It's not your father's anion gap anymore.
Back when I was starting out in emergency medicine and toxicology, the differential diagnosis for an increased anion gap was fairly simple. The mnemonic was MUDPILES: Methanol, Uremia, Diabetic ketoacidosis (or alcoholic ketoacidosis,) Paraldehyde, Iron (or Isoniazid,) Lactic acidosis, Ethylene glycol, and Salicylates.
Recent evidence indicates that this mnemonic is no longer adequate because it misses a number of important toxicological causes. New laboratory technology and methods of measuring electrolytes also have resulted in a change of what's considered a normal anion gap.
A normal value for the anion gap is now lower than in the past. The law of electroneutrality states that the positive charges (cations) in a system such as the serum must equal the negative charges (anions). Because the number of positive charges typically measured on routine lab testing is larger than the number of negative charges, the difference is called the anion gap. The formula for calculating this is anion gap = [Na+] − [Cl− + HCO3−].
Originally, a normal value was considered 12 + 4 mEq/L. Winter and Pearson et al. studied serum from healthy volunteers and blood donors, however, and determined a reference range between 3 and 11 mEq/L, with most subjects having an anion gap less than 6. (Arch Intern Med 1990;150:311.) We routinely look at the anion gap to determine whether there is a clinically significant metabolic acidosis. I still use a gap of 15 mEq/L as my cutoff for that purpose while realizing that a lower number does not rule out mild metabolic acidosis.
Massive acetaminophen (APAP) overdose can cause a high-anion gap metabolic acidosis. This is an important point that some clinicians, still wedded to the old MUDPILES mnemonic, do not yet realize. The toxic acetaminophen metabolite NAPQI in massive APAP overdose impairs mitochondrial function, impairing oxidative phosphorylation in a manner similar to that of cyanide. This occurs early, within four to six hours after ingestion, long before hepatic failure sets in.
Recent recommendations from the Extracorporeal Treatment in Poisoning Workgroup (http://www.extrip-workgroup.org) suggest that an early metabolic acidosis with altered mental status and a level greater than 900 mcg/mL is an indication for hemodialysis in an acute acetaminophen overdose. (Clin Toxicol (Phila) 2014;52:856.) A mnemonic for causes of high-anion gap metabolic acidosis that does not include acetaminophen is grossly inadequate.
Propylene glycol can also cause lactic acidosis. It is used as a diluent in a number of intravenous medications. Propylene glycol is metabolized in the liver to lactic acid, so a large-dose infusion of these medications can cause a high-anion gap lactic acidosis, especially in patients with renal dysfunction. Associated manifestations include neurotoxicity, ECG changes, and increased osmolarity. Common intravenous medications that contain propylene glycol include lorazepam, diazepam, digoxin, phenobarbital, and phenytoin.
Ibuprofen overdose also can cause high-anion gap metabolic acidosis. The number of reported overdose cases has increased dramatically since over-the-counter ibuprofen became available in 1984. Fortunately, most of these cases involve only mild toxicity and resolve with supportive care. Massive ibuprofen overdose can cause severe toxicity, however, with manifestations that include coma, hypothermia, hypotension, seizures, acute renal failure, and, rarely, death despite aggressive supportive care.
High-anion gap metabolic acidosis can also occur. This results from a combination of lactic acidosis and accumulation of exogenous acids consisting of ibuprofen and its metabolites. Treatment is generally supportive. Ibuprofen is highly protein-bound, so hemodialysis would not be expected to increase elimination significantly, but may be indicated to help correct severe acidosis.
Following changes in the anion gap can replace arterial blood gas tests for monitoring progression of metabolic acidosis. Many clinicians will perform an arterial puncture to determine whether acidosis from a known cause such as ethylene glycol poisoning is getting worse or resolving. This is completely unnecessary and unwise, given the discomfort and risk of arterial injury, though admittedly slight. A simple venipuncture for basic electrolytes will allow calculation of the anion gap, which will indicate trends and reflect whether metabolic acidosis is worsening or resolving.
Clearly, MUDPILES is no longer adequate as a memory aid for recalling the complete differential diagnosis for a high-anion-gap metabolic acidosis. We need an expanded version. The best one I've seen is A CAT MUDPILE. (See table.)
Speaking of mnemonics, I thought I'd pass along my favorite of them all. See if you can determine what it represents: Frank Sinatra Takes Four Fifths Seagram's Seven Each Night To Ease Tension. The answer is at the bottom of the table.
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