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Toxicology Anion Gap, Osmolar Gap & Toxic Alcohols

Toxicology Anion Gap, Osmolar Gap & Toxic Alcohols. Christine Kennedy Pediatric Emergency Fellow Oct 15, 2009. Objectives. Review the causes of an anion gap Review the causes of an osmolar gap Review the “toxic alcohols” Methanol Ethylene Glycol Isopropyl Alcohol

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Toxicology Anion Gap, Osmolar Gap & Toxic Alcohols

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  1. ToxicologyAnion Gap, Osmolar Gap & Toxic Alcohols Christine Kennedy Pediatric Emergency Fellow Oct 15, 2009

  2. Objectives • Review the causes of an anion gap • Review the causes of an osmolar gap • Review the “toxic alcohols” • Methanol • Ethylene Glycol • Isopropyl Alcohol • Discuss the evidence for Fomepizole

  3. Anion Gap • AG = Na - (Cl + HCO3). Is it this simple? • AG = Measured cations - measured anions • Na is the primary measured cation • Cl & HCO3 are the primary measured anions • What are the other cations & anions?? • Normal plasma AG is 7-13 meq/L • lab dependant • Interpret with caution

  4. Anion Gap

  5. Anion Gap

  6. Anion Gap • AG= Unmeasured anions-unmeasured cations • An increase in the AG can be induced by: • a fall in unmeasured cations • Hypocalcemia, hypomagnesemia, hypokalemia • a rise in unmeasured anions • hyperalbuminemia due to volume contraction • the accumulation of an organic anions in metabolic acidosis

  7. Anion Gap • Primarily determined by the negative charges on the plasma proteins (albumin) • As a result, the expected normal values for the AG must be adjusted downward in patients with hypoalbuminemia • AG falls by 2.5 meq/L for every 10 g/L reduction in the plasma albumin concentration

  8. Anion Gap-The DDx we all learned in medical school • Methanol • Uremia • DKA, SKA, AKA • Paraldehyde • Isoniazid/Iron • Lactate • Ethylene glycol • Salicylates

  9. Anion Gap-DDx • Now, this is an okay mnemonic…although Tintinalli isn’t a fan of it • If you use it, be aware that… • There are other things to include in your Differential • It doesn’t really tell you what causes the anion gap

  10. What causes the AG? • Methanol ----> formate • Uremia--->Chronic renal failure (GFR<20=impaired excretion of acids) • DKA, SKA, AKA---> Acetaldehyde  acetylCoA B-hydroxybutyrate, acetoacetate • P • Isoniazide--->lactic acidosis 2o to seizure activity • Iron---> lactic acidosis (uncoupling of oxidative phosphorylation) • Lactate • Ethylene glycol ----> glyoxylate, glycolate, oxalate • Salicylates ----> ketones, lactate

  11. Anion Gap • Other causes of AG (due to lactate) • Metformin • Phenformin • Propylene Glycol • Carbon Monoxide • Hydrogen sulfide • Cyanide • Methemoglobinemia

  12. Anion Gap-DDx • Methanol/Metformin/Methemoglobinemia • Uremia • DKA, SKA, AKA • Paraldehyde/Phenformin/Propylene glycol • Isoniazid/Iron • Lactate…… • Ethylene glycol • Salicylates

  13. Osmolar Gap • Osmolar gap • Measured serum osmolality-calculated osmolarity • should be <10 mmol/L • Plasma osmolarity • Determined by the concentration of the different solutes in the plasma • Posm = 2[Na] + [Glc] + [BUN] + 1.25[ethanol] • Na multiplied by 2 to account for accompanying anions

  14. Osmolar Gap…which method to use???

  15. Osmolarity Formulas • Calgary • 1.86Na + BUN + