All of us at the Tox and the Hound want to thank you, dear readers, for continuing to stick with us on this incredible and strange journey. While we haven’t been with you as much as we’ve liked, there still has been an exciting range of topics covered. We kicked off the year with the awesome and controversial post “MALA-ficence”, which then provided fuel for our Fellow Friday series. Dr. Curry, with the help of Dr. Robert Robergs, explored ‘Whence the Protons of Lactic Acidosis’, in part one and part two. Dr. Curry showed us that there is always another, deeper complexity to the story we think we understand.
We covered the use of sub-dissociative ketamine as an alternative analgesic, pondered the complexities of valproic acid, and clarified the meaning of half-life (in less time than it will take you to metabolize that glass of champagne, or three . . .) And in an incredible debate, we learned that there are many ways to skin the cardiotoxic poisoned cat (N.B. no cats were harmed in the crafting of this post).
If only he had worn boxers instead of briefs
My toxicologic story of the year has got to be “Encyclopedia Navalny and the Case of the Poison Underpants”. For those of you unfamiliar with the comings and goings of the Russian “elite toxins team” (favored over Manchester United in its upcoming match), this is the tale for you.
Alexei Anatolievich Navalny is a Russian politician, jurist, anti-corruption activist, and a major opposition leader to Russian President Vladimir Putin. A top pick for best case report of the year, published on December 22nd, the authors provide a detailed description of what Mr. Navalny experienced after being poisoned by a “novichok” nerve agent on August 20th, 2020.1 Shortly after boarding a domestic flight, he developed prominent cholinergic symptoms and collapsed. After an emergency landing, he was taken to a local hospital and was intubated and ventilated. Two days later, he was airlifted to a German hospital and had a prolonged course. Seriously. Read the case report. I can’t do it justice here. Fortunately, he survived and demonstrated near-complete neurologic recovery on a follow-up visit, fifty-five days after exposure.
This is not the first time we’ve described these agents. Dan first wrote about this back in 2018 after the attack on Sergei Skripal and his daughter Yulia. We learned more about these agents with the two secondary victims of that initial poisoning, one unfortunately fatal, which became known as the 2018 Amesbury poisonings. We’ll work on a future post discussing the diagnosis and management of the “wet opioid syndrome” of organophosphate poisoning, but here are some references to get you started.2–4
The coda to this story is what cinches it for my story of the year. In an almost unbelievable turn of events, Mr. Navalny pulled of a piece of investigative journalism that would have made Chris Hansen proud. Posing as a senior official from Russia’s National Security Council, Navalny determined that the novichok agent had been “. . . applied to a pair of Navalny’s underpants.” More specifically, “The insides, the crotch.” This solid formulation of a novichok agent is different from the liquid that was applied to the door knob in the Skripal incident. The idea is that the agent is held close to the skin in areas where moisture would be present. Further evidence that boxers are a wise choice, always, and that “going commando” is just poison prevention.
My nominee for the tox story of the year is certainly not new. It is a continuation of a 10 year (and last years) story. This year though, it is confounded by a global pandemic. In the early days of March through May 2020, COVID-19 ravaged and crippled the United States (sadly, not much has changed in the last 9 months). Major cities faced unprecedented hospitalizations and deaths from this new disease. Cities and states went into lockdown. The economy took a downturn. Unemployment rates soared. For many of us, masks became part of our daily wardrobes. 6 feet away signs donned stores and elevators. All the while, another silent, deadly epidemic was wreaking havoc, as overdose deaths reached a record high. The Centers for Disease Control reported nearly 81,320 drug-overdose deaths in the 12-months ending in May 2020, a staggering 18.2% increase from the previous year. These deaths were driven by synthetic opioids linked largely to illicitly manufactured fentanyl.
How does the COVID-19 pandemic play into this increase? How could a 12-month time frame with only a few months’ overlap with the pandemic have any influence in this dramatic rise? In my opinion, the most striking piece of the data is that the largest monthly increases occurred from March through May 2020, exactly in the height of the first wave of the pandemic. (Figure 1)
These statistics certainly don’t establish causation, but we would be remiss to ignore the association. The time has come for the collective “we” to stop ignoring the health inequities that this pandemic uncovered and that many of us have known intimately during our careers. The trickle down effect from lack of access to care, social isolation and health disparities, just to name a few, have been devastating especially for the most vulnerable, at risk people. Blacks and hispanics are 2.8 times more likely to die from COVID-19. Advancing age comes with a higher risk of requiring hospitalization and death from COVID-19. People aged 65-74 years of age have a 90 time risk of dying compared to an 18-24 year old. That number keeps going up as age increases. There have admittedly been some ‘wins’ for medicine as a whole this year — like managing patients with opioid use disorder (OUD) using telemedicine and increasing access to buprenorphine.5 But, so much more needs to be done and these recent statistics are a stark reminder of the challenges ahead.
And so, as we enter 2021 (aka “2020 won”), with a glimmer of hope at the end of a very long tunnel, let’s use what we have learned this past year to better care for the most vulnerable of patients. Individually we may not be able to change the world, but we certainly can change one person’s life. And didn’t 2020 teach us the value of life? Let’s make some resolutions for 2021 . . . How about we brush up on buprenorphine? How about we send a patient home with naloxone? And maybe, just maybe, the tox story to wrap up 2021 will be entitled “Dramatic decline in overdose deaths with a dramatic increase in access to care.”
The Balance of Skepticism
This past year has resided in an interesting crossroads between medicine, science, public health, and human nature. When COVID-19 hit the global stage, we found ourselves in the position of facing an enemy that we didn’t know. Social media became the most steady source of information, and with that came complication. The process of designing a research study, conducting the study, analyzing the data, submitting it for peer review, and then having it published was not fast enough for what we were facing. Early therapies for COVID-19 were disseminated like a game of telephone, with rumors that harmless therapies were dangerous, such as ibuprofen. At the same time, rumors that prone positioning seemed to help hypoxic patients have now become a standard part of therapy.
The prototype for this phenomenon is the story of hydroxychloroquine in the management of COVID-19. A small study where 36 patients, 20 who received hydroxychloroquine and 16 who were controls, seemed to show that hydroxychloroquine promoted viral clearance after six days of treatment.6 This study was e-published on March 20, 2020, and on March 28, 2020, the FDA had issued an emergency use authorization (EUA) for the use of chloroquine and hydroxychloroquine for the treatment of COVID-19 patients. However, by June 15, 2020, the FDA revoked it’s EUA due to increasing data that these therapies showed no proven benefit for COVID-19 patients and only exposed them to harm.
Not only were COVID-19 patients affected by the rapid rise and fall of hydroxychloroquine, but there were unintended effects. Patients who rely on the therapy for their chronic diseases were faced with a sudden shortage of the medication. On March 24, there was a high-profile overdose of a couple who took an aquarium cleaner that contained chloroquine. Poison center calls regarding hydroxychloroquine and chloroquine were on the rise, even doubling the usual rate. The United States was left with 65 million doses that were stockpiled in anticipation of COVID-19 management.
What do we do as a medical community when we’re faced with a new threat and a paucity of information about how to manage it? With every new therapy, there will be early adopters and late adopters, roughly following a bell curve. The benefit of early adoption is that with proven therapy, your patients benefit from cutting-edge treatment. The downside is that you may be exposing your patients to unknown harm that may only be revealed with time or with better data. If you’re a late adopter, you benefit from having a more comprehensive picture of the therapy you’re providing, but it comes at the cost of the patients who were treated with older therapies. They may have worse outcomes that could have been prevented had they gotten the newer therapy. It’s important to maintain a balance of skepticism, where we recognize benefits without believing in them too strongly. We ought to approach new therapies with a measured skepticism, which allows us to be cautiously optimistic while using emerging data to recalibrate our therapeutic approach. There is harm in jumping head-first into the fervor of a new treatment, but there is also harm in taking no action.
The toxicology problems of any place are a natural reflection of its environment and behavior. Arizona has many snakes, so they have many snake bites. Sri Lanka uses a lot of pesticides, so they have a disproportionate amount of organophosphate poisoning. Florida has methamphetamine and alligators, so they have meth gators.
When the pandemic struck, public health officials asked people to stay home and to clean and disinfect high touch surfaces. So, perhaps unsurprisingly, we witnessed increased reports of poisoning from disinfectants in the home.
In some cases, the omnipresent bottles of hand sanitizer were ingested by curious toddlers. In others, people inadvertently mixed incompatible products — like bleach and ammonia — resulting in formation of noxious gases. According to a review of national poison center calls, exposures to cleaners and disinfectants spiked sharply in early March.
While bleach, soap, and hand sanitizer are safe to have in the house, CDC realized that the pandemic exposed gaps in knowledge of storage and use of these products. A new public information campaign was needed to help people use these products safely.
