Pill Paradox
Want to know what over the counter drug is lethal to pets? What important toxicology tool was plotted on a cocktail napkin? What’s the medical use of a barbiturate coma? 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 patient survive this podcast? It’s up to you and the choices you make. Our episode today is called the Pill Paradox . Want to know what over the counter drug is lethal to pets? What important toxicology tool was plotted on a cocktail napkin? What’s the medical use of a barbiturate coma? Listen to find out!
The next chart is a 16-year-old girl with a chief complaint of nausea and vomiting. The nursing note says overdose, suicide attempt. A glance at the monitor as you enter the room shows the following vital signs: heart rate 100 beats per minute, respiratory rate 18 breaths per minute, blood pressure 110/60 and oxygen saturation 100% on room air. The nurse holds a thermometer in the teen’s mouth. After a few seconds it beeps, temp 98.0 F or 36.6 C. All completely normal.
The nurse says a friend called 911 after receiving a text from the patient saying goodbye. She also texted she wanted to die and took an overdose. The patient is laying on the bed, lethargic. She opens her eyes to voice but isn’t speaking. Her affect is flat, meaning she's not reacting, positively or negatively, to anything happening around her. Other than the mental status and affect, the rest of her physical exam is normal.
She doesn’t answer any questions, including your questions about what she overdosed on. Hoping for more information, you call the patient's family. They are enroute to the hospital, extremely distraught and have no idea what’s happened.
It’s a mystery case. We have absolutely no information. What now?
This is a fairly common presentation in the emergency department and definitely a common call for toxicologists. Some patients with suicidal ideation don't want to tell you what they did, some are so depressed they’re withdrawn and can barely speak, and others have an altered mental status from the overdose itself, so we're used to caring for these patients without knowing what happened. Fingers crossed, let’s hope we figure it out before something bad happens.
Question number one. Which of the following tests do you want?
a. an EKG
b. Electrolytes
C. an acetaminophen (ie Tylenol or Paracetamol) level
d. an aspirin level
e. a urine drug screen
f. all of the above
Answer: if you answered F. all of the above, I'll give you full credit. I’d order an EKG, basic labs including electrolytes and acetaminophen and aspirin levels. We often order liver function tests along with an acetaminophen level. Toxicologists understand the limitations of urine drug screens and most of us don't order them routinely. However, this is not the case as I've mentioned before, with emergency medicine physicians, psychiatrists, hospitalist, and other consultants, so generally they are ordered.
Why an EKG did I hear you ask? Do we think this is a heart attack? No. The EKG screens for totally different things with an ingestion or overdose. We are screening for interval prolongation. QRS interval prolongation is caused by sodium channel blockade, including TCAs an old category of antidepressants. More commonly these days, we’re looking for QTc prolongation, from potassium channel blockage. If present, it means there’s a risk of a lethal arrhythmia, ventricular fibrillation. See the poisoner’s poison episode for more. If these findings are present, it can direct treatment, risk stratification and help narrow down the exposure.
You’ve ordered the tests. What next? That’s question #2.
A. administer an antidote
B. wait and see what happens
C. admit her to psychiatry
Answer B. Watchful waiting on the cardiac monitor is the best approach. Currently, the patient is awake, with normal vital signs so no immediate intervention is needed. I’d monitor her clinical status while awaiting the lab results. Clearly, she needs psychiatric help, but she’s not medically clear and medical treatment comes first. Once we’ve treated, or at least observed for a period of time until they are out of danger, then psychiatric admission can be considered.
The distraught parents arrive at the bedside. They say she seemed depressed over the past few weeks, was being bullied in school, but hadn’t expressed suicidal thoughts. Yesterday evening, she complained of abdominal pain and vomited several times. This morning, she was a little better, though not well enough to go to school. They were shocked to hear she’d overdosed when the friend’s mom called about the texts.
This is a good time to try to determine potential exposures. Of course, anyone can be exposed to anything, and we toxicologists love unusual and unexpected exposures. That said, common things are common, so it’s useful to find out what medicines are in the house, what toxins are in the garage, etc, to generate a list of possibilities.
The patient doesn’t take any medicines according to the parents. Dad takes blood pressure medicine, metoprolol, a beta blocker. What do you think about this as an antihypertensive overdose? Currently, the blood pressure and heart rate are normal, so no. Of course, patients can overdose and be asymptomatic. They may have taken a small amount and never develop symptoms. Also, it takes time for symptom onset; this is one of the most common questions EM physicians will ask toxicologists, when to expect toxicity. If it’s extended release pills, for example, onset could be delayed by 12 or even 24 hours. Continued observation for development of hypotension or a low heart rate is the best approach to determine if this is what she overdosed on.
