The Poison Lab: Recent Episodes

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Ryan on others shows

• Ryan on "22 at the Lips"

• Ryan on "Continuing Studies"

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In this exciting live episode from the 2024 North American Congress of Clinical Toxicology (NACCT) in Denver, Ryan dives into 12 of the most impactful research abstracts presented at the conference directly with the authors themselves. Covering a wide range of toxicology topics—from the NACSTOP2 trial on acetaminophen overdose, ECG intervals, cannabis toxicity in young children, and more—each guest breaks down their study’s findings and clinical relevance. If you missed the conference or want a deeper understanding of the year's most important toxicology research, this episode is for you. Check the show notes for links to the published abstracts, the full list of studies discussed, and time stamps for where you can find those studies.

Link to published abstract manuscript

Abstracts

• 07:48-Abstract #1. The NACSTOP2 trial: a multi-center randomized controlled trial investigating the early cessation of n-acetylcysteine in acetaminophen overdose
  • Guest- Dr. Anslem Wong, MD, PhD
• 21:33- Abstract #36. ECG intervals: does one size really fit all?
  • Guest- Dr. Caitlin Roake, MD, PhD
• 25:41- Abstract #85. Do abnormal electrocardiographic intervals predict death in poisoned patients older than 65 years?
  • Guest- Dr. Michael Chary, MD
• 30:06- Abstract #61. Minimum tetrahydrocannabinol dose that produces severe symptoms in children <6 years old with
• cannabis edible ingestions
  • Guest- Dr. Keahi Horowitz, MD
• 36:25- Abstract #114. Frequency and severity of cannabis toxicity before and after legislative change to increase cannabis edible package size
  • Guest- Dr. Robert Hendrickson, MD
• 38:24- Abstract #101. Quantification of acetaminophen line-crossers in the setting o f overdose with delayed gastric absorption
  • Guest- Dr. Jamie Sterr, PharmD
• 41:41- Abstract #175. Cause for pause: bradycardia induced by transdermal rivastigmine in anticholinergic delirium
  • Guest- Dr. Santiago Batista Minaya, MD
• 46:21- Abstract #199. Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) Syndrome with poor neurological outcome in the setting of suspected opioid use
  • Guest- Jack Yang and Dr. Avery Michienzi, DO
• 49:49- 191. Severity scores for caustic injury: Zargar they even used?
  • Guest- Dr. Amar Chakrabortya, MD
• 53:!2- Abstract #9. Disparity in immune-mediated reactions to Crotalidae polyvalent immune fab (ovine) and Crotalidae immune F(ab’)2 [equine] in alpha-gal endemic regions and alpha-gal sensitized adults
  • Guest- Dr. Ari Filip, MD
• 59:10- Abstract # 26. Acute propranolol overdose and dose thresholds of severe toxicity
  • Guest- Dr. Katherine Isoardi, MBBS
• 1:06:05- 28. Risk of serotonin toxicity following acute lamotrigine overdose
  • Guest- Dr. Angela Chiew, MBBS, PhD (Introduction at 1:00:00)

• 1:12:36- Interview with AACT President Elect

  • Guest- Dr. Jillian Theobald, MD, PhD

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In this episode the poison lab hosts scientific discourse . Three listeners (Dr. Michael Mullins, Dr. Donna Seger, and Dr. Leon Gussow) write in their critiques surrounding specific recommendations and language used with the AHA 2023 Management of Poisoning Cardiac Arrest or Life-Threatening Toxicity guidelines. Lead author of the guidelines Dr. Eric Lavonas then responds to and addresses their points with counterpoints or appraisals. Tune in and draw your own conclusions!

• Link to guidelines

• Link to high yield review

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Have a burning question you have always wanted to ask a toxicologist? What are tips for managing an anticholinergic overdose? What is the deadliest poison? Why are they called lead pencils if there is no lead?! Send your questions in to toxtalk1@gmail.com to take part in a future episode! (If you would like to be anonymous simply state it in the email)

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In this episode Ryan is joined by two expert guests to help read listener guesses for the cause of this poisoning murder and shed light on the toxin involved in the case, which puzzled medicolegal investigators. Ryan is joined by Dr. Dan McCabe, MD (emergency medicine physician, medical toxicologist, medical director of Iowa poison center) and Dr. Crissy Lawson PharmD (emergency medicine pharmacist).

• SPOLIER ALERT
  • Mystery case from the show
  • Review Paper from Dr's Lawson, McCabe, and Feldman (PMID: 38613376)
• Toxo's show note references
  1. TV special about Mary Yoder colchicine murder
  2. Colchicine potential arrhythmic effects
  3. Go fund me for Dr. Betty Bowman

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In this bonus episode Ryan highlights some of the great episodes done in 2023 and compiles ALL of the stump the toxicologist segments from 2023 into one easy to consume episode. Test your toxicology differential skills with more than six poisoning cases. Check out the actual episodes for more information in the show notes on each of the poisonings.

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Do you think you know the cause of these symptoms? Send your guesses to toxtalk1@gmail.com to take part in the next episode

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A quick update to share some other shows Ryan has been on in the last few weeks! Check the show notes for links to each episode!

• Ryan on "The Larry Meiller Show" discussing delta cannabanoids
  • Link to stream
  • Link to download
• Ryan on EMS2020 talking prehospital overdose
  • Link to episode
  • Show homepage

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In this episode Ryan interviews Dr. Alex Krotulski PhD from the Center for Forensic Science Research and Education. Together take a look at trends in novel opioids, benzodiazepines, stimulants, hallucinogens, synthetic cannabinoids, and "hemp products" that are showing up in your patients, drug products, and fatal overdoses. The conversation takes places around the Center for Forensic Science Research and Education quarterly report on Novel Psychoactive Substances found in patients and drug products.

The episode starts with a discussion of the novel benzodiazepines market, highlighting bromazolam and how long it may remain in the market. Then they discuss the opioids highlighting where we are seeing carfentanil, what is happening with Para Fluorofentanyl, and other super potent opioids emergening (such as N -pyrrolidino etonitazene). After a quick discussion of synthetic cathinone's and PCP/ketamine derivatives they jump to synthetic cannabinoids, examining the history of brodifacoum contamination and how regulation has led to market changes.

1. Resources
   1. https://www.cfsre.org/
   2. Quarterly report discussed on this episode
   3. More on Dr. Krotulski
   4. Poster from Dr. Kortulksi on naming conventions for NPS
2. Time stamps to jump to any portion of the episode you want to revisit
   1. Introduction-5:00-32:50
      • 06:30-25:16- Discussion CSFRE mission, history of NPS reports, and other available reports
      • 25:14- "Miscellaneous drugs: Furanyl UF17, medetomidine"
      • 28:15- Difference between GC/MS and LCqTOF
   2. Novel Benzodiazepines- 32:50
   3. Novel Opioids-43:00
   4. Stimulants and hallucinogens- 1:01:43
   5. Synthetic cannabinoids- 1:07:40
   6. Novel psychedelics markets, hemp products, phenibut, tianeptine, and kratom-1:25:12

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Dr. Ann Arens, MD an emergency medicine physician and medical toxicologist with Oschner Medical center in New Orleans, LA joins the show to educate us on some HOT toxins, solve toxic cases, and opine on the philosophical and existential reasons drugs even exist. Tune in for a fantastic discussion with Dr. Arens and to hear the answer to our mystery case.

• Case report for mystery case
• Review paper cited by Dr. Arens
• Interview with DNP user by Chubby Emu
• Case 1
  • Some also contain CALCIUM NITRATE and can cause methemoglobinemia
• Case 2
• Case 3

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Do you think you know the cause of these symptoms? Send your guesses to toxtalk1@gmail.com to take part in episode 18

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In this episode Ryan is joined by a guest panel (Dr. Grant Comstock MD, Dr. Joshua Trebach MD, Dr. Emily Kiernan DO, and Dr Frank Paloucek PharmD, DABAT) to review nine of the most interesting or clinically impactful research abstracts that were presented at the 2023 North American Congress of Clinical Toxicology (NACCT) in Montreal Canada. If you didn't get a chance to read all 363 research abstracts from some of Toxicology's best and brightest this year, tune in for a high yield review as well as clinical a break down of the studies and their relevance from the expert panel.

Check the show notes for a link to the published abstracts and the list of all studies discussed in the show

Abstracts available here

• 10:40- Abstract 1 (PDF #225) Methotrexate toxicity in the setting of therapeutic error, a multicenter retrospective review
  • Lead author: Andrew Chambers
• 24:12- Abstract #2 (PDF #251) Oleander seeds in candlenut weight loss product strike again
  • Lead author: Masha Yemets
• 31:16- Abstract #3 (PDF #2) Efficacy of sodium tetrathionate when administered intramuscularly for the treatment of acute oral cyanide toxicity in a swine model (Sus scrofa)
  • Lead author: Brooke Lajeunesse
• 39:45- Abstract #4 (PDF #10) Is HOUR enough after out-of hospital naloxone for opioid overdose? Prospective preliminary data from real-world implementation of the modified St. Paul’s early discharge rule
  • Lead author: Stephen Douglas
• 49:05- Abstract #5- Poster titles at NACCT 2013–2022: is NACCT experiencing a pun-demic?
  • Lead author: Dayne Laskey
• 52:40- Rivastigmine discussion
  • Lead author: none
• 58:40- Abstract #6 (PDF #5) Randomized controlled trial of ANEB-001 as an antidote for acute cannabinoid intoxication in healthy adults
  • Lead author: Andrew Monte
• 1:08:00- Abstract #7 (PDF#216) Successful use of expired physostigmine to treat anticholinergic delirium in a pediatric patient
  • Lead author: Bryan Hayes
• 01:20:00- Abstract #8 (PDF #202) Enough negativity? Clinically significant salicylism with first detectable concentration twelve hours )post-ingestion
  • Lead author: Stacey Bangh
• 01:25:24 - Abstract #9 (PDF #267) High sensitivity troponin is frequently elevated after carbon monoxide exposure
  • Lead author: Abdullatif Aloumi

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In this episode, Ryan dives into cutting-edge research on the treatment of acetaminophen (APAP) overdose, featuring interviews with authors of several key abstracts from the North American Congress of Clinical Toxicology (NACCT) in Montreal Canada (Abstracts and posters available in the show notes). We get first looks insights into research evaluating the impact of fomepizole high risk acetaminophen overdose, as well as who gets fomepizole for acetaminophen overdose and dies. Then we evaluate the effectiveness of standard N-acetylcysteine (NAC) treatment in high risk patients and high dose NAC in high risk patients. Join us for an insightful discussion on these advancements that are reshaping the management of APAP toxicity. Guests include Dr. Masha Yemets PharmD, Dr. Molly Stott PharmD, Dr. Alexandru Ulici PharmD, and Dr. Michael Moss MD.

• Link to published abstracts
  • (First guest) Abstract #126 Characterizing fomepizole use in acetaminophen deaths reported to US poison centers- Dr. Yemets
  • (Second guest) Abstract #125 Clinical impact of fomepizole as an adjunct therapy in massive acetaminophen overdose- Dr. Stott
  • (Third guest) Abstract #131 Comparison of low-risk and high risk acetaminophen ingestions using the standard prescott protocol of intravenous N-acetylcysteine- Dr. Ulici
  • (Fourth guest) Abstract #130 High-risk acetaminophen overdose outcomes after treatment with standard dose vs. increased dose N-acetylcysteine- Dr. Moss
• Other studies discussed regarding NAC dosing
  • ATOM 2 Angela Chiew
  • Outcomes of massive APAP treated with regular NAC (Virginia group, lead author Dr. Downes)

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In this episode, Ryan sits down with Dr. Eric Lavonas MD, a seasoned EM resuscitation guideline writer, emergency medicine physician, medical toxicologist, and lead author of the latest update to the American Heart Association's guidelines for the management of cardiac arrest and life-threatening toxicity due to poisoning. They have an in-depth discussion as they explore the key aspects of the 2023 AHA treatment recommendations and the rationale behind each decision point. A great review to discover how to effectively apply these guidelines in real-world scenarios and find out what knowledge gaps exist in the realm of toxin resuscitation. Be sure to also check out the accompanying mini-episode for a high-yield review of the major treatment recommendations.

• Link to guidelines
• Link to high yield review
• Cyanide paper mentioned in the show
• Adult calcium channel blocker toxicity guidelines

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In this episode Ryan does a high yield "just the facts" break down of the recently released "2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Tune in to learn about the most recent treatment recommendations made by AHA via a panel of toxicology experts. This was released alongside a full interview with the lead author Dr. Eric Lavonas MD. Be sure to check out the full interview to hear it straight from the source! (link in show notes).

• Link to guidelines
• Link to full in depth interview

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In this enlightening episode, Ryan engages in a deep conversation with Dr. Paul Hutson, PharmD, a renowned researcher in the field of psilocybin and director of the Transdisciplinary Center for Research in Psychoactive Substances at the University of Wisconsin Madison. Dr. Hutson shares his extensive knowledge and insights into the promising role of psilocybin in the treatment of depression and substance use disorder.

Throughout the discussion, they delve into the research that supports the use of psilocybin in medical therapy, shedding light on the rigorous processes involved in conducting such studies. Dr. Hutson elucidates the efficacy and safety findings that have emerged from his and others research, offering listeners a glimpse into the potential future of psilocybin in mainstream medical practices. Listeners will gain a deeper understanding of the meticulous approach to research that ensures both safety and effectiveness. Dr. Hutson shares firsthand experiences and observations, providing a rich and detailed perspective on the current state of psilocybin research. Moreover, the conversation ventures into the practical aspects of integrating psilocybin into contemporary medical practices, discussing the potential frameworks and guidelines that would govern its use. They explore what the future might hold for patients and practitioners alike as they stand on the cusp of a revolutionary shift in mental health treatment.

Whether you're a healthcare professional keen on the latest developments in medical research or someone interested in the evolving landscape of mental health treatment, this episode promises to be a rich source of information and insight. Tune in to be informed and to foster a deeper understanding of the promising horizon that psilocybin research is unveiling in the medical community.

• Biography for Dr. Paul Hutson PharmD
• Transdisciplinary Center for Research in Psychoactive Substances
• Dr Hutson's Publications
  • Single Dose Psilocybin for Major Depression- JAMA 2023
  • Psilocybin and QTc in healthy volunteers
  • Meta-Analysis of research supporting Psilocybin use in anxiety and depression
  • Pharmacokinetics of Psilocybin
  • Subjective effects of high dose Psilocybin
• Other referenced studies
  • Single dose psilocybin for treatment resistant depression
  • Psilocybin for alcohol use disorder
  • Psilocybin for For tobacco cessation

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New Art and New Tox Trinkets. If you want to share your tox joy in the real world, find some trinkets here: https://www.etsy.com/shop/thepoisonlab

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• Mini episode- High-yield over view of Management of Acetaminophen Poisoning in the US and Canada Consensus Statement

In this Ryan sits down with Dr. Richard Dart MD, PhD. He is the lead author of the recently released "Management of Acetaminophen Poisoning in the US and Canada Consensus Statement" from the American Academy of Clinical Toxicology, American College of Medical Toxicology, Americans Poisons Centers, and the Canadian Association of Poison Centers. Listen to be informed on the most recent treatment recommendations. They dive in to the definitions established by the guideline and notable treatment recommendations, dissecting the ratinonale for each desiscion point and how to apply the guidelines. A mini episode was released along side this episode that is a high yield review of major treatment recommendations and definitions estabilished by the consensus statement.

