We here at the hive mind of the Tox and the Hound just want to thank you, dear readers, for joining us on this incredible journey. We’ve had an exciting year, where we’ve talked about a wide range of topics and ideas. We discussed . . .
Our Fellow Friday series was incredible. From endozepines and idiopathic recurrent stupor to the cardiovascular toxicity of plant sodium channel openers to anaphylactoid reactions from rattlesnake bites, Dr. Curry showed us that there is always another, more complex story to explore.
And, of course, a special thank you to Scott and our colleagues of the EMcrit collective, Rory and Josh, for sharing your #FOAM home with us and inspiring us with your posts. To a bright and bountiful 2020!
The Toxicology Year in Review 2019
A few of the hounds put together some of their favorite stories of the toxicologic year. Enjoy!
A major poisoning story of 2019 may not have been a poisoning story after all. On May 25, a 41 year-old American psychotherapist died at a Dominican Republic resort after drinking a beverage from the minibar. While in the hotel room with her husband, she reported feeling a pain, and then collapsed. Five days later, an American couple (63 and 49) was found dead at the same resort. Preliminary autopsy results revealed pulmonary edema. Poisoning was immediately suspected.
What kind of poison could cause this? Sudden collapse after drinking or eating can be caused by any cytochrome oxidase inhibitor such as cyanide or sodium azide. Metal phosphides, intended as fumigants and not uncommonly associated with poisoning, will cause both rapid loss of consciousness and pulmonary edema after ingestion.
While death investigations and autopsies were methodically conducted – with cooperation from the US State Department – the Internet filled the information void with hysteria. Trips booked to the Dominican Republic in July and August dropped by 74%. The website “IWasPoisoned.com” received 1600 reports of suspected poisonings in the Dominican Republic, up from 10 the prior year. IWasPoisoned.com, which relies on unverified user reports, has been described as the “Yelp of poisoning”.
Ultimately, the Dominican authorities concluded that the tragic deaths were not a result of poisoning. The two deaths, although at the same resort, were at different hotels. Ms. Schaup-Werner died from a “heart attack.” This is unusual in a 41-year-old woman, but not unheard of. The couple reportedly died from “respiratory failure and pulmonary edema.” The cause of this condition was never specified, but reports mentioned a bottle of oxycodone in the room. If this was a tox case, it wasn’t an exotic, unknown toxin.
When the dust settled, Dominican authorities and US State Department confirmed that there was actually no uptick in American deaths in the Dominican Republic. The IWasPoisoned.com reports were probably just increased reporting of usual diarrheal illness that people get when they travel. People were more likely to report minor illness but they weren’t more people getting sick, and there wasn’t evidence that people were being maliciously poisoned. The ultimate lesson is to take care not to prematurely connect tragic data points. Sometimes, the dots don’t connect. Sometimes, there is no underlying narrative. The truth is more likely to be found in the cool-headed review of autopsy and epidemiology.
My nominee for the story of the year is actually a person and representative of what our nation has been facing for years. He is also, unfortunately, a continuation of @toxicologist12’s nominee for 2018. Tyler Skaggs. His name joins the list of hundreds of thousands of people across this country all with one thing in common. They died due to opioid use disorder.
Admittedly, I knew very little about Tyler Skaggs until the day he died. Skaggs was a major league baseball pitcher. His major league baseball career started in 2010 with the Arizona Diamondbacks. In 2011, he was named their pitcher of the year. In 2014, after an ulnar collateral ligament injury, he had “Tommy John” surgery and missed the entire 2015 season. He continued to struggle with injuries during the 2018 and 2019 seasons, while pitching for the Los Angeles Angels. In June 2019 he was pitching again and from what baseball enthusiasts have told me, looked pretty good. Tragically, he died on July 1, 2019 after being found unresponsive in a hotel room while traveling with his team. A few months later, suspicion was confirmed and his autopsy revealed the cause of death as accidental poisoning, from oxycodone, fentanyl, and alcohol. The details surrounding the investigation into his death are chilling. His team reportedly knew of his opioid use long before that fateful day of July 1, and, in fact, at least one team employee has come forward and admitted to supplying him with oxycodone for several years.
