2006 that lipid rescue was used in humans. The first published case reports the dramatic recovery of a 50-year-old-patient with an extensive cardiac history, underdoing a nerve block for rotator cuff surgery. Thirty seconds after the needle was withdrawn, he had a seizure and within a minute and a half, a cardiac arrest. He didn’t respond to standard therapy, like epinephrine and CPR. In a last ditch attempt, he was given 100 mg of 20% lipid. Within 15 seconds, he got a pulse back.
I think it's fair to say this drug took the medical community by storm. It's not every day we get a new antidote. A 2016 review article found that 81 of 83 patients with last treated with lipid rescue survived. This is a really striking number. Lipid does work, but not every patient can be saved. These types of studies are subject to publishing bias. Research showing positive effects are more likely to be published than research showing negative effects. Essentially, medical journals are interested in articles where lipid works, rather than cases where it doesn’t. Bias notwithstanding, it's still a pretty amazing antidote.
We toxicologists love antidotes and jumped at the chance for a new one. A case in 2007, was the first case report of lipid rescue used for compounds other than local anesthetics. Desperate to save a suicidal teenager, her doctors decided there was nothing to lose by trying it. I had the good fortune to train under several involved in the case an heard the story first hand. I want to share it with you because it's such an incredible story.
A 17-year-old girl texted a friend saying she'd overdosed. The friend called 911, the patient was admitted to the ICU after overdosing on lamotrigine and bupropion. A mood stabilizer and an antidepressant. Bupropion is well-known for causing lethal arrythmias in overdose. After several hours, she suffered a cardiac arrest.
They coded her, did CPR for 70 minutes much longer than normal, but because she was only 17 they wanted to give her every possible chance. The anesthesiologist, part of the code team for airway management, remembered an article he'd read about lipid emulsion therapy. Reportedly, he called his wife to check the article on his desk and tell him the dose. He then called the inpatient pharmacy and was told there was no lipid. However, he knew every hospital has lipid preparations, used for TPN, or total peripheral nutrition, IV nutrition for people who can’t eat. Someone was sent to the TPN pharmacy to get it.
As with the other published cases, the patient had a dramatic recovery, regaining her pulse within minutes. Not only did she have cardiovascular recovery, she walked out of the hospital with almost no neurological effects, despite being dead for 70 minutes.
After this, we toxicologists started using lipid for everything. It’s side effects are minimal, though it can interfere with lab values, cause pancreatitis, and very rarely ARDS and renal failure. It's been used to treat overdoses ranging from psychiatric medicines, to cardiac medicines, to seizure medicines, to over-the-counter overdoses like diphenhydramine or Benadryl, and drugs of abuse like cocaine. Many published case reports show positive outcomes, unfortunately, these remain case reports, rather than large studies. Publication bias applies. It's impossible to conduct randomized controlled trials of poisoned patients undergoing cardiac arrest to see if intralipid is helpful. Like Mithradates with his universal antidote, theriac we hoped it work for everything, all the time. Like theriac, this hasn’t proven to be the case. It’s unquestionably useful in LAST. It’s also useful in life-threatening bupropion toxicity.
The consensus from a very large group of toxicologists and poison centers from the US, Europe and Asia concluded it hasn’t proven to be of benefit in most other causes of poisoning. The reason for the neutrality? A lack of evidence. Research is ongoing and certainly if the evidence changes, the recommendations may as well.
LAST can occur via multiple routes. It’s been reported after both oral and topical exposure. Creams exist to numb skin before procedures. Tragically, a 20-year-old woman died after applying lidocaine cream to her legs and wrapping them in plastic wrap in preparation for laser hair removal.
People feeling suicidal have taken lidocaine. It’s been used maliciously. A serial killer nurse, dubbed the “Lidocaine” killer was convicted of killing nursing home patients with IV injections. Horrifically, he was caught and convicted after he started killing two patients per shift.
I want to tell you about local anesthetic toxicity via a route that most doctors don't know about. It’s a drug on my list of least favorites, cough drops with benzonatate, brand name Tessalon pearls. These are prescription cough drops, benzonatate is a local anesthetic, you might have heard of them since they were given out like water during covid. What’s the issue? First, the evidence for cough suppression is minimal. Second, they can kill you.
Like other local anesthetics, they can cause ventricular fibrillation and death. This isn't a theoretical concern. Children are particularly at risk and have died from exposure. In many cases, people assume cough drops are safe and pop them like candy, rather than taking them as prescribed like a prescription drug.
Fortunately, for our patient we had the antidote and administered it quickly. Fictional or not, I don’t like to contemplate the alternative before lipid rescue existed. He woke up with no memory of what happened. Orthopedics repaired the hip fracture in the OR and the patient was discharged uneventfully to rehab for physical therapy. The resident is devastated about the error and harm it caused the patient. You remind him we are all human, despite the heavy weight of expectation to never err, even while learning. He won’t forget what he learned from this case and that knowledge, however hard earned, will benefit future patients. To protect the innocent, this isn’t a real case, but it is based in fact on real poisonings.
A quick word about the history of local anesthetics before we go. Local anesthetics have been used as far back as the Incas. How? Cocoa leaves. The active ingredient, cocaine, is a great topical anesthetic, so much so head and neck surgeons used it until very recently for nasal surgery. The utility of coca leaves in this capacity was recognized in Europe in the 1500s, however attempts to bring the leaves from South America failed as they deteriorated on the journey. In 1859, they were successfully transported to Europe and the active ingredient, cocaine was extracted. Medically it was first used to numb the cornea of the eye.
Question 4, the last in today’s podcast. Which person is famously, or infamously, credited with popularizing the medical use of cocaine in the treatise Uber Cocaine?
A. Ignaz Semmelweis
B. Sigmund Freud
C. Albert Schweitzer
D. William Halstead
Post your answers on our Twitter and Instagram feeds both @pickpoison1. Follow and you’ll see the answer when I post it. Remember, never try anything on this podcast at home or anywhere else.
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