Toxicology Rounds

Figure: poison, toxicology, toxicity treatmentFigureTreating poisoned patients in the ED can be a challenge, especially with the constant barrage of new drugs that can lead to adverse effects for our patients. From sodium-glucose cotransporter-2 inhibitors for type 2 diabetes mellitus to toxic alcohols and digoxin toxicity, emergency physicians have to be on their toes. Hopefully, these pearls will help. Toxicology of Medications for Diabetes Mellitus Baumgartner K, Devgun J Crit Care Clin. 2021;37(3):577 Sodium-glucose cotransporter-2 (SGLT2) inhibitors are FDA-approved for controlling blood glucose levels in type 2 diabetes mellitus, and emergency physicians should be aware that patients taking them can present with euglycemic diabetic ketoacidosis. Baumgartner and Devgun point out that these agents have a unique mechanism of action because they do not work by increasing insulin release or decreasing insulin resistance, unlike other oral hypoglycemics. Rather, they increase renal excretion of glucose. Glucose in healthy nondiabetics is filtered through the glomerulus and then completely resorbed in the proximal tubule. That is why normal urine is negative for glucose. SGLT2 inhibitors interfere with this resorption, increasing renal excretion of glucose, lowering serum glucose levels, and secondarily decreasing insulin release. The SGLT2 inhibitors approved at this time in the United States are canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance), and ertugliflozin (Steglatro). If you're like me, all the relatively new diabetes medications on the market make it difficult to distinguish the glucagon-like peptide-1 receptor agonists like dulaglutide (Trulicity) from the dipeptidyl peptidase-4 inhibitors like sitagliptin (Januvia) and the SGLT2 inhibitors. Remember that all SGLT2 inhibitors end in flozin, and as a result of taking them, glucose flows into the proximal tubule but does not flow out. Fans of Disney movies might better remember the mechanism of these drugs by thinking: flozin sounds like the movie “Frozen,” which makes you think of its hit song, “Let It Go.” They make the kidney let go of glucose rather than holding on to it. Use whichever version works for you. I know it's kind of silly, but this is how I got through medical school. As a result of increased levels of glucose in the urine, adverse effects associated with SGLT2 inhibitors include UTIs and genital mycotic infections. But as Baumgartner and Devgun suggested, the most clinically significant adverse effect for emergency physicians to be aware of is increased incidence of euglycemic diabetic ketoacidosis (eDKA). This term is somewhat of a misnomer because the serum glucose isn't really abnormal, just lower than expected, with levels in the high 100s to low 200s. This makes the diagnosis easy to miss. Patients with eDKA usually present with nonspecific symptoms such as nausea, vomiting, abdominal pain, decreased appetite, fatigue, and dyspnea. Crucial tests that can confirm the diagnosis include arterial blood gas (physician of <7.3), serum bicarbonate (<18 mEq/L), and serum ketones. Urine ketone testing alone is not adequate because this will detect only acetoacetate and acetone but not beta-hydroxybutyrate, which is the major ketone in DKA. Clinicians should also try to identify factors that may have precipitated the episode of DKA. (See table.) Baumgartner and Devgun noted that treating DKA associated with SGLT2 inhibitors is similar to standard DKA therapy except that dextrose infusion should be started immediately. Of course, the SGLT2 inhibitor should be discontinued at least temporarily, and serious consideration should be given to whether the drug should be resumed at all. If it is, the patient should be counseled about the significance of nonspecific symptoms and how to deal with acute infection and other precipitating factors. Toxic Alcohols Ross JA, Borek HA, Holstege CP Crit Care Clin. 2021;37(3):642 Ethylene glycol and methanol are often elided in clinicians' minds under the general category of toxic alcohols without considering the nuanced subtle distinctions between the two. These researchers from the University of Virginia make the important observation that “[u]nlike ethylene glycol, there is no significant renal elimination of methanol.” Instead, unchanged methanol is eliminated through the lungs in exhaled air, and has an elimination half-life about three times greater than that of ethylene glycol (52 v. 17 hours, respectively). Because of this, some ethylene glycol-poisoned patients with intact renal function and no other indication for hemodialysis can be treated with fomepizole alone, letting unmetabolized ethylene glycol be cleared through the kidneys. Native clearance with methanol, however, will be extremely prolonged once alcohol dehydrogenase is blocked, and hemodialysis will be indicated more frequently. As always, the local poison control center, which should be consulted on any alcohol-poisoned patient who requires fomepizole or hemodialysis, can help sort through the different treatment options. Cardiovascular Drug Toxicity St-Onge M Crit Care Clin. 2021;37(3):563 Less may be more when considering the dose of antidote in digoxin toxicity. St-Onge from the Centre Antipoison du Quebec remarked that “in chronic [digoxin] toxicity, one vial of digoxin-Fab at a time should be sufficient for reversal.” She referenced the work of Chan, et al., in Australia, who have argued that changes in hemodynamics seen in these patients are often due to comorbidities and concurrent medications, not primarily digoxin overdose. (Clin Toxicol [Phila]. 2019;57[7]:638.) I have also advocated for the less-is-more approach. (EMN. 2018;40[5]:20; http://bit.ly/2HZAoBB.) This method is only appropriate for a relatively stable patient. Administering a full neutralizing dose of 10 vials would be reasonable in rare cases of cardiac arrest or peri-arrest thought to be caused by digoxin toxicity. There is no consensus on this issue. The current version of Goldfrank's Toxicologic Emergencies (11th edition, McGraw Hill: New York; 2019), for example, recommends an empiric dose of three to six vials of digoxin Fab in chronic toxicity. Again, consultation with the local poison control center is recommended for any patient with digoxin toxicity in whom therapy with digoxin-Fab is being considered. Dr. Gussowis a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Follow him on Twitter@poisonreview, and read his past columns athttp://bit.ly/EMN-ToxRounds.

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