Skaggs isn’t the only professional athlete to struggle with substance use disorder. Professional athletes have numerous injury-related pain issues and are likely at increased risk of opioid use and misuse. We all can remember hearing news stories about professional athletes being suspended secondary to drug use.1 Interestingly, in a retrospective review done in the late 1990s, pitchers had the most poisoning deaths.1 A recent survey of former National Football League (NFL) players reveal that 52% of respondents reported use of opioids during their careers with 71% reporting misuse.2 In fact, the prevalence of current opioid use in this survey was found to be 7%, which is much higher than the general population (3%).2
Until recently, professional organizations had a zero tolerance policy regarding substance use. Their mindset was basically, if you get caught, you get fined or suspended. Or worse. This only leads me to think . . . what would have happened to Tyler Skaggs if, rather than turning a blind eye, he was given the ability to receive treatment. Access to treatment and medication for opioid use disorder (MOUD) should be the mainstay of care for everyone. Professional athletes are no exception. There may be some light to the darkness of Skagg’s untimely death. The MLB players union and league are close to adopting a new policy on opioids.
My hope is that this tragic, preventable death, will bring some much needed changes not only to the culture of professional sports but to everyone. There needs to be action to improve access to care and treatment for all patients with substance use disorder.
by Dan Rusyniak
My pick for most important tox story of 2019 is the reemergence of methamphetamine. It is a classic “good news, bad news” story. The good news, and it is truly good news, is that opioid-related deaths have finally plateaued, and in many places around the country are decreasing. Although I am cynical about many things in medicine, I am not about this. I believe this reduction is, in part, the cumulative effect of federal, state, and local efforts. The list of these is long and includes access to naloxone3, needle exchanges4, safe injection sites, changes in Medicaid payments for treatment of substance-use disorder, efforts to decrease stigma, and efforts to address social determinants of health5 among others. But, if 20 years in toxicology has taught me anything, it is that illicit drugs follow typical market economics. Decreased access and use of one substance creates opportunities for others. (OK, I lied. I am cynical.)
This is exactly what we are seeing with methamphetamine. Meth is everywhere. This should not be a surprise. Since 2015, there has been a steady increase in overdose deaths in which methamphetamine is detected. This is because epidemics are not because of a substance but rather the underlying drivers of addiction (e.g., trauma, poverty, poorly treated mental illness, and social isolation). And, despite our efforts, these are largely unchanged. As a result, the collective risks for addiction, whether from fentanyl, methamphetamine, alcohol, cocaine or any substance for that matter, are still great. Meth’s rapid resurgence is in large part a testament to Mexican drug cartels. No longer a dirty concoction made in garages or camper vans, today’s meth is nearly pure and very cheap. This is why it is again the most prevalent substance detected in overdose deaths in many parts of the US. But over time this, too, will likely change. If we don’t control the underlying drivers of addiction, we will simply cycle between different substances as market forces change. My hope for 2020 is that all of the efforts we have collectively put forth to decrease opioid deaths continue. But, that we shift our focus from the specific substances (e.g., the opioid or the meth epidemic) to the individuals with the disorder. After all, while the substances change over time, the people stay the same.
Just when you thought you understood mercury poisoning – if that were possible – think again. My puzzling tox story of 2019 involves a 47-year-old female with dysesthesias and weakness, which progressed to slurred speech, ataxic gait, blurred vision and then agitated delirium. Both urine and blood levels of mercury were exceedingly high (blood 2520 ug/L and urine 110ug/L). Upon further history, the patient’s family mentioned the long-term use of a skin-lightening cream obtained from Mexico. She applied the product twice daily to the face for 7 years.6
While these lightening creams are a known source of inorganic mercury exposure, and can lead to mercury neurotoxicity, this case is different. Upon analysis, the cream contained very high levels of methylmercury iodide. Best known as a developmental neurotoxin (as in the Minamata Bay disaster) and the source of insidious and fatal neurodegeneration in a chemistry professor (dimethylmercury in Karen Wetterhahn)7, organic mercury is a most unwelcome piece of news. It causes a delayed-onset neurotoxicity which can be rapidly progressive, and chelation likely confers no benefit.