The surface cleaner issue resurfaced in April when the President openly asked in a White House Press Briefing if disinfectant could be injected inside the body, as the Coronavirus Task Force head could only helplessly look on.
The following day, the President tried to sanitize his prior comments by saying he was asking a “sarcastic question” and had been taken out of context.
As 2020 comes to a close, the primacy of airborne coronavirus spread has been recognized.7 Surface cleaning has been deemphasized relative to masking and distancing.
In 2021, we will continue to have coronavirus, and we will continue to have household cleaners. Thankfully, come January 20, we will almost assuredly have less confusing, toxic messaging emanating from the White House
Covfefe Coronavirus Task Force.
2020 saw the return of numerous historical poisons, including methanol, one of our most familiar and deadly toxicologic foes. Methanol is extremely toxic; a fatal dose in an adult can be as small as 30 mL (one fluid ounce!). In smaller doses it causes life-threatening acidosis and a characteristic blindness that is typically not reversible. Methanol poisoning in the U.S. typically occurs due to ingestion of windshield wiper fluid; methanol is also found in numerous perfumes, colognes, model airplane & car fuel, photocopying fluid and gasoline antifreeze (“dry gas”). In 2020, however, methanol appeared in an unexpected place — in everyday hand sanitizers.8,9
As Covid-19 took over our lives in 2020, we all became obsessed with cleanliness (or at least, the perception of cleanliness). Everyday cleaning products became scarce, particularly hand sanitizer. Prices skyrocketed and bizarre cases of price-gouging became everyday news. Suddenly, the hand sanitizer business became extremely profitable.
Hand sanitizer is typically either ethyl alcohol (AKA ethanol — the alcohol in, among other things, alcoholic beverages) or isopropyl alcohol, another common disinfectant and solvent. Ethanol intoxication is so common that, over time, humans have evolved a specific set of enzymes to metabolize it into acetate and then ultimately into energy. Isopropyl alcohol is a bit more toxic than ethanol, but is still relatively benign. In ordinary times, exposure to these ethanol- or isopropyl-based hand sanitizers is a frequent call to Poison Centers we can mostly treat with watchful waiting and reassurance.10 Cases usually involve either unintentional exposures in children, who strive to put everything in their immediate vicinity in their mouths (at least once), and in adults with alcohol use disorder, who typically use it as a substitute for traditional alcoholic beverages.11 Adults who drink hand sanitizer for intoxication are typically treated like any other patients in the emergency department who’ve had too much to drink. We monitor their vital signs and their airways, and as they metabolize their alcohol and sober up we re-evaluate them and discharge them when they are safe to care for themselves. In July 2020, we received a similar call to our Poison Center, but with a very different outcome. In this case, after hand sanitizer ingestion, the patient’s mental status worsened; a profound acidosis rapidly developed, and the patient died. The hand sanitizer in question was evaluated and found to contain methanol. Poison Centers from around the country reported similar cases, and an FDA investigation was launched. Since then, the FDA has kept an updated list of hand sanitizer products known to contain methanol.
It’s not exactly clear why this happened. When hand sanitizer became scarce numerous DIY methods of hand sanitizer became popular, many of which were dubious in terms of safety.12 Methanol is ubiquitous, and is easy to make. It also, initially, results in similar intoxication to ethanol. As such, during times of ethanol scarcity, such as during prohibition, methanol is frequently substituted for (or combined with) ethanol (either to “denature” it to discourage ingestion, or as an outright substitution for ethanol). This tainting of ethanol is so common over the past few centuries that there is an entire Wikipedia page devoted to mass poisonings from methanol, and as &Howard noted in our 2019 year-end post, can happen accidentally from sloppy distillation practices or for more nefarious reasons. It’s almost as though, throughout history, mass methanol poisoning is a sign of society collectively failing a stress test. It’s not surprising we saw methanol rear its ugly head again in 2020.
As for the present safety of hand sanitizers, severe poisoning at this time seems to be isolated to cases where adults intentionally ingested large amounts of hand sanitizer. Our Poison Center continued to see cases (fortunately all non-fatal) throughout the summer and early fall; they have since tapered off. Everyday use of hand sanitizer on skin is likely safe.13 While it is possible to get methanol poisoning from a dermal exposure, such cases are extremely rare and typically involve prolonged exposures, such as this woman who massaged her aches and pains routinely over the course of three days with methanol-containing cologne.14 As was true before Covid-19, consuming hand sanitizer for any reason is ill-advised, and home products used as intended to cleanse hands should be checked against the FDA list and discarded if they appear among the list of tainted products. If there are any questions, a call to your local Poison Center at 1-800-222-1222 to determine if your home hand sanitizers are safe is always welcome and warranted. And if anyone drinks or licks hand sanitizer — even those small accidental ingestions in kids — please call your local Poison Center, which is available 24/7/365 to answer any poisoning questions and keeps a lot of people safe each year. Hopefully, in 2021 hand sanitizer returns to being a mundane, pedestrian, (quotidian even) poison center call, along with many other things in our lives.