Links :

• Mini episode- High-yield over view of Management of Acetaminophen Poisoning in the US and Canada Consensus Statement
• Guidelines https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808062

Definitions made by the guideline

• Acute ingestion
  • Any overdose taken with 24 hours period
    • Overdose "dose" not defined

      • 7.5 g in 24 h was criteria for Rumack Matthew nomogram

      • Consensus statement
        • Adult overdose at 10g/d or 200 mg/kg/d in <24 hours= potentially toxic
        • Pediatric <6 year at 150 mg/kg/d in <24 h = potentially toxic
• Repeated Supra Therapeutic Ingestion (RSTI)
  • Overdose "dose"
    • Repeated dosing totaling
      • 6g/d or 150 mg/kg/day x 24-48 h = potential toxic
      • 4g/d or 100 mg/kg/day x >48 h = potential toxic (Recognize this means some people could be toxic at therapeutic dosing, but if they do not have symptoms not likely)
• High risk ingestion
  • Reported dose >30 grams OR
  • [APAP] 2 x Rummack-Matthew nomogram treatment line
• NAC stopping criteria
  • APAP<10
  • INR<2
  • AST/ALT Normal for patient or decreased by 25-50%
  • Patient clinically well

Notable treatment recommendations

• RSTI
  • If patient has history of RSTI (>6 g x 24-48 h, >4 g x >48 hours) AND signs of APAP toxicity (vomiting, RUQ abd pain, AMS)
    • Treat if APAP >20 ug/ml OR AST/ALT elevated
• Acute
  • Non-detectable [APAP] between 2 and 4 hours excludes ingestion
  • Give SDAC w/in 4 hours (something I’ve been a proponent of since ATOM2)
• Treat
• Start treatment with NAC if unable to plot on nomogram by 8 hours
• NAC dose
  • “Higher dose” NAC (undefined) for high risk ingestion
  • Minimum NAC regimen should include 300 mg/kg orally or within 20-24 hours
  • CAP NAC dose at 100 kg (this was known with PO, but IV there was always some question since it delivers less overall)
• Unique scenarios
  • Line crossers
    • APAP with anticholinergic or opioid
      • If 1st concentration below treatment line repeat in 4-6 hours
    • APAP Extended release
      • If 1st concentration below treatment line @ 4-12 hours, repeat in 4-6 hours
  • Dialysis-
    • Dialyze If APAP >900 w/ AMS or acidosis.
    • NAC IV rate during HD 12.5 mg/kg/hr minimum. No dose change for PO (not new but good reminders)
• Consult liver transplant for rapid AST/ALT inc w/ coagulopathy, AMS, or mulistytem organ failure
• The addition of fomepizole to acetylcysteine in the treatment of serious acetaminophen ingestions has been proposed. The panel concluded that the data available did not support a standard recommendation. As for any complicated or serious acetaminophen poisoning, a PC or clinical toxicologist should be consulted.

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This episode is a a high yield "just the facts" break down of the recently released "Management of Acetaminophen Poisoning in the US and Canada Consensus Statement" from the American Academy of Clinical Toxicology, American College of Medical Toxicology, Americans Poisons Centers, and the Canadian Association of Poison Centers. Listen to be informed on the most recent treatment recommendations. This was released alongside a full interview with the consensus statement corresponding author Dr. Richard Dart MD, PhD. Be sure to check out the full interview to hear it straight from the source! (link in show notes).

Link to the guidelines:

• Full interview with consensus statement author Dr. Richard Dart
• https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808062

Definitions made by the guideline

• Acute ingestion

  • 7.5 g in 24 h per Rummack Matthew initial studies

  • 10 g/d or 200 mg/kg/day in <24 h also suggested
• Repeated Supra Therapeutic Ingestion (RSTI)
  • Repeated dosing totaling
  • 10g or 200 mg/kg in 24 hour
  • 6g/d or 150 mg/kg/day x 48 h
  • 4g/d or 100 mg/kg/day x >48 h
• High risk ingestion
  • Reported dose >30 grams OR
  • [APAP] 2 x Rummack-Matthew nomogram treatment line
• NAC stopping criteria
  • APAP<10
  • INR<2
  • AST/ALT Normal for patient or decreased by 25-50%
  • Patient clinically well

Notable treatment recommendations

• RSTI
  • If patient has history of RSTI (>6 g x 24-48 h, >4 g x >48 hours) AND signs of APAP toxicity (vomiting, RUQ abd pain, AMS)
    • Treat if APAP >20 ug/ml OR AST/ALT elevated
• Acute
  • Non-detectable [APAP] between 2 and 4 hours excludes ingestion
  • Give SDAC w/in 4 hours (something I’ve been a proponent of since ATOM2)
• Start treatment with NAC if unable to plot on nomogram by 8 hours
• NAC dose
  • “Higher dose” NAC (undefined) for high risk ingestion
  • Minimum NAC regimen should include 300 mg/kg orally or within 20-24 hours
  • CAP NAC dose at 100 kg (this was known with PO, but IV there was always some question since it delivers less overall)
• Unique scenarios
  • Line crossers
    • APAP with anticholinergic or opioid
      • If 1st concentration below treatment line repeat in 4-6 hours
    • APAP Extended release
      • If 1st concentration below treatment line @ 4-12 hours, repeat in 4-6 hours
  • Dialysis-
    • Dialyze If APAP >900 w/ AMS or acidosis.
    • NAC IV rate during HD 12.5 mg/kg/hr minimum. No dose change for PO (not new but good reminders)
• Consult liver transplant for rapid AST/ALT inc w/ coagulopathy, AMS, or mulistytem organ failure
• The addition of fomepizole to acetylcysteine in the treatment of serious acetaminophen ingestions has been proposed. The panel concluded that the data available did not support a standard recommendation. As for any complicated or serious acetaminophen poisoning, a PC or clinical toxicologist should be consulted.

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• Introduction
  • Chisolm lead papers
  • Tylenol murders suspect dies
  • Franks book
  • Toxikon fellowship
• Stump the toxicologist
  • Case 1
    • CDC article
    • NEJM Article
  • Case 2
    • A review paper written by the Frank Paloucek himself on toxin #2
  • Case 3
    • Case report
    • Case where toxin was found in stomach on autopsy published by colleagues Dr. Amy Zosel and Dr. Matt Stanton
  • Case 4
    • A very SIMILAR case to case 4

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• 00:00-19:00 Introduction to brain death guidelines
• 19:00-28:00 Introduction to limitations in guidelines regarding overdose
• 28:30-38:00 Interview with ACMT Position statement author
• 39:00- End- Interview with Bupropion brain death mimic authors and summary

Links references in show

• American Academy of Neurology Bran death guidance
• ACMT Position statement on brain death in overdose
• Brain death mimics with cerebral edema
  • Case report of “hypoxic patient with diffuses cerebral edema” who recovered in 48 hour
  • Carbamazepine with diffuse cerebral edema who recovered
• Cases taking >2 months to recover brain stem reflexes
  • https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)07577-3/fulltext
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543058/
• Attempts to withdraw care in as little as 48 hours
• Dr. Stranges case report
• Dr. Reyes case report
• Narrative review of brain death mimics
• Introductory cases
  • Caroline Burns- Patient who woke up on operating table
  • Paul Maturo- Patient woke up in a morgue

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• Dr. Blumenberg' s projects
  • www.ToxicHistory.co
  • Medical vital/imaging simulator
  • Toxicology questions bank (tox runner)
• Things discussed in the intro
  • Mithradata
  • Ohio vinyl chloride disaster
  • Arizona nitric acid spill
  • Ohio metal factory explosion
• Cases
  • Case 1
    • Case 1 triage guidelines
    • Case 1 video demonstration
  • Case 2
    • Full text
  • Case 3
    • Review article
    • Mechanism
  • Case 4
    • Full text
  • Case 5
    • Not the actual case from the show but close enough
• Questions
  • BHO explosions

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1. Bupropion is the #1 antidepressant cause of major (life threatening) reported to U.S. Poison Centers
2. It is difficult to manage due to
   1. Potential for delays seizures
   2. Unique cardiogenic shock in overdose
   3. Potential wide complex arrhythmia refractory to Sodium Bicarbonate
   4. Potential interference with brain death testing
3. Treatment
   1. Decontamination
      1. Aggressive whole bowel irrigation or charcoal may be indicated if large ingestion
   2. Supportive care
      1. Intubation if airway compromised
      2. Benzodiazepine for agitation
      3. Benzodiazepines and GABA-ergic AED's for status epileptics
         1. Tachycardia, tremor, and agitation are risk factor for seizures
         2. Tachycardia may be masked by alpha 2 agonist co ingestions
         3. Seizures may occur 24 hour out
      4. Sodium bicarbonate for wide QRS (it may be refractory)
      5. Inodilators and vasopressors for cardiogenic shock
      6. ECMO for refractory shock or arrhythmia
      7. Awareness that severe bupropion toxicity can mimic brain death
         1. send analytical confirmation of bupropion if possible to rule out confounding
   3. Enhanced elimination
      1. limited options due to protein binding, not routine
   4. Focused antidote
      1. Consider IV fat emulsion if the patient is peri arrest
   5. Observation times
      1. Talk to a toxicolleague about observation times, decontamination, and use of invasive therapies to avoid falling into a trap