Mom takes glipizide for diabetes. The patient’s blood sugar comes back normal, so less likely, though again onset can be delayed.
Per the parents, there are no other prescription drugs in the house. They have vitamins, ibuprofen, brand name Motrin, as well as acetaminophen brand name Tylenol or paracetamol. Multivitamins, rarely cause toxicity in adults. Ibuprofen, also rarely causes toxicity. Massive overdose causes nausea and vomiting with elevated an anion gap due to a metabolite propionic acid. This is a potential, though altered mental status is unlikely. Acetaminophen can cause nausea and vomiting, along with abdominal pain. It’s definitely on the list of potential exposures. We sent a level and are waiting on the results.
The parents deny supplement use. They live in an apartment, no garage with toxic alcohols or pesticides. As far as they know, the patient doesn't use any drugs. Of course, parents might not know about substance use issues. Drugs are often easy to obtain at school. Considering drug of abuse, is this an opioid overdose? No, her breathing is fine, and her pupils are normal. Benzodiazepines, like Xanax can be misused. Benzos are absolutely on my list of potential exposures because they cause altered mental status and sedation. Cannabis is common in this age group, but this isn't a marijuana overdose, and isn’t a common toxin in suicidal ingestions anyway. Amphetamines such as Adderall are easy to find in schools. Cocaine and methamphetamine are considerations. Is this a sympathomimetic overdose? Again, no. If you remember, they cause high blood pressure, high heart rate and sweatiness.
You return to your desk to check on her results. The labs come back with an abnormal drug level. We sent an aspirin level and an acetaminophen level. Which one do you think is elevated?
A. Aspirin
B. Acetaminophen
Answer b. The acetaminophen level. How do we know it’s not an aspirin overdose? Her vital signs. Aspirin overdoses cause acidosis. To compensate, the body breaths rapidly, on way of eliminating acids. See episode the Therapeutic Misadventures for more. In adults, it’s almost impossible to have a significant, acute aspirin overdose with normal vital signs.
Acetaminophen, brand name Tylenol in the US. and Paracetamol outside of the US, brand name Panadol is one of the most common overdoses we treat. 60 million people per week take acetaminophen in the US alone. Overdoses, both intentional and unintentional, account for 56,000 ED visits in the US, 2,600 hospitalization and 500 deaths per year. It’s the number one cause of liver transplants in the US and number 2 worldwide. This is the paradox. Acetaminophen is one of the safest drugs we have, in therapeutic doses. In overdose, it’s one of the most dangerous.
Her acetaminophen level is 300 mg/dL and her liver function tests are 10,000 ALT and AST. Question 3. What is the best treatment at this time?
a. NAC or n-acetylcysteine
b. barbiturate coma
C. liver transplant
Answer: A. NAC is the antidote for acetaminophen toxicity. She needs this immediately. She may need a liver transplant, but that’s not the first step. Barb comas can be used to treat cerebral edema, or brain swelling, more on this in a bit.
Let’s talk about acetaminophen overdoses first, then come back around to the antidote. As I said APAP- why do we call it APAP in medicine because of its chemical name N-acetyl-para-aminophenol. Is an extremely common overdose in the US and Europe. Acetaminophen is classified as an antipyretic and analgesic, meaning it treats fever and pain. It has minimal anti-inflammatory effect. Surprising, exactly how it works is clear. Generally, it inhibits cyclooxygenase and prostaglandins, parts of the pathways mediating pain and fever.
In therapeutic doses, APAP has very little toxicity. At higher doses however, it overwhelms the liver's capacity to safely metabolize the drug. These secondary elimination pathways result in toxic metabolites including one called NAPQI. NAPQI is hepatotoxic, damaging and killing liver cells. Patients with low glutathione stores, chronic alcohol users, malnourished patients and those with AIDS, are at higher risk of toxicity because they have reduced capacity for safe metabolism.