Colleagues in a Dark Time
I am alone in crowded rooms
But not with you
Life rafts in an ignorant sea
We commune in disbelief and despair
I check on you
You check on me
Neither of us ok
But still standing
And breathing, masked.
I listen, wordless Then offer small comforts While dreaming of our reinvention We are forever changed Together We breathe We stand, masked but not unseeing In the light of the dawn.
Happy, healthy and safe New Year to all!
- 1.Steindl D, Boehmerle W, Körner R, et al. Novichok nerve agent poisoning. Lancet. Published online December 22, 2020. doi:10.1016/S0140-6736(20)32644-1
- 2.Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning. The Lancet. Published online February 2008:597-607. doi:10.1016/s0140-6736(07)61202-1
- 3.Hulse EJ, Haslam JD, Emmett SR, Woolley T. Organophosphorus nerve agent poisoning: managing the poisoned patient. British Journal of Anaesthesia. Published online October 2019:457-463. doi:10.1016/j.bja.2019.04.061
- 4.Eddleston M, Chowdhury FR. Organophosphorus poisoning: the wet opioid toxidrome. The Lancet. Published online December 2020. doi:10.1016/s0140-6736(20)32749-5
- 5.Davis C, Samuels E. Continuing increased access to buprenorphine in the United States via telemedicine after COVID-19. Int J Drug Policy. Published online August 15, 2020:102905. doi:10.1016/j.drugpo.2020.102905
- 6.Gautret P, Lagier J, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949. doi:10.1016/j.ijantimicag.2020.105949
- 7.Prather K, Wang C, Schooley R. Reducing transmission of SARS-CoV-2. Science. 2020;368(6498):1422-1424. doi:10.1126/science.abc6197
- 8.Yip L, Bixler D, Brooks D, et al. Serious Adverse Health Events, Including Death, Associated with Ingesting Alcohol-Based Hand Sanitizers Containing Methanol – Arizona and New Mexico, May-June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(32):1070-1073. doi:10.15585/mmwr.mm6932e1
- 9.Welle L, Medoro A, Warrick B. Tainted Hand Sanitizer Leads to Outbreak of Methanol Toxicity During SARS-CoV-2 Pandemic. Ann Emerg Med. 2021;77(1):131-132. doi:10.1016/j.annemergmed.2020.07.011
- 10.Santos C, Kieszak S, Wang A, Law R, Schier J, Wolkin A. Reported Adverse Health Effects in Children from Ingestion of Alcohol-Based Hand Sanitizers – United States, 2011-2014. MMWR Morb Mortal Wkly Rep. 2017;66(8):223-226. doi:10.15585/mmwr.mm6608a5
- 11.Jones R, Schuhmann L, El-Mallakh R. A patient who prefers to imbibe ethanol-based hand sanitizer over traditional alcoholic beverages. Am J Addict. 2013;22(2):148-149. doi:10.1111/j.1521-0391.2013.00309.x
- 12.Hakimi A, Armstrong W. Hand Sanitizer in a Pandemic: Wrong Formulations in the Wrong Hands. J Emerg Med. 2020;59(5):668-672. doi:10.1016/j.jemermed.2020.07.018
- 13.Batterman S, Franzblau A. Time-resolved cutaneous absorption and permeation rates of methanol in human volunteers. Int Arch Occup Environ Health. 1997;70(5):341-351. doi:10.1007/s004200050228
- 14.Adanir T, Ozkalkanli M, Aksun M. Percutaneous methanol intoxication: case report. Eur J Anaesthesiol. 2005;22(7):560-561. doi:10.1017/s0265021505270941
- Tox and Hound — Happy New Year! - December 31, 2020
- The Dantastic Mr. Tox & Howard – S03E04 – For The Greater Good - December 28, 2020
- Tox and Hound – Fellow Friday – Endozepines and Idiopathic Recurrent Stupor – UPDATE! - November 30, 2020