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1. This antidepressant is the #1 cause of major (life threatening) effects in overdose reported to U.S. Poison Centers
2. It is difficult to manage due to
   1. Potential for delays seizures
   2. Unique cardiogenic shock in overdose
   3. Potential wide complex arrhythmia refractory to Sodium Bicarbonate
   4. Potential interference with brain death testing
3. Toxicity
   1. It increases dopamine and norepinephrine, it also blocks the gap junction in the cardiac myocyte
      1. Rohr 2004- Gap junction blockade can cause a wide QR
      2. Vink 2004 Connexin 43 is the most important protein for connexon formation and cardiac signal transmission
      3. Callier 2012- Bupropion does not block sodium channels, and does exhibit similar effects on the cardiac action potential as known gap junction
      4. Burnham 2014 Bupropion has an IC50 for connexin 43 >50 uMol, larger than other drugs such as fluoextine and lamotrigine
      5. Shaikh Quereshi 2014 Bupropion interferes with connexin43 production and localization in chicken cardiac myoctes at concentration >50 uMol
4. Effects
   1. Sympathetic toxidrome
   2. Seizures
      1. TL;DR
         1. Your patient can seize 8-24 hours in, usually they have neurologic symptoms and tachycardia before hand
         2. Tachycardia may be masked by coingestions and symptoms may be very delayed
         3. Do not discharge a patient without discussing observation time with a toxicologist or poison center
         4. Do not dismiss tachycardia and anxiety as situational in a bupropion overdose
      2. Shepherd 2004- Seizures in primarily sustained release products
         1. Most seizures had prodromal neuropsychiatric symptoms
      3. Starr 2009- Seizure in XL products.
         1. Tachycardia, tremor, agitation most associated with seizures
         2. Seizure occured as late as 24 hours and 25% occurred after 8 hours
      4. Offerman 2020- Primarily sustained/extended release products
         1. Tachycardia duration, and extent (>120) predicted seizure. (Hypotnesion and neuropsych symptoms also predict)
         2. Late seizure occurred only in those with symptoms on presentation
         3. Those who had cardiac arrest had prehospital seizure= bad sign
      5. Rianprakaisang 2021- ToxIC review of risk factors for seizures
         1. QTc and HR>140 predict seizures
   3. Unique cardiogenic shock in overdose
   4. Potential wide complex arrhythmia refractory to Sodium Bicarbonate
   5. Potential interference with brain death testing
5. Treatment
6. 1. Decontamination 1. Aggressive whole bowel irrigation or charcoal may be indicated if large ingestion
   2. Supportive care
      1. Intubation if airway compromised
      2. Benzodiazepine for agitation
      3. Benzodiazepines and GABA-ergic AED's for status epileptics
         1. Tachycardia, tremor, and agitation are risk factor for seizures
         2. Tachycardia may be masked by alpha 2 agonist co ingestions
         3. Seizures may occur 24 hour out
      4. Sodium bicarbonate for wide QRS (it may be refractory)
      5. Inodilators and vasopressors for cardiogenic shock
      6. ECMO for refractory shock or arrhythmia
      7. Awareness that severe bupropion toxicity can mimic brain death
         1. send analytical confirmation of bupropion if possible to rule out confounding
   3. Enhanced elimination
      1. limited options due to protein binding, not routine
   4. Focused antidote
      1. Consider IV fat emulsion if the patient is peri arrest
   5. Observation times
      1. Talk to a toxicolleague about observation times, decontamination, and use of invasive therapies to avoid falling into a trap
      2. Not all ingestions are made the same

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1. Rohr 2004- Gap junction blockade can cause a wide QRS
2. Vink 2004 Connexin 43 is the most important protein for connexon formation and cardiac signal transmission
3. Callier 2012- Bupropion does not block sodium channels, and does exhibit similar effects on the cardiac action potential as known gap junction
4. Burnham 2014 Bupropion has an IC50 for connexin 43 >50 uMol, larger than other drugs such as fluoextine and lamotrigine
5. Shaikh Quereshi 2014 Bupropion interferes with connexin43 production and localization in chicken cardiac myoctes at concentration >50 uMol

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1. TL;DR
   1. Your patient can seize 8-24 hours in, usually they have neurologic symptoms and tachycardia before hand
   2. Tachycardia may be masked by coingestions and symptoms may be very delayed
   3. Do not discharge a patient without discussing observation time with a toxicologist or poison center
   4. Do not dismiss tachycardia and anxiety as situational in a bupropion overdose
2. Spiller 1994- Review of instant release product overdoses
3. Shepherd 2004- Seizures in primarily sustained release products
   1. Most seizures had prodromal neuropsychiatric symptoms
4. Starr 2009- Seizure in XL products.
   1. Tachycardia, tremor, agitation most associated with seizures
   2. Seizure occured as late as 24 hours and 25% occurred after 8 hours
5. Offerman 2020- Primarily sustained/extended release products
   1. Tachycardia duration, and extent (>120) predicted seizure. (Hypotnesion and neuropsych symptoms also predict)
   2. Late seizure occurred only in those with symptoms on presentation
   3. Those who had cardiac arrest had prehospital seizure= bad sign
6. Rianprakaisang 2021- ToxIC review of risk factors for seizures
   1. QTc and HR>140 predict seizures

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All published abstracts can be found here 

Abstracts

1. Category 1: Amlodipine Vasoplegia
   • Abstract 1: Vasodilation in patients with calcium channel blocker poisoning treated with high dose insulin: a comparison of amlodipine versus non-dihydropyridines
     • Study of HDI on propranolol poisoned pigs
     • Study of Minnesota HDI protocol
   • Abstract 2: Amlodipine anxiety: a 10-year review of amlodipine associated fatalities
   • Abstract 3: Extracorporeal membrane oxygenation utilization for vasoplegic shock due to pediatric toxic ingestions
     • Data of ECMO in poisoning
2. Category 2: Xylazine
   • Abstract 4: “Tranq dope” opioid overdose: clinical outcomes for emergency department patients with illicit opioid overdose adulterated with xylazine
3. Category 3: Case Reports with Terrifying Clinical Implications
   • Abstract 5: Recovery after poly-drug overdose despite blood flow imaging demonstrating no brain perfusion
   • Abstract 6: Challenges in diagnosing an environmental cause of recurrent methemoglobinemia
   • Abstract 7: Acute thiamine deficiency as a complication of insulin euglycemic therapy for an amlodipine overdose
4. Category 4: Comparative evidence, Prognostication, and Triage
   • Abstract 8: Utility of pre four-hour iron concentration in predicting toxicology
   • Abstract 9: Andexanet alfa vs 4-factor prothrombin complex concentrate for intracranial hemorrhage at a level I trauma hospital
5. Category 5: Rapid Review
   • Abstract 10: Fentanyl and fentanyl analogue exposure among emergency personnel and first responders: a systematic review
   • Abstract 11: Significance of falsely low creatinine values in diagnosing massive acetaminophen ingestion
   • Abstract 12: Large dose intentional ciprofloxacin ingestion associated with false-positive urine immunoassay for oxycodone and fentanyl
   • Abstract 13: Don’t make it a double?: a 20- year review of supratherapeutic amlodipine ingestions while on chronic therapy
   • Abstract 14: Evaluation of pediatric lisdexamfetamine exposures reported to a statewide poison control system
   • Abstract 15: An assessment of the reliability of stated quantity in acute acetaminophen overdoses reported to a regional poison center

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Do you think you know the cause of these symptoms? Send your guesses to toxtalk1@gmail.com to take part in episode 18

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• Recent Healthcare poisoning in the news
  • Nurse reportedly feeding children insulin (all information is uncomfirmed) and killing 7 neonates (not all insulin related)
  • Anesthesiologist charged with murder for 2000 mcg fentanyl doses given during care in ICU
  • Diethylene glycol and Ethylene glycol outbreak in Gambia
  • Not talked about in the show but physician spiking liter bags with bupivicaine to try to kill a colleague in 2022

• Cases

  • Case 1

• Case 2 toxins

  • The burden of empty Gatorade bottles on society
• Case 3 toxins
• Case 4 toxins

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• More on St Anthony's fire
• CDC MWR Study documenting increased poison center exposures (Dr. Graves & Dr. Liebelt)
• Phenibut case series from Dr. McCabe
• All published cases of phenibut withdrawal, reported baclofen regimens, clinical outcomes, multimodal therapies
• THEORETICAL UNTESTED Phenibut withdrawal treatment schema (Not tested, not intended as treatment, intended to stimulate discussion and highlight key considerations in managing withdrawal)

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Do you think you know the cause of these symptoms? Send your guesses to toxtalk1@gmail.com to take part in episode 16

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• Case report Ryan Feldman wrote about himself
• Stump the Tox cases
  • Case #1
  • Case #2
    • case series from Dr Jillian Theobald
  • Case #3
  • Case #4
• Ask drugs
  • Fanconi syndrome in expired tetracycline

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• Digoxin kinetics
• Amiodarone overdose
• Post market safety review
• Review of published exposures and severe outcomes from US poison center
• Case from the show

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Send in your guesses to toxtalk1@gmail.com

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Music from Pixabay

• Additional information on toxins from fatal poisoning cases
  • Toxin 1
  • Toxin 2
  • Toxin 3
  • Toxin 4
• Popper article referenced by Dr. Greller

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No episode today. Head here for the live radio show!