APAP toxicity develops over 4 stages. Patients in stage 1 may have nausea, vomiting and or they may be completely asymptomatic. Stage 2 occurs within the first 24 hours and is characterized by liver injury with rising liver function tests. Stage 3 is hepatic failure, occurring within 72-96 hours. Patients can have renal failure, bleeding, low blood pressure, acidosis and encephalopathy, or an altered mental status. Interestingly, bleeding is common with other causes of hepatic failure, because the liver makes the blood clotting factors, however it’s relatively rare in APAP toxicity. Death occurs during this stage, between days 3-5. Patients die from ARDS, sepsis, or commonly cerebral edema, brain swelling. More on this in a minute. Bad news, our patient is in Stage 3. Stage 4 is recovery. One of the amazing things about APAP toxicity, if you survive, your liver completely regenerates and returns to normal with no residual damage. If you survive, your liver will be 100% back to normal.
The antidote, N-acetylcysteine, or NAC for short, protects the liver several ways. It limits NAPQI formation and helps detoxify it. It also has a general protective effect in liver failure, the mechanism of which is well established, but not well understood. In fact, we use NAC for other types of liver failure, despite a lack of proven benefit, in the hopes it will work for things like mushroom poisoning.
NAC is very safe with few side effects. The main adverse effect is anaphylactoid reactions, histamine release causing rash, itching and fever. It looks like, but isn’t a true allergic reaction. The symptoms resolve with slowing or briefly stopping the infusion. You can buy oral NAC over the counter from supplement stores. This brings up the route of administration. It can be given orally or IV. They both work equally well. Originally it was available only by mouth and the protocol was every 4 hours for 72 hours total. It skinks like rotten eggs. Just imagine trying to get somebody who's already suicidal, to drink a foul-smelling concoction every 4 hours for three days. These days, we mostly use the IV preparation. If you start NAC within 8 hours of the overdose it’s essentially 100% effective. Pretty amazing. The mortality after an acetaminophen overdose is only 0.5%, thanks to NAC and liver transplants.
Our patient is critically ill. I’m worried she’s about to become one of those who do die.
Did we start the NAC in time? Let’s talk more about her case, specifically. She has a high acetaminophen level and high liver function tests, both at the same time. Additionally, the parents said the symptoms started yesterday, meaning this is a delayed presentation. None of these are good prognosticators.
One of the best tools we have in toxicology is the Rumack-Matthew nomogram, used to determine if an APAP level is toxic. It’s a graph where you plot the level against the time of ingestion. If the level is above the line, you treat with NAC, if below you don’t have to worry about significant liver damage and no treatment is necessary. I’m told Barry Rumack and Henry Matthew drew the first graph on a cocktail napkin. The original line they drew started at an APAP level of 200 mg/dL at 4 hours, however the FDA wanted to introduce a margin of safety, so they lowered it by 25% and in the US we use a cut off of 150 mg/dL at 4 hours as the treatment line. Different countries have different protocols, some using the 200 line, others lowered further to 100 mg/dL.
Given that our patient has a level of 300 at least 12 hours after ingestion, I’m very worried she took a massive overdose. She didn’t arrive at the hospital within the 8-hour window, but NAC is still critical. Studies have shown NAC reduces the need for vasopressors, medicines for dangerously low blood pressure, and it reduces cerebral edema.
You order an infusion of NAC and go back into the room to talk to the parents. Mom’s shaking the patient who’s not responding at all. This is not good. You intubate her and put her on a ventilator.
What happened? Most likely cerebral edema. You order a CT scan on the way up to the ICU. The CT results are just as we feared. Instead of a normal brain with ridges and indentations, sulci and gyri, her brain looks smooth, basically swollen. The radiologist reports signs of brain herniation. The inside of your skull is a fixed space, if your brain swells to much it starts to become squished with loss of the normal spaces inside, called herniation. The ICU team consults neurosurgery for recommendations to try to reduce this. Unfortunately many patients die of cerebral edema after APAP overdose, despite treatment. Barbiturate coma, rarely used these days, are an option to try to reduce the intracranial pressure.
Her life is hanging in the balance. What else can we do? New treatments are emerging for massive APAP overdoses. Data on efficacy is limited so let’s discuss the risks and benefits. First, there’s evidence higher than standard doses of NAC maybe helpful. The downside? Basically none, so let’s increase the dose of the infusion. Second, a different antidote may be useful, the antidote for toxic alcohol poisoning. Remember what it is? Fomepizole has shown some promise, again it essentially has no side effects, so let’s give it as well. Third, dialysis removes some APAP. Dialysis has significant side effects, you need a large catheter, there’s a risk of infection, it’s not a benign procedure. However, she’s dying, so the benefits outweigh the risks. I’d call nephrology. The specific indications for these therapies are massive APAP overdose. This is variously defined as levels from 300 – 900, cerebral edema, hepatic failure. At this point, there’s no question our patient took a massive APAP overdose.
