This is a special post based on recent FDA and CDC advisories
Reviewed by Dr. Sage Wiener
A 42-year-old man presents to the ED with a history of alcohol use disorder, brought in by EMS for intoxication and acute vision loss.
Triage vitals are BP 108/90 mm Hg, HR 105/min, RR 20 /min, Sat 100% RA, FS 125 mg/dL
The patient is not able to answer any questions. He is accompanied by his daughter who says that he hasn’t been able to get alcohol due to social distancing requirements and closed businesses. The patient has been drinking his family’s cheap hand sanitizer to manage his habit.
You luckily remember that the FDA (through product recalls) and the CDC [through a HAN (Health Alert Network) alert] both released warnings about methanol-containing hand sanitizers.[1,2] So far, at least three have died with seven total cases in New Mexico and at least six cases in Arizona involving the Apache and Navajo nations have been linked to alcohol-based hand sanitizers or rubs (ABHSR) containing methanol.[3,4]
Basic Background Basic Pathophysiology: Methanol is readily absorbed and rapidly distributed. One study with healthy volunteers (Graw et al) found a volume of distribution of 0.77 L/kg with a distribution half-life of about eight minutes. This half-life is only slightly longer than absorption half-life, leading to peak concentration shortly after absorption.[5,13] Methanol then quickly undergoes metabolism similar to ethanol (figure 1) first via Alcohol Dehydrogenase (ADH) to formaldehyde and then via Aldehyde Dehydrogenase (ALDH) to formic acid.[5] Like ethanol, metabolism of methanol follows zero-order kinetics at about 10 mg/dL/h.[5] Methanol is not significantly eliminated by the kidney and is presumed to be eliminated via vapor in expired air, leading to a half-life of about 30 – 54 hours (Palatnick et al). However, Palatnick et al tracked the half-life for patients who received fomepizole but not hemodialysis, further supporting the need for emergent hemodialysis.[5,14] Fomepizole and ethanol are competitive ADH antagonists, preventing the metabolism of methanol to formate, thereby preventing metabolic acidosis and retinal toxicity. Fomepizole is generally favored when available due to comparative ease of use and potential adverse effects of ethanol. ADH antagonists do nothing to eliminate methanol, so it is still very important to obtain hemodialysis. Giving folic acid enhances the conversion of formate to carbon dioxide, and water and is a reasonable adjunctive therapy. Figure 1: Metabolism of Methanol, EBM Consult[15] In terms of the laboratory evaluation, it is important to consider timing. Early on after toxic exposure, you will see a large serum osmolar gap because methanol and other toxic alcohols are unaccounted for osmotically active molecules. But because they aren’t charged they won’t cause an anion gap. However, as methanol is metabolized to formic acid you will decrease your osmolar gap, while simultaneously increasing your anion gap because the metabolites aren’t osmotically active, but they are unaccounted for anions in your laboratory panels. This timing change can be seen in Figure 2. Figure 2: Time Course of Osm Gap and Anion Gap, EMCRIT[16] The traditional CATMUDPILES (Cyanide/CO Aminoglycosides/Acetaminophen Toluene/Theophylline Methanol Uremia DKA/AKA/SKA Phenol/Phenformin/Metformin/Paraldehyde INH/Iron/Inborn errors of metabolism Lactate Ethanol/Ethylene glycol/Salicylates) acronym for the differential diagnosis of metabolic acidosis with an elevated anion gap can be more easily simplified: KULTS (Ketones Uremia Lactate Toxic-alcohols Salicylates) focuses on the most common etiologies. This approach is supported by many toxicologists including the Tox and the Hound.[17] You might still see elevated lactate as formate is an inhibitor of oxidative phosphorylation and can lead to increases in anaerobic respiration. Additionally, both ADH and ALDH require NAD+ resulting in an increased NADH:NAD+ ratio, which favors the conversion of pyruvate to lactate.[5] End-Organ Damage: Summary: 1. FDA advises consumers not to use hand sanitizer products manufactured by Eskbiochem | FDA. Drug Safety and Availability. https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-consumers-not-use-hand-sanitizer-products-manufactured-eskbiochem. Published 2020. Accessed July 9, 2020.
Management:
So you know the diagnosis, but what do you do?