Join us next show for Dr. Howard Greller of  Sirius XM Doctor Radio, Dantastic Mr Tox & Howard,  and Tox & Hound

Find the article about the poison lab here 

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Music in this episode from pixabay.com

• Intro
  • Case report of hemolysis after sodium deoxycholate injection
• History
• Epidemiology
  • ASPS stats
  • Florida Unlicensed Activity Unit
  • Cost of surgeon fee for buttock implant 2018
  • Recent new stories
    • Botox and Bubbles grifter
    • Quick bio on cases mentioned in show
• Common injection practices
  • Feminizing body contouring (pumping parties)
  • Synthol muscles
  • Capsule face cosmetics
• Toxicity
  • Infection
    • Self explanatory
  • Filler embolism
    • Review 1, Review 2, Review 3
      • Filler lodges in pulmonary vasculature->clotting, bleeding, inflammation
      • 95% occur within 72 hours
      • Primarily respiratory symptoms (cough/hypoxemia)
      • Chest x ray ground glass opacity
      • Treat with supportive care (oxygen all the way through ECMO) +/- steroids
  • Filler Blindness
    • CRAO from body filler
    • No effective treatment (exception, can use hyaluronidase if filler is hyaluronic acid)
  • Granuloma
    • Inflammatory nodules from prolonged filler exposure
      • May occur months to year after injection
      • Illegal cosmetic= frequently lipogranuloma due to oil being present in many illegal cosmetic
  • Granulomatous hypercalcemia
    • Excess calcitriol production from ganuloma causes hyperCA
    • Can be extremely delayed (up to 28 years)
    • Recurrence up to 45%
    • Treat with standard therapies (fluid, bisphosphonate) + steroids and/or ketoconazole to turn down granuloma CYP27B1 calcitriol production
• Case from the show
  • Some details changed for educational purposes

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Send in your guesses to toxtalk1@gmail.com

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• Research from Dr Farkas
• Additional information on toxins from Fatal poisoning cases
  • Toxin 1
  • Toxin 2
  • Toxin 3
  • Toxin 4
• "Toxicologist vs the internet" segment
  • Cocaethylene review
  • Benzodiazepine urine drug screening - Blog post

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• History
  • Discovery of Ketamine
  • Melamine outbreaks
• Clinical Effects
  • Index cases
  • Survey of Ketamine use prior to symptoms
• Mechanism/Treatment
  • Mechanism/Treatment systematic review
  • Rat models

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What substance could cause these symptoms? Send your guesses to Toxtalk1@gmail.com to participate in episode 10!

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• "Toxicologist vs the internet" segment
  • Everythingisosm.com (Blog post)
  • Biased Mu Receptor ligands
    • Oliceridine mouse studies
  • Opioid hearing loss (Blog post)
  • Opioid hearing loss review
  • Tox pupils  (Blog post)
  • Why tramadol is awful (Blog post)
• Additional information on toxins from Fatal poisoning cases
  • Toxin 1
  • Toxin 2
  • Toxin 3
  • Toxin 4

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• New york times article on delta 8 THC
  • https://www.nytimes.com/2021/02/27/health/marijuana-hemp-delta-8-thc.html
• Studies of delta 8 THC in man
  • Systematic review that summarizes single study
    • https://pubmed.ncbi.nlm.nih.gov/29385080/
  • Actual study
    • (may not be accessible) https://www.karger.com/Article/Abstract/136375
• HPLCS-MS-MS delta 8 testing strategies
  • https://academic.oup.com/jat/advance-article-abstract/doi/10.1093/jat/bkaa184/6018445?redirectedFrom=fulltext testing
• Cannabanoid receptor binding
  • https://pubmed.ncbi.nlm.nih.gov/27398024/

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• Case from the show
  • https://pubmed.ncbi.nlm.nih.gov/22163140/
• Mithradates
  • https://www.wemjournal.org/article/S1080-6032(11)00043-3/pdf
• Case series on mad honey effects
  • https://pubmed.ncbi.nlm.nih.gov/20575670/
• Blog post on sodium channel openers
  • https://emcrit.org/toxhound/ff-plant-sodium-channel-openers/

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• Things from the show!
  • Ketamine for depression, patient experience blog
    • https://humanparts.medium.com/30-years-of-depression-gone-3dffafabc7cf?fbclid=IwAR1gh08Kn3uSczlKbvMH54yjkWILzyA_6O3Y82q4hVqcAr3shozxwegCnmg
  • Fasoracetam
    • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770454/#CR14
  • Kava
    • Hepatic injury- https://pubmed.ncbi.nlm.nih.gov/15114493/
    • Anti anxiety effects- https://pubmed.ncbi.nlm.nih.gov/33207379/
  • Cocaine chest pain
    • Propranolol effects on coronary constriction- https://pubmed.ncbi.nlm.nih.gov/1971166/
    • Labetalol effects on coronary constriction- https://pubmed.ncbi.nlm.nih.gov/8506886/
    • Management of amphetamine compound toxicity-> https://pubmed.ncbi.nlm.nih.gov/25724076/
  • Heavy metals in cakes
    • https://pubmed.ncbi.nlm.nih.gov/18802411/

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Quick review

• Toxic dose
  • Chloroquine  >5g  severe toxicity is expected (toxicity may develop below this)
  • HCQ less well defind
• Clinical effects
  • Seizures (sodium channel blockade)
  • Arrhythmia (sodium channel blockade)
  • Hypotension  (Alpha blockade)
  • Hypokalemia
• Management
  • Activated Charcoal if awake and alert and no risk of emesis
  • Early invasive supportive care based on the following retrospective case control series  https://www.nejm.org/doi/full/10.1056/NEJM198801073180101
    • High dose epinephrine (0.25 mcg/kg/min)
    • Diazepam 1-2 mg/kg over 30 minutes followed by 1-2 mg/kg over 24 hours (seizure prevention)
      • Evidence supports this may be cardio protective as well
    • Early intubation
  • Consultation with poison center recommended 1-800-222-1222

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• Historical perspective on use of cinchona bark powder for malaria
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973170/
• Evolutionarily pressure of malaria on beta thalassemia (sickle sell) traits
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499995/
• Cinchonism
  • Classic toxicities causes by ingestion of quinoline derivatives found in the bark of the cinchona tree
  • Brief review- https://pubmed.ncbi.nlm.nih.gov/32644745/
• Etiology
  • Powdered cinchona bark
    • Used by people to make tonic water, treat restless legs, or viruses
  • Prescription quinoline derivatives may cause cause similar effects
    • Quinine
    • Quinidine
    • Hydroxychloroquine
    • Chloroquine
• Clinical effects
  • Dizzy
  • Flushed
  • Head ache
  • Tinnitus
  • Potential for vision loss
• Laboratory assessment
  • Hypoglycemia
  • Hypokalemia
  • Long QRS
• Treatment
  • Supportive care for ABCs
    • Potential role for epinephrine as preferred pressor from animal data and chloroquine data
  • Correct endocrine/metabolic abnormalities
  • Hypertonic sodium for wide QRS (be careful of worsening hypokalemia)
  • Consider multi dose activated charcoal
• More on toxicity/studies from the episodes
  • Incidence of caridac arryhmias in patients taking quinine alone
    • Padmaja UK, Adhikari P, Periera P. Experience with quinine in falciparum malaria. Indian J Med Sci. 1999 Apr;53(4):153-7. PMID: 10695226.
  • Negative inotropic effects of quinidine
    • Hoffmeister HM, Hepp A, Seipel L. Negative inotropic effect of class-I-antiarrhythmic drugs: comparison of flecainide with disopyramide and quinidine. Eur Heart J. 1987 Oct;8(10):1126-32. doi: 10.1093/oxfordjournals.eurheartj.a062178. PMID: 3119341
  • Occular toxicity, can be permanent
    • Treatment is debated, not clear what is preferred , HBO used often
    • Vision may recover centrally first, than peripheral
    • Vision loss usually delayed from initial symptoms
    • Quinine >15 associated w/ more ocular tox- https://pubmed.ncbi.nlm.nih.gov/3983356/
      • Hall AP, Williams SC, Rajkumar KN, Galloway NR. Quinine induced blindness. Br J Ophthalmol. 1997;81(12):1029. doi:10.1136/bjo.81.12.1029
      • Dyson EH, Proudfoot AT, Prescott LF, Heyworth R. Death and blindness due to overdose of quinine. BMJ 1985; 291:31–3.
  • Otooxicity -A hall mark toxicity of tinnitus appears to be caused by
    • Additionally, vasoconstriction and local prostaglandin inhibition within the organ of Corti contributes to decreased hearing.
    • Microstructural lengthening of the outer hair cells of the cochlea and organ of Corti occurs.
      • Jastreboff PJ, Brennan JF, Sasaki CT. Quinine-induced tinnitus in rats. Arch Otolaryngol Head Neck Surg. 1991 Oct;117(10):1162-6. doi: 10.1001/archotol.1991.01870220110020. PMID: 1910705
      • Jung TT, Rhee CK, Lee CS, Park YS, Choi DC. Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine. Otolaryngol Clin North Am. 1993 Oct;26(5):791-810. PMID: 8233489.
      • Jung TT, Rhee CK, Lee CS, Park YS, Choi DC. Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine. Otolaryngol Clin North Am. 1993 Oct;26(5):791-810. PMID: 8233489.
      • Roche RJ, Silamut K, Pukrittayakamee S, et al. Quinine induces reversible high-tone hearing loss. Br J Clin Pharmacol. 1990;29(6):780-782. doi:10.1111/j.1365-2125.1990.tb03704.x
      • Jarboe JK, Hallworth R. The effect of quinine on outer hair cell shape, compliance and force. Hear Res. 1999 Jun;132(1-2):43-50. doi: 10.1016/s0378-5955(99)00031-3. PMID: 10392546.

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• Article authored by Ryan and Matt regarding potential toxicity of vitamin e acetate in THC vape cartridges
  • https://pubmed.ncbi.nlm.nih.gov/32451600/
  • https://pubmed.ncbi.nlm.nih.gov/33528766/
• News article about the man arrested 1 floor below our Host where co-author of above paper is quouted. for selling vape cartridges
  • https://www.jsonline.com/story/news/2019/08/29/vaping-deaths-thc-cartridges-investigated-wisconsin-cases/2154799001/
• False Positive for Fentanyl
  • https://pubmed.ncbi.nlm.nih.gov/25248490/
• Serotonin syndrome
  • Great review of serotonin syndrome
    • https://pubmed.ncbi.nlm.nih.gov/15784664/
  • LSD Partial agonism at 5HT2A
    • https://pubmed.ncbi.nlm.nih.gov/8819525/
  • Review containing 5HT2A binding affinity for pyschoactive compounds
    • https://pubmed.ncbi.nlm.nih.gov/27216487/
  • Discussion of some cases of LSD related deaths
    • https://pubmed.ncbi.nlm.nih.gov/29408722/
  • Review of risk of serotonin syndrome with stimulant compounds
    • https://pubmed.ncbi.nlm.nih.gov/17620161/
  • Case report of methamphetamine serotonin syndrome
    • https://www.longdom.org/open-access/serotonin-syndrome-following-single-ingestion-of-high-dose-methamphetamine-2161-0495.1000111.pdf
• Cases
  • Review of toxicity from poison case 1
    • https://pubmed.ncbi.nlm.nih.gov/21739343/
  • Review of methemoglobinemia (case)
    • https://pubmed.ncbi.nlm.nih.gov/22024786/
  • Review of case 3 poison toxicity
    • https://pubmed.ncbi.nlm.nih.gov/21731786/
  • Case report of case 4 poisoning
    • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC130147/

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• Action potential
  • Sodium/Potassium ATPase pumps create more positively charged ions outside the cell than inside the cell, this creates a relative negative charge in the cell
  • Phase 4- Resting (~ -90 mv)
  • Phase 0- Sodium enters the cell (+10 mv)
  • Phase 1- Potassium efflux from cell as now there is no negative charge holding it in (0 mv)
  • Phase 2- Calcium channels open and allow calcium in, calcium triggers the ryandoine receptor and allows for calcium dependent calcium release from the sarcoplasmic reticulum occurs
  • Phase 3- Potassium continues to leave the cell  allowing return to -90 mv

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Great review of potential torsades mechanisms based off experimental data- https://www.sciencedirect.com/science/article/pii/S1880427611800050

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Buying as much loperamide as you possibly can

• Loperamide history
  • 1969- Synthesized (1)
  • 1976 FDA Approved as schedule V (2)
  • Jaffe trial of "abuse potential"- https://pubmed.ncbi.nlm.nih.gov/7438696/
  • 1982- Descheduled (3)
  • 2010-Annually Increasing in # of poison center calls, cases of arrhythmia and hospitalization (4,5,6)
  • 2016- Submission to DEA for rescheduling of loperamide denied (7)
  • 2019- FDA works with manufactures to reduce package size to 48 tablets (8)
  • Pharmacist knowledge of abuse remains low https://pubmed.ncbi.nlm.nih.gov/32641253/
• Toxic Mechanism
  • Fun theories about co evolution of PGP and CYP https://pubmed.ncbi.nlm.nih.gov/10837556/
  • Inhibition of sodium channels, and to a higher affinity, Human Ether a Go-Go Related (HERG) channel leads to prolonged repolarization (9)
    • IC50 for HERG Ikr ~ 40 nm/l (1908 ng/dl), inhibits as low as 10 nm/l (10)
    • Case reports of conduction disturbance with level of 22 ng/ml (14)
    • Levels in fatalities vary but reported as high as 270 ng/ml in some studies (15)
  • Prolonged re polarization leads to torsades
    • Early after depolarizations may trigger, which are then propagated torsades via re entrant rhythms (11)
• Treatment
  • ACMT loperamide guidelines (12)
  • Supportive care
    • Arrhythmia management
      • Torsades (13)
        • Electrical cardioversion (terminates re entrant rhythm)
        • Magnesium (prevents early after depolarization)
        • Target Mg >2 and K >4
        • Lidocaine-> Recommended in 2006 Sudden cardiac death guidlines, not mentioned in 2017, however one of the only VT recommended antiarryhtmics that do not prolong QTc (others, sotalol, amiodarone, and procainamide, do)
        • If preceded by bradycardia, Overdrive pacing with isoproterenol to target HR~ 100
        • Beta blockers are recommended in patients with LQTS
      • Sodium channel blockade induced wide QRS complex tachycardia (12)
        • Hypertonic sodium to over whelm sodium channel blockade (1-2 amps of 8.4% Sodium Bicarbonate given IV)
  • Where do we go in the future?
    • More research will help us understand the true incidence of how often this occurs and what impact the FDA decisions will have
    • Any concerned citizen can submit for rescheduling of loperamide. Interested? Reach out at toxtalk1@gmail.com
      • Drug Enforcement Agency. The Controlled Substances Act. Available at: https://www.dea.gov/controlled-substances-act.
• Florey, Klaus (1991). Profiles of Drug Substances, Excipients and Related Methodology, Volume 19. Academic Press. p. 342. ISBN9780080861142.
• "IMODIUM FDA Application No.(NDA) 017694". U.S. Food and Drug Administration (FDA). 1976.
• https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf.
• Miller H, Panahi L, Tapia D, Tran A, Bowman JD. Loperamide misuse and abuse. J Am Pharm Assoc (2003). 2017;57(2S):S45eS50.
• Feldman R, Everton E. National assessment of pharmacist awareness of loperamide abuse and ability to restrict sale if abuse is suspected [published online ahead of print, 2020 Jul 5]. J Am Pharm Assoc (2003). 2020;S1544-3191(20)30264-8. doi:10.1016/j.japh.2020.05.021
• Eggleston W, Marraffa JM, Stork CM, et al. Notes from the Field: Cardiac Dysrhythmias After Loperamide Abuse — New York, 2008–2016. MMWR Morb Mortal Wkly Rep 2016;65:1276–1277. DOI: http://dx.doi.org/10.15585/mmwr.mm6545a7
• https://www.chpa.org/PDF/09_05_17_CommentsCitizenPetitionLoperamide.aspx
• https://www.fda.gov/drugs/drug-safety-and-availability/fda-limits-packaging-anti-diarrhea-medicine-loperamide-imodium-encourage-safe-use
• Kang J, Compton DR, Vaz RJ, Rampe D. Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(10):1133-1137. doi:10.1007/s00210-016-1286-7
• Klein MG, Haigney MCP, Mehler PS, Fatima N, Flagg TP, Krantz MJ. Potent Inhibition of hERG Channels by the Over-the-Counter Antidiarrheal Agent Loperamide. JACC Clin Electrophysiol. 2016;2(7):784-789. doi:10.1016/j.jacep.2016.07.008
• https://www.sciencedirect.com/science/article/pii/S1880427611800050
• Eggleston W, Palmer R, Dubé PA, et al. Loperamide toxicity: recommendations for patient monitoring and management. Clin Toxicol (Phila). 2020;58(5):355-359. doi:10.1080/15563650.2019.1681443
• Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society [published correction appears in J Am Coll Cardiol. 2018 Oct 2;72(14):1760]. J Am Coll Cardiol. 2018;72(14):e91-e220. doi:10.1016/j.jacc.2017.10.054
• Marraffa JM, Holland MG, Sullivan RW, et al. Cardiac conduction disturbance after loperamide abuse. Clin Toxicol (Phila). 2014;52(9):952-957. doi:10.3109/15563650.2014.969371
• Miller H, Panahi L, Tapia D, Tran A, Bowman JD. Loperamide misuse and abuse. J Am Pharm Assoc (2003). 2017;57(2S):S45-S50. doi:10.1016/j.japh.2016.12.079

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• Case report from beginning of show
  • https://pediatrics.aappublications.org/content/130/6/e1700
• "One Pill Can Kill Resources"
  • http://missouripoisoncenter.org/wp-content/uploads/2015/02/2011-One-Pill-Can-Kill.pdf
  • https://pubmed.ncbi.nlm.nih.gov/16419734/
  • https://www.healthychildren.org/English/safety-prevention/at-home/medication-safety/Pages/Poison-Prevention-One-Pill-Can-Kill.aspx
• Respiratory centers and the effects drugs can have on them
  • https://www.ncbi.nlm.nih.gov/books/NBK482414
• Buprenorphne studies
  • Epidemology
    • AAPCC Annual report
      • https://pubmed.ncbi.nlm.nih.gov/31752545/
    • Trends in opioid exposures in pediatrics
      • https://pubmed.ncbi.nlm.nih.gov/32178937/
    • Trends in ED visits for unsupervised medication exposures
      • https://pubmed.ncbi.nlm.nih.gov/26347435/
  • Exposure Studies
    • US Poison center data
      • https://pubmed.ncbi.nlm.nih.gov/29941678/
    • Harvard EM group-
      • https://pubmed.ncbi.nlm.nih.gov/27756148/
    • MD Poison center/RADARS data
      • https://pubmed.ncbi.nlm.nih.gov/18381506/
    • ICU exposures
      • https://pubmed.ncbi.nlm.nih.gov/20921918/
• Triage questions
  • Symptoms
  • Causative agent + Characteristics of exposure (qty ingested/scenario)
  • History (past medial, weight, how long ago was exposure)
  • Onset (when should we expect symptoms)
  • Labs (conduct toxin specific toxicity assessment)
  • Aggravating/Remitting factors (what has been done already that has made it better or worse?)

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• Excellent review of sources, clinical effects, and management
  • Calello DP, Henretig FM. Lead. In: Goldfrank's Toxicologic Emergencies, 10th ed, Hoffman RS, Howland MA, Lewin NA, et al (Eds), McGraw Hill Education, New York 2015. p.1219.
  • Toxic substances database for lead https://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=96&tid=22
• Clinical Case from today's show
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353372/
    • Weiss D, Lee D, Feldman R, Smith KE. Severe lead toxicity attributed to bullet fragments retained in soft tissue. BMJ Case Rep. 2017;2017:bcr2016217351. Published 2017 Mar 8. doi:10.1136/bcr-2016-217351
• History
  • More lead exists now than at the dawn of time due to radioactive decay of heavier chemicals. https://iopscience.iop.org/article/10.1086/375492
  • Lead has been deeply intertwined with human culture, used as currency, building material. cosmetics and innumerable other uses. It has has even been proposed to be the fall of Rome due to use in their aqueducts and wine.https://pubmed.ncbi.nlm.nih.gov/14261844
• Lead in society - Great review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522252
  • Lead Paint, up to 50% lead until 1940, tens of millions of houses still have lead paint which crumbles and creates lead dust
  • Soil, from tetra ethyl leaded gasoline contamination, added to gasolone by Thomas Midgley https://interestingengineering.com/thomas-midgley-jr-the-man-who-harmed-the-world-the-most
  • Lead piping- https://www.epa.gov/sites/production/files/2016-10/documents/508_lcr_revisions_white_paper_final_10.26.16.pdf
    • The 1986 amendment to the Safe Drinking Water Act required lead-free solder, flux, fittings, and pipes as of June 1988.
    • The Lead and Copper Rule originally required replacement of the public and private service pipelines; however, the rule was revised in 2000 to allow for only partial service line replacement in the publicly owned sectors
  • Older homes, higher soil lead burden, and unjust housing discrimination have led to disparities in lead racial/ethnic and socioeconomic disparities in lead exposure https://scholar.harvard.edu/files/alixwinter/files/sampson_winter_2016.pdf
  • https://pubmed.ncbi.nlm.nih.gov/22752852/.
• Other lead sources
  • Traditional medicines- Ayurveda (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538609/)
  • Kohl- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1567936/
  • BULLETS-https://pubmed.ncbi.nlm.nih.gov/30939573/
• "Lead crime hypothesis"- https://pubmed.ncbi.nlm.nih.gov/27035924/
• Lead and the economy
  • https://pubmed.ncbi.nlm.nih.gov/23797342/
  • https://pubmed.ncbi.nlm.nih.gov/29134344/
• Clinical effects from
  • "Ben Franklins dangles and bellyach(gripes) https://pubmed.ncbi.nlm.nih.gov/22910081/
    • Lead colic/constipation (gripes)
    • Neuropathy (dangles)
    • Easy to access origiinal letter on lead from Ben Franklin- https://bit.ly/2Yqgoze
• Neurocognitive/Behavioral, especially in exposed young- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909981/
  • Lower IQ
  • Visual spatial effect
  • Processing speed reduction
  • Irritable affect
  • May contribute to cognitive and behavioral disorder
• Chronic kidney and vascular disease- https://www.atsdr.cdc.gov/toxprofiles/tp13-c2.pdf
• Hematologic- https://www.atsdr.cdc.gov/toxprofiles/tp13-c2.pdf
  • Hemolytic anemia- From fragility due to decreased calcium/magenisum ATPase acitivity
  • Basophillic stippling- Pyrimidine 5 nucleotidase inhibtion causes RNA clumping
  • Build up of zinc and erythrocyte Protoporphyrin (ZPP/EPP) from ferrochetalase inhibition of heme synthesis
• Muscoloskeletal
  • Burton lines- Lead sulfate deposition between teeth and gums in mouth- https://www.amjmed.com/article/S0002-9343(12)00286-0/pdf
  • Lead lines- ostoclast inhibition leading to osteoblast induced hypercalcification at the metaphys https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1912933/
• Toxic mechanism- (gold franks)
  • Binding of sulfhydryl groups
  • Appearance as a divalent cation
• Good resources for broad overview and some nitty gritty info on mechanisms and effects
  • Calello DP, Henretig FM. Lead. In: Goldfrank's Toxicologic Emergencies, 10th ed, Hoffman RS, Howland MA, Lewin NA, et al (Eds), McGraw Hill Education, New York 2015. p.1219.
  • https://www.atsdr.cdc.gov/csem/csem.asp?csem=34&po=10
  • https://www.atsdr.cdc.gov/toxprofiles/tp13-c2.pdf
• Treatment
  • Chelators
    • BAL- IM, painful, peanut oil, hemolysis if G6PD defcient
    • CA2NAEDTA- IV, usually given with other chelator if level >70 or encephalopathic- https://www.sciencedirect.com/science/article/pii/S0041008X99987252
    • Succimer- PO, may increase lead absorption, ensure lead i s past small intestine before starting https://www.sciencedirect.com/science/article/abs/pii/S0013935184710632
  • What to do with your lead level (if its a capillary blood lead make sure you confirm it with venous blood lead!)
    • Kids https://www.cdc.gov/nceh/lead/advisory/acclpp/actions-blls.htm