The intensivist calls the transplant teams to determine if she’s a candidate. Question 4. Patients with acetaminophen overdose do better after transplant then patients with other causes of liver failure.
a. True
b. False
Answer: B false. Transplantation after APAP overdose is a very tricky issue. Liver transplant in general is a tricky issue. We don’t have enough organs, so as a result, there’s a narrow window where the patient is sick enough to qualify for transplant, but not too sick to survive the operation itself.
Overdose patients are often much healthier than other patients with liver failure, for example from cirrhosis due to alcohol or hepatitis. They are often younger in age with fewer comorbidities. Despite this, they often have worse outcomes.
Why? Most patients undergoing transplant have undergone psychiatric screening to qualify. Patients with significant barriers, for example concern about being able to take rejection medicine regularly, are not candidates for transplant. Patients with overdoses are not screened prior. You don’t need me to tell you patients with suicidal ideation aren’t in top psychiatric shape. Some are not happy to wake up, alive, with their health now much worse than it was before they overdosed, committed to a lifetime of daily medicine use. Medicines with potentially serious side effects themselves. The facts: about 12% of post-transplant patients attempt suicide again or intentionally stop taking their anti-rejection medicines causing life-threatening consequences. Patients with liver transplants have overdosed on APAP again. These facts have been used to justify not transplanting, however transplants are lifesaving. Sick patients who weren’t transplanted after acetaminophen overdoses have survival rates of 25 to 40%. With transplant, survival rates are 69 to 83% immediately after surgery, and in 3 to 5-years 50 to 66%.
Not all overdoses are intentional. Accidental overdoses are also common. Unintentional overdoses happen when patients are confused by doses, timing, or ingredients in medicines they’re taking. For example, Percocet and Vicodin are both opioid acetaminophen combinations. Patients who take extra doses for pain or who are misusing it often don’t know they might be taking too much APAP. This became a big issue during the opioid crisis, many misusers of opioids developed APAP toxicity, liver failure and need liver transplants. To address it in 2014, the FDA mandated combination products can contain a max 325mg of APAP.
Question # 5. True or False. APAP is contraindicated after a liver transplant or in patients with cirrhosis?
A. True
B. False
Answer: False. Patients often tell me they’ve been told not to take APAP, but it is safe up to a maximum dose of 2-3 grams per day.
APAP was rarely used in the US until the 1980s when the associate between aspirin and Reye’s syndrome in children was discovered. Acetaminophen became a safer alternative. That is until Sept 1982. Some of you may remember the tragic Tylenol murders in Chicago when seven people died after taking Tylenol contaminated with cyanide. The murders remain unsolved to this day. Johnson and Johnson introduced tamper-proof packaging to prevent poisoning which soon became standard for all over-the-counter medicines.
Management of APAP overdoses is often much more nuanced and much complicated than plotting points on the nomogram. For example, the time of ingestion is often unknown, rendering the nomogram useless, extended-release preparations can’t be plotted on the nomogram, either. Acetaminophen toxicity is a huge topic covered in great detail during toxicology fellowships and the finer points of management are debated even amongst the most famous toxicologists. In the interest of time, I’ve focused on a serious, but classic presentation. If you are concerned you’ve taken too much acetaminophen, have a patient who’s taken too much, or otherwise need help, the best approach is to call the poison center at 1800-222-1222 or consult your local toxicologist for help.
Back to our patient. She’s listed for transplant rising higher on the list as she continues to worsen despite aggressive management. Her liver fails, her brain swelling doesn’t respond to any neurosurgical recommendations. No liver matches are found. The ICU team does what they can to prepare the family for the likelihood she won’t survive the overdose. After 2 more days, against the odds, she slowly begins to improve. The brain swelling resolves and she wakes up. Her family is overjoyed she’s alive, hopefully with some psychiatric treatment she’ll feel the same. 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.
One last interesting fact before we go. What if your dog or cat gets a fever? Can you treat with acetaminophen? Interestingly no. Tylenol is extremely lethal to cats as they do not have the enzyme to metabolize it. It is slightly less, but still very significantly, toxic in dogs. Bringing us to our last question in today's podcast. Acetaminophen has been used as a lethal bait for what animal?
A. Rats
B. Snakes
C. Toads
D. Africanized honeybees
Follow the Twitter and Instagram feeds both @pickpoison1 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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