Episode 82- “Bad Shrooms”: Part Two: Treatment
Wrapping up the two-part series discussing poisonous mushrooms. This week, we focus on treatment with agents like silibinin.
“‘Bad Shrooms’: Part Two: Treatment”:
– Amatoxins have a low volume of distribution (0.3 L/kg) and are < 1% protein bound. They are excreted in the urine and biliary tract and undergo enterohepatic recirculation for up to 5 days after ingestion
– Multi-dose activated charcoal should be given (0.5 g/kg every 4 hours) and continued until 4 days after ingestion. Renal excretion should be optimized by giving IV fluids to maintain a urine output of 100-200 mL/hr
– Prevention of amatoxin uptake is a major treatment strategy. Silibinin (Legalon SIL) is an extract of the Mediterranean milk thistle. It’s the most potent inhibitor of amatoxin uptake, has the cleanest side-effect profile, and is the most well-studied. It also stimulates RNA polymerase, has antioxidant effects, and increases amatoxin excretion into the bile. It’s given as an IV load of 5 mg/kg then a continuous infusion of 20 mg/kg/day for 6 days or until clinical recovery
– Silibinin isn’t available in the US, but you can get it for emergency compassionate use as an investigational product. First, contact the FDA (301-796-3400 8AM- 4:30 PM on weekdays OR email [email protected]. After 4:30 PM or on weekends, contact the emergency call center at 866-300-4374). Once you do that and get an Expanded Access IND number, complete and email a form to the manufacturer ([email protected] or call 484-754-7500; if you have any questions on the form, contact Marken Customer Service: 484-754-7500 (monitored 24/7)) to start the shipping process
– Less effective alternatives to silibinin include high doses of IV penicillin G (continuous infusion of 300,000 – 1,000,000 units/kg/day (max 40 MU/day)) and ceftazidime (4.5 g IV Q2H)
– IV N-acetylcysteine, cimetidine, and vitamin C 3 g IV daily should also be given
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Hello and welcome to Episode 82 of ER-Rx, a podcast tailored to your clinical needs. I’m your host, Adis Keric, and in Part Two of the “Bad Shrooms” Mini Grand Rounds series, I’ll be talking about treatment options for amatoxin toxicity. If you haven’t heard Episode 81 yet, where I talked about the background of poisonous mushrooms and the toxicokinetics of amatoxin, it would be a great idea to do that before you dive into this episode.
The first thing we should do when we suspect amatoxin toxicity is contact the local poison control center or your tox service. Patients with acute liver failure should be transferred to a liver transplant center, all the while focusing on optimal supportive cares. This includes addressing things that can commonly happen with liver toxicity, like treating hypoglycemia and giving lactulose for hyperammonemia as well as managing things like AKI, sepsis, hepatic encephalopathy, and cerebral edema.
Amatoxins have a low volume of distribution of about 0.3 L/kg and are < 1% protein bound. They are excreted in the urine and biliary tract and they undergo enterohepatic recirculation for up to 5 days after ingestion. So, GI decontamination with multi-dose activated charcoal should be attempted to reduce this recirculation. Activated charcoal is given at a dose of 0.5 g/kg every 4 hours and is typically continued until 4 days after ingestion.
In addition to charcoal, we should optimize renal excretion by giving patients IV fluids to maintain a urine output of 100-200 mL/hr. Also remember that there is no role for hemodialysis since these toxins are not dialyzed out. Remember that I mentioned that amatoxins are delivered to the liver by OATP transporters—well prevention of amatoxin uptake at the cellular level is another major treatment strategy. And this is where a really cool drug comes in. Silibinin, an extract of the Mediterranean milk thistle, is produced by Mylan under the brand name Legalon SIL. It’s the most potent inhibitor of amatoxin uptake, has the cleanest side-effect profile, and is the most well-studied for this indication. It also stimulates RNA polymerase, has antioxidant effects, and increases amatoxin excretion into the bile.
Silibinin is most effective if given within 24 hours of ingestion. It’s given as an IV load of 5 mg/kg then a continuous infusion of 20 mg/kg/day for 6 days or until clinical recovery. The most common side effects are flushing and itching. The kicker is that silibinin isn’t available in the US, but you can get it for emergency compassionate use as an investigational product. If you’re in the US, you can get a hold of it through Expanded Access by contacting the FDA (301-796-3400 8AM- 4:30 PM on weekdays OR email [email protected] After 4:30 PM or on weekends, contact the emergency call center at 866-300-4374.) Once you do that and get an Expanded Access IND number, you have to complete and email a form to the manufacturer ([email protected] or call 484-754-7500; if you have any questions on the form, contact Marken Customer Service: 484-754-7500 (monitored 24/7)). Once you do this, a customer service rep will send you the “Legalon Patient Treatment Plan” for specific instructions on how to administer silibinin. I’ll link all of the contact information for the FDA and the manufacturer to the Show Notes, on the episode transcript, and on the blog at errxpodcast.com should you ever need to use this.
From personal experience, silibinin can take a couple of days to arrive. But in the meantime, super-high doses of IV penicillin G can also inhibit amatoxin uptake- although not as well as silibinin. Penicillin G is given as a continuous infusion of 300,000 – 1,000,000 units/kg/day (max 40 MU/day). If the patient has a real penicillin allergy, we can give IV ceftazidime, again at super high doses, of 4.5 g IV Q2H as an alternative. As you can imagine neither of these two are as safe as silibinin, with their potential side effects of seizures, electrolyte imbalances, interstitial nephritis, and renal tubular damage- especially at these really high doses. And once that silibinin arrives, turn off the penicillin G and discontinue the ceftazidime infusions since they have no role when given in combination with silibinin.
To round out our optimal treatment, we should also give some antioxidants like IV N-acetylcysteine, using the same regimen as that used for acetaminophen toxicity. Other suggested treatments include cimetidine at a dose of 300 mg IV every 8 hours and vitamin C 3 g IV daily. These two have only shown improved outcomes in animal models, but given their safety profile they are still recommended for human intoxications as well.
And finally, as I mentioned earlier, if the poisoning is bad enough and all of these treatments are failing, liver transplantation may be the only thing that will save your patient.
So, to wrap up this series, mushrooms that contain amatoxin are rare, but they are easy to confuse for edible, safe mushrooms. Eating as little as 1-2 mushroom caps can potentially be fatal. Once the amatoxins are absorbed from the intestine, they’re sent to the liver by OATP transporters, and once there, they cause apoptosis of cells by inhibiting RNA polymerase. Treatment is largely supportive; by managing the common syndromes associated with liver failure and by providing IV agents like silibinin and N-acetylcysteine, we can keep mortality rates to < 5%.
As always, thank you so much for your time, and thank you for wanting to learn more about pharmacotherapy. If you have any comments or anything you’d like to add to this episode, please give me a shout out on the @errxpodcast Instagram page, or reach out to me on errxpodcast.com- I’d love to respond to all comments and criticisms.
I also want to take a second to shout out friend-of-the pod and amazing PA resident, Danielle, for her very generous donation on BuyMeACoffee.com- donations like hers keep the podcast running and free for everyone. If you’d like to sponsor an episode, the link to donate is super easy to get to. It’s linked in the bottom of the episode description wherever you get your podcasts, on YouTube, and on the website. I’ll see you next time.