A great many questions remain here. Why is the compound in this product? Are there unique toxicologic considerations for methylmercury iodide specifically? Also puzzling is the presence of high mercury concentrations in the urine, since organic (methyl) mercury concentrates in erythrocytes and doesn’t undergo renal elimination. Lastly, the implications for this patient will extend way into 2020, and the prognosis is very uncertain. Hopefully the new year will bring some answers, and this will never happen again.
plus ça change, plus c'est la même chose
- Jean-Baptiste Alphonse Karr, Les Guêpes, July 1848
Riyadh, Tripoli, Irkutsk, Phnom Penh, Pärnu, Vikhroli, Nicaragua, and just this week, Laguna . . . What do all of these places have in common? They’re not my choice territories to capture in Risk™ , but something far worse: locations of mass poisoning with methanol.8–12
Every few months, you’ll hear a new report about a large group of people that fall ill after a gathering – a wedding, a celebration, or some other venue where alcohol is served. The illness and the inevitable deaths are blamed on “bad alcohol”, which is often an easier and cheaper home brew of a popular liquor, or a product from a bootleg distillery. The “bad” in the alcohol is not ethanol, but rather contamination (both intentionally and unintentionally) with methanol. This happens so frequently, that Wikipedia has a whole page dedicated to methanol mass poisoning incidents (the sub-section from India is bonkers). If you really want to be humbled, take a look at this list from the Methanol Poisoning Initiative (MPi) as well. This week we saw the same story play out in the Laguna and Quezon provinces of Luzon, southeast of the capital Manila on the Philippines main island. Lambanog, or coconut wine, distilled from coconut sap and typically 40-45% ABV (80-90 proof), was found to contain between 11.4 to 18.2% methanol. As of this writing, there were 12 dead and over 500 ill.
Foreshots, Heads, Hearts, and Tails
Why does this keep happening? Part of this has to do with the science of distillation. When distilling a liquor, timing and temperature are key factors in separating out the ethanol you desire, and the other volatile alcohols you don’t. You take an alcoholic liquid (the ‘wash’) and distill it to concentrate the spirit you want (the ‘potable’ ethanol). You’re trying to keep some of the desirable congeners (the chemicals that give a particular spirit its character or flavor – think juniper for gin), while getting rid of the badness (e.g., methanol). If you’re not careful, you can collect the wrong portion and serve that to your unwitting guests. Unfortunately, there are less savory distillers who intentionally cut their product with the foreshots, or sell that separately.
Methanol is metabolized through alcohol dehydrogenase and then through aldehyde dehydrogenase to formic acid, the ultimate toxic metabolite. Formate is a mitochondrial toxin and interferes with oxidative phosphorylation. The basal ganglia neurons are particularly susceptible. Renal and pancreatic toxicity is reported. Most well known, methanol causes visual impairment that can range from blurry or hazy to total blindness.
I won’t get into the debate over the osmol gap, and I’ll leave diagnostic strategies, including the utility of formic acid testing, to others.13–15 Therapy is fomepizole if you have it, and ethanol if you don’t.16,17 The MPi has some wonderful algorithms to help depending on the resources you have available. And regardless of locale, public awareness of the risks and symptoms of methanol poisoning from contaminated alcohol may save lives.
Be careful when enjoying your holiday libations and have a safe and healthy 2020!
by Jon Cole
Lots of things made noteworthy returns in 2019, and my choice for tox story of the year is similar. In 2019 we saw the return of droperidol, one of the most beloved medications in my primary specialty of emergency medicine. Droperidol is a drug approved for post-operative nausea and vomiting, but found great success in the emergency department as a treatment for nausea and vomiting18, migraines19, other types of pain20, and acute agitation.21 My own hospital at its peak used over 2,500 doses of droperidol a year in the emergency department alone.22 This year at the North American Congress of Clinical Toxicology there was even new data that droperidol might be a preferred antiemetic for cannabinoid hyperemesis syndrome.