      • history, abatement, education

      • 20 x ray and anemia labs

      • 45 X ray, anemia labs, decon, oral chelation

      • 70 consider x ray, labs, decon IV chelation + oral or IM 4 h before

    • Adults
      • https://pubmed.ncbi.nlm.nih.gov/17431500/

If you have an elevated blood lead level- call your toxicologist or poison center. Thanks for listening!

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Concepts in this episode

1. testing our tests
   • Sensitivity: Rate of Positive test in those who have the disease
   • Specificity: Rate of negative test in those without the disease
   • Positive predictive value: True positive/ True Positive + False Positive
   • Negative predictive value: True negative/True negative + False negative
2. (PK) Bioavailablity = Amount of drug available to be used by the body
   • Oral Bioavailablity= Dose- Fraction excreted unchanged- Fraction metabolized in gut- Fraction metabolized by liver
3. How drugs interact with the body (PD)
   • Agonist- stimulates receptor
   • Partial agonist- Activation of receptor with ceiling effect, never achieves maximal activation
   • Antagonist- Prevents receptor activation
   • Inverse agonist- induces an opposite effect as an agonist after binding receptor
4. Addiction vs dependance
   • Addiction- Relationship between user and substance
     • A few definitions but frequently involving consequences in life from use and loss of control over use of substance
   • Dependence- Physiologic changes in body due to chronic use
     • Down regulation of stimulated receptors
     • Physiologic basis for tolerance and withdrawal

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• Key points
  • Bleach mixed with various chemicals can make many toxic substances
    • Bleach + acid= chlorine gas
      • Bartholette original Cl2 + H2O ⇄ HCl + HClO
      • To drive the reaction to the right, a base was added, to neutralize HCl and reduce the amount of product
      • The reaction is reversed when an acid is added
      • http://www.chm.bris.ac.uk/motm/bleach/Sodium%20Hypochlorite%20-%20Molecule%20of%20the%20Month%20October%202011.pdf
    • Bleach + ammonia= chloramine gas
    • Bleach + rubbing alcohol (isopropyl)= chloroform
    • Bleach + soap= carbon tetrachloride
  • Chlorine gas is a high solubility irritant, it dissolves quickly in the mucous membranes and causes severe irritation of upper airway, eyes and nose (moist mucous membranes), effects are noticed quickly
    • Treatment for most chemical inhalation injuries involves removal from ongoing exposure, maintenance of a patent airway, and supportive care
      • Oxygen for hypoxemia
      • Bronchodilators (albuterol)
      • Intubation if needed
    • If the exposure is to chlorine gas there may be a role for nebulized sodium bicarbonate.
    • Due to initial irritation, exposure may present looking vary severe, but may turn around with good supportive care
  • If you accidentally make chlorine gas, get to fresh air, open windows if you can and call your local poison center or 911
  • Bleach ingestion are basic and can cause a liquefactive necrosis
    • Some may result in oral irritation
    • Treatment involves assessing the injury to determine risk of stricture and possible esophageal stenting
• Brief summary of steroid use with irritant gases: Reproduced with permission from : Pape KO, Feldman R. Smoke inhalation and Toxic Exposure. Chapter In: Erstad B, ed. Critical Care Pharmacotherapy. Lenexa: American College of Clinical Pharmacy. January 2020.
  • Steroid use in pulmonary irritant induced pneumonitis is not well evaluated in randomized controlled trials. Reviews of animal data suggest no significant benefit for poorly water soluble or high doses of water-soluble irritants. They may also have a negative effect on the recovery phase (deLange 2011).Numerous case reports exist detailing positive outcomes from use of steroids in patients exposed to pulmonary irritants (deLange 2011).However, without an appropriate comparator it is not known if symptom resolution is related to the intervention or the natural progression of the disease. Small human crossover trials evaluating the effects of mild ozone exposure found a reduction in bronchiolar lavage inflammatory markers with inhaled fluticasone or budesonide but no difference in clinical effects (deLange 2011, Nightingale 2000, Alexis 2008, Vagaggini 2001). Due to the absence of well controlled trials, steroids are not routinely recommended for chemical pneumonitis. However, there is also a lack of negative data and institutional protocols or patient specific factors may govern their use.
    • 1. De Lange DW, Meulenbelt J. Do corticosteroids have a role in preventing or reducing acute toxic lung injury caused by inhalation of chemical agents? Clin Toxicol (Phila) 2011;49:61-71.
    • Vagaggini B, Taccola M, Conti I, et al. Budesonide reduces neutrophilic but not functional airway response to ozone in mild asthmatics. Am J Respir Crit Care Med 2001;164:2172–6.
    • Alexis NE, Lay JC, Haczku A, et a. Fluticasone propionate protects against ozone-induced airway inflammation and modified immune cell activation markers in healthy volunteers. Environ Health Perspect 2008;116:799–805.
    • Nightingale JA, Rogers DF, Chung KF, et al. No effect of inhaled budesonide on the response to inhaled ozone in normal subjects. Am J Respir Crit Care Med 2000;61:479–86.
• New story from initial case- https://www.msdsonline.com/2015/02/27/fatal-accident-in-ca-even-small-quantities-of-chlorine-pose-danger/
• History
  • Claude Bertholtte- https://www.britannica.com/biography/Claude-Louis-Berthollet
  • Antoine Labarraque- https://peoplepill.com/people/antoine-germain-labarraque/
• Data on sodium bicarbonate in CL2 gas
  • Systematic review
    • Huynh Tuong A, Despréaux T, Loeb T, Salomon J, Mégarbane B, Descatha A. Emergency management of chlorine gas exposure - a systematic review. Clin Toxicol (Phila). 2019;57(2):77‐98. doi:10.1080/15563650.2018.1519193
  • Summary of many trials
    • https://chemm.nlm.nih.gov/countermeasure_sodium-bicarbonate.htm
• Sodium bicarbonate probably doesn’t help Chloramine gas exposure
  • Pascuzzi TA, Storrow AB. Mass casualties from acute inhalation of chloramine gas. Mil Med. 1998;163(2):102‐104.
• Chloramine physical properties
  • https://pubchem.ncbi.nlm.nih.gov/compound/Chloramine
• Reactions of Sodium Hypochlorite wit other compounds to make nasty products -
  • Odabasi M. Halogenated volatile organic compounds from the use of chlorine-bleach-containing household products. Environ Sci Technol. 2008;42(5):1445‐1451. doi:10.1021/es702355u
• Good review of the basics of caustic ingestions such as bleach
  • Hoffman RS, Burns MM, Gosselin S. Ingestion of Caustic Substances. N Engl J Med. 2020;382(18):1739‐1748. doi:10.1056/NEJMra1810769
  • Pulmonary irritants- Nelson LS, Odujebe OA. Simple asphyxiants and pulmonary irritants. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds.Goldfrank's Toxicologic Emergencies, 11e New York, NY: McGraw-Hill; 2019.
• Incidence data
  • Gummin DD, Mowry JB, Spyker DA, et al. 2017 Annual report of the American association of poison control centers’ national poison data system (NPDS): 34th annual report. Clin Toxicol (Phila) 2017;55:1072–254.

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Information about medical and clinical toxicology can be found at 

American Academy of Clinical Toxicology (AACT)- clintox.org

American College of Medical Toxicology (ACMT)- acmt.net

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Welcome to the poison lab! Tune in to satisfy your taste for the history, science, and medical management of the infinite poisons the world has to offer!