ABHSRs are the most common form of hand sanitizers, in which 99.1% of product by volume is ethanol based according to an FDA report.[7] Further, in 2019 the FDA made a rule change only allowing hand sanitizers to contain one of three ingredients; ethanol, isopropyl alcohol, or benzalkonium chloride.[8] Ethanol is probably the safest option, but due to concerns for unintentional ingestions by children and abuse, many brands such as Purell have a bittering agent added, as recently recommended by the FDA.[9] ABHSRs contain 60 – 90% alcohol and are generally cheaper and more easily obtainable than alcoholic beverages. In places where alcohol availability is restricted, such as some Native American reservations, it is a readily available alternative for consumption. Further, the COVID-19 pandemic has forced many people to stay at home and many businesses to close, reducing access to alcohol. With the increased demand for ABHSRs, more manufacturers have stepped in, and many of them not following standard distillation practices to remove methanol. Even some microbreweries and microdistilleries have started producing hand sanitizers, and it is suspected that some people may be making their own.[10]
Methanol is the lowest molecular weight alcohol, 32 Da, compared to 46 Da of ethanol, and an animal study by Wallgren H suggests this makes it the least intoxicating alcohol.[5,11] The most common mode of exposure is through oral ingestion, however, there have been cases of both inhalational and transdermal exposures. Transdermal exposures are potentially relevant to ABHSRs, however, such exposures are more likely to be common in infants due to their increased surface area to mass ratio. A cluster of deaths in Egypt was reported after the application of methanol as a topical antipyretic.[5,12]
For methanol, the classic finding is a change in vision, which can be blurriness, hazy vision, defects, snowfield vision, or total blindness, and might even be asymmetric. You may find an afferent pupillary defect, hyperemia, pallor of the optic disc, and papilledema. Methanol toxicity can also cause CNS injury, such as bilateral basal ganglia necrosis with or without hemorrhage. These injuries are often permanent.
References
2. CDCHAN-00434. Serious Adverse Health Events Associated with Methanol-based Hand Sanitizers. CDC Health Alert Network. https://emergency.cdc.gov/han/2020/han00434.asp. Published 2020.
3. Fazio M. 3 Die in New Mexico After Drinking Hand Sanitizer, Officials Say – The New York Times. New York Times. https://www.nytimes.com/2020/06/26/us/3-dead-drinking-hand-sanitizer.html. Published 2020. Accessed July 9, 2020.
4. UArizona Poison Center Warns of Toxic Alcohol Poisonings from Contaminated Hand Sanitizer | The University of Arizona Health Sciences. https://uahs.arizona.edu/news/uarizona-poison-center-warns-toxic-alcohol-poisonings-contaminated-hand-sanitizer. Accessed July 9, 2020.
5. Wiener S. Toxic Alcohol. In: Goldfrank’s Toxicologic Emergencies. 10th ed. McGraw-Hill Education; 2015:1346-1357.
6. Roberts DM, Yates C, Megarbane B, et al. Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement. Crit Care Med. 2015;43(2):461-472. doi:10.1097/CCM.0000000000000708
7. Staff E, Planning O of, Office of Policy, Planning, Legislation and A, Commissioner O of the. Safety and Effectiveness of Consumer Antiseptic Rub Products; Topical Antimicrobial Drug Products for Over-the-Counter Human Use.; 2016. https://www.fda.gov/media/129482/download. Accessed July 11, 2020.
8. Federal Register :: Safety and Effectiveness of Consumer Antiseptic Rubs; Topical Antimicrobial Drug Products for Over-the-Counter Human Use. https://www.federalregister.gov/documents/2019/04/12/2019-06791/safety-and-effectiveness-of-consumer-antiseptic-rubs-topical-antimicrobial-drug-products-for. Accessed July 11, 2020.
9. Coronavirus (COVID-19) Update: FDA Continues to Ensure Availability of Alcohol-Based Hand Sanitizer During the COVID-19 Pandemic, Addresses Safety Concerns | FDA. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues-ensure-availability-alcohol-based-hand-sanitizer-during. Accessed July 11, 2020.
10. GRIBBINS K. We honor these craft brands helping make hand sanitizer, from Two Brothers and 3 Daughters to Rogue and SanTan (updated). Craft Brewing Business. https://www.craftbrewingbusiness.com/featured/we-honor-these-craft-brands-helping-make-hand-sanitizer-from-two-brothers-and-3-daughters-to-rogue-and-santan/. Published 2020. Accessed July 12, 2020.
11. WALLGREN H. Relative intoxicating effects on rats of ethyl, propyl and butyl alcohols. Acta Pharmacol Toxicol (Copenh). 1960;16:217-222. doi:10.1111/j.1600-0773.1960.tb01205.x
12. Darwish A, Roth CE, Duclos P, et al. Investigation into a cluster of infant deaths following immunization: evidence for methanol intoxication. Vaccine. 2002;20(29-30):3585-3589. doi:10.1016/s0264-410x(02)00293-1
13. Graw M, Haffner HT, Althaus L, Besserer K, Voges S. Invasion and distribution of methanol. Arch Toxicol. 2000;74(6):313-321. doi:10.1007/s002040000107
14. Palatnick W, Redman LW, Sitar DS, Tenenbein M. Methanol half-life during ethanol administration: implications for management of methanol poisoning. Ann Emerg Med. 1995;26(2):202-207. doi:10.1016/s0196-0644(95)70152-4
15. Anthony J. Busti, MD, PharmD, FNLA F. Methanol Toxicology – An Overview. EBM Consult. https://www.ebmconsult.com/articles/methanol-toxicology. Published 2015. Accessed July 11, 2020.
16. Spiegel R. You Don’t Understand the Osm Gap – Guest Post by Rory Spiegel. EMCRIT. https://emcrit.org/emnerd/osm-gap/. Published 2015. Accessed July 11, 2020.
17. Spyres M. Tox and Hound – The KULTS of Toxicology. Tox and the Hound. https://emcrit.org/toxhound/kults-of-toxicology/. Published 2018. Accessed July 11, 2020.
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