So why is the return of droperidol a toxicology story? One of the fundamental elements of our specialty is the study and practice of medication safety, and the story of droperidol is a fascinating dive into this part of our toxicologic world. Until 2001 droperidol was one of the most commonly used drugs for postoperative nausea and vomiting, and was used for all the above indications in emergency departments all across the U.S. Then in late 2001 the FDA added a boxed (“black box”) warning (their sternest warning possible) that droperidol was associated with QTc prolongation and torsades des pointes23 and that an ECG was necessary before administering droperidol, and that ECG monitoring was required for the following 2-3 hours after administration. The use of droperidol in all specialties of medicine in the U.S. suddenly plummeted, while the use of the (then on-patent and exponentially more expensive) ondansetron soared. Sales of droperidol fell 90% in the first year after the black box warning.24 As usage fell over time, availability of droperidol became scarce due to manufacturing delays (and reported shortages of raw materials), and by 2013 the drug was essentially unavailable to most U.S. hospitals.
The data the FDA used to administer this warning is worth its own deep dive, but essentially this warning stemmed from a few small studies of OR patients receiving 10-fold (or more) larger doses than typically given in American hospitals for any indication that showed droperidol was associated with a dose-dependent prolongation of the QT. In addition, there were approximately 270 post-marketing surveillance reports of adverse events submitted to MedWatch. Many of our toxicologic brothers and sisters have opined on and analyzed these reports over the years24–28 but there are some real notable facts about these 270 or so cases. Over 80% of these reports came from outside the U.S.28 Many of these were duplicate reports (some individual cases were submitted up to 5 times)29 and involved huge doses (up to 250 mg – 100 times the FDA-approved dose of 2.5 mg)29 There’s also the notable fact that 71 of these 270 or so events submitted to MedWatch were done so on a single day (July 9, 2001), including 53 of the 94 reported deaths.27 This large single-day bolus of reports came from Janssen-Cilag30, the company that until March of 2001 sold and marketed droperidol in Europe (but not in the United States). These 270 reports stood in stark contrast to the decades of experience anesthesiologists31, emergency physicians28, and psychiatrists32 had with droperidol that showed it was safe and effective. Conspiracy theories about why these reports occurred abounded and subsequent large data sets have shown droperidol to be extremely safe (or at least as safe as ondansetron)33,34; nevertheless droperidol went the way of the dodo.
Then, in the winter of 2019, the Prodigal Son returned (at about 7 times the old price, but still relatively cheap). There was great rejoicing on medical social media. It was followed almost immediately by the publication of data from the few centers who were fortunate enough to have access to droperidol during the shortage35, and opinion pieces, social media posts, and podcasts about how to handle the cognitive dissonance of the stern FDA black box warning with the scores of data that show droperidol is safe and effective now that it is once again widely available. While there are certainly far more important toxicologic stories in 2019, the boxed warning, subsequent loss of droperidol and its heralded return is a fascinating summary (and commentary) about if and how boxed warnings keep our patients safe, the availability of cheap, effective generic drugs (and who manufactures them), and the interaction of medical social media with these two unique and powerful forces. Here’s hoping for the return of more cheap, effective, safe medications in 2020.Fireworks 2020 by Jude Beck
- 1.Boren S, Erickson T. Toxicological deaths of major league baseball players. J Toxicol Clin Toxicol. 1998;36(7):737-742. doi:10.3109/15563659809162625
- 2.Cottler L, Ben A, Cummings S, Barr J, Banks R, Forchheimer R. Injury, pain, and prescription opioid use among former National Football League (NFL) players. Drug Alcohol Depend. 2011;116(1-3):188-194. doi:10.1016/j.drugalcdep.2010.12.003
- 3.Abouk R, Pacula R, Powell D. Association Between State Laws Facilitating Pharmacy Distribution of Naloxone and Risk of Fatal Overdose. JAMA Intern Med. 2019;179(6):805-811. doi:10.1001/jamainternmed.2019.0272
- 4.Dasgupta S, Broz D, Tanner M, et al. Changes in Reported Injection Behaviors Following the Public Health Response to an HIV Outbreak Among People Who Inject Drugs: Indiana, 2016. AIDS Behav. 2019;23(12):3257-3266. doi:10.1007/s10461-019-02600-x
- 5.Barocas J, Wang J, Marshall B, et al. Sociodemographic factors and social determinants associated with toxicology confirmed polysubstance opioid-related deaths. Drug Alcohol Depend. 2019;200:59-63. doi:10.1016/j.drugalcdep.2019.03.014
- 6.Mudan A, Copan L, Wang R, et al. Notes from the Field: Methylmercury Toxicity from a Skin Lightening Cream Obtained from Mexico – California, 2019. MMWR Morb Mortal Wkly Rep. 2019;68(50):1166-1167. doi:10.15585/mmwr.mm6850a4
- 7.Nierenberg D, Nordgren R, Chang M, et al. Delayed cerebellar disease and death after accidental exposure to dimethylmercury. N Engl J Med. 1998;338(23):1672-1676. doi:10.1056/NEJM199806043382305
- 8.Rulisek J, Balik M, Polak F, et al. Cost-effectiveness of hospital treatment and outcomes of acute methanol poisoning during the Czech Republic mass poisoning outbreak. J Crit Care. 2017;39:190-198. doi:10.1016/j.jcrc.2017.03.001
- 9.Paasma R, Hovda K, Tikkerberi A, Jacobsen D. Methanol mass poisoning in Estonia: outbreak in 154 patients. Clin Toxicol (Phila). 2007;45(2):152-157. doi:10.1080/15563650600956329
- 10.Rostrup M, Edwards J, Abukalish M, et al. The Methanol Poisoning Outbreaks in Libya 2013 and Kenya 2014. PLoS One. 2016;11(3):e0152676. doi:10.1371/journal.pone.0152676
- 11.Galvez-Ruiz A, Elkhamary S, Asghar N, Bosley T. Visual and neurologic sequelae of methanol poisoning in Saudi Arabia. Saudi Med J. 2015;36(5):568-574. doi:10.15537/smj.2015.5.11142
- 12.Hovda K, Hunderi O, Tafjord A, Dunlop O, Rudberg N, Jacobsen D. Methanol outbreak in Norway 2002-2004: epidemiology, clinical features and prognostic signs. J Intern Med. 2005;258(2):181-190. doi:10.1111/j.1365-2796.2005.01521.x
- 13.Hovda K, Gadeholt G, Evtodienko V, Jacobsen D. A novel bedside diagnostic test for methanol poisoning using dry chemistry for formate. Scand J Clin Lab Invest. 2015;75(7):610-614. doi:10.3109/00365513.2015.1066847
- 14.Zakharov S, Kurcova I, Navratil T, Salek T, Komarc M, Pelclova D. Is the measurement of serum formate concentration useful in the diagnostics of acute methanol poisoning? A prospective study of 38 patients. Basic Clin Pharmacol Toxicol. 2015;116(5):445-451. doi:10.1111/bcpt.12338
- 15.Hoffman R, Smilkstein M, Howland M, Goldfrank L. Osmol gaps revisited: normal values and limitations. J Toxicol Clin Toxicol. 1993;31(1):81-93. doi:10.3109/15563659309000375
- 16.Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009;360(21):2216-2223. doi:10.1056/NEJMct0806112
- 17.Burns M, Graudins A, Aaron C, McMartin K, Brent J. Treatment of methanol poisoning with intravenous 4-methylpyrazole. Ann Emerg Med. 1997;30(6):829-832. doi:10.1016/s0196-0644(97)70060-x
- 18.Furyk J, Meek R, Egerton-Warburton D. Drugs for the treatment of nausea and vomiting in adults in the emergency department setting. Cochrane Database Syst Rev. 2015;(9):CD010106. doi:10.1002/14651858.CD010106.pub2
- 19.Miner J, Fish S, Smith S, Biros M. Droperidol vs. prochlorperazine for benign headaches in the emergency department. Acad Emerg Med. 2001;8(9):873-879. doi:10.1111/j.1553-2712.2001.tb01147.x
- 20.Richards J, Richards I, Ozery G, Derlet R. Droperidol analgesia for opioid-tolerant patients. J Emerg Med. 2011;41(4):389-396. doi:10.1016/j.jemermed.2010.07.005
- 21.Calver L, Page C, Downes M, et al. The Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department. Ann Emerg Med. 2015;66(3):230-238.e1. doi:10.1016/j.annemergmed.2015.03.016
- 22.Chase P, Biros M. A retrospective review of the use and safety of droperidol in a large, high-risk, inner-city emergency department patient population. Acad Emerg Med. 2002;9(12):1402-1410. doi:10.1111/j.1553-2712.2002.tb01609.x
- 23.Mullins M. Mon bête noir (my pet peeve). J Med Toxicol. 2011;7(2):181. doi:10.1007/s13181-011-0153-7
- 24.Mullins M, Van Z, Blunt J. Unexpected cardiovascular deaths are rare with therapeutic doses of droperidol. Am J Emerg Med. 2004;22(1):27-28. doi:10.1016/j.ajem.2003.09.003
- 25.Matlock A, Allan N, Wills B, Kang C, Leikin J. A continuing black hole? The FDA boxed warning: an appeal to improve its clinical utility. Clin Toxicol (Phila). 2011;49(6):443-447. doi:10.3109/15563650.2011.564585
- 26.Richards J, Schneir A. Droperidol in the emergency department: is it safe? J Emerg Med. 2003;24(4):441-447. doi:10.1016/s0736-4679(03)00044-1
- 27.Kao L, Kirk M, Evers S, Rosenfeld S. Droperidol, QT prolongation, and sudden death: what is the evidence? Ann Emerg Med. 2003;41(4):546-558. doi:10.1067/mem.2003.110
- 28.Horowitz B, Bizovi K, Moreno R. Droperidol–behind the black box warning. Acad Emerg Med. 2002;9(6):615-618. doi:10.1197/aemj.9.6.615
- 29.Jackson C, Sheehan A, Reddan J. Evidence-based review of the black-box warning for droperidol. Am J Health Syst Pharm. 2007;64(11):1174-1186. doi:10.2146/ajhp060505
- 30.van Z, Mullins M, Jang T. Droperidol and the black box warning. Ann Emerg Med. 2004;43(1):139-140. doi:10.1016/j.annemergmed.2003.05.006
- 31.Habib A, Gan T. Pro: The Food and Drug Administration Black box warning on droperidol is not justified. Anesth Analg. 2008;106(5):1414-1417. doi:10.1213/ane.0b013e31816ba463
- 32.Chambers R, Druss B. Droperidol: efficacy and side effects in psychiatric emergencies. J Clin Psychiatry. 1999;60(10):664-667. https://www.ncbi.nlm.nih.gov/pubmed/10549682.
- 33.Nuttall G, Eckerman K, Jacob K, et al. Does low-dose droperidol administration increase the risk of drug-induced QT prolongation and torsade de pointes in the general surgical population? Anesthesiology. 2007;107(4):531-536. doi:10.1097/01.anes.0000281893.39781.64
- 34.Nuttall G, Malone A, Michels C, et al. Does low-dose droperidol increase the risk of polymorphic ventricular tachycardia or death in the surgical patient? Anesthesiology. 2013;118(2):382-386. doi:10.1097/ALN.0b013e31827dde8d
- 35.Gaw C, Cabrera D, Bellolio F, Mattson A, Lohse C, Jeffery M. Effectiveness and safety of droperidol in a United States emergency department. Am J Emerg Med. November 2019. doi:10.1016/j.ajem.2019.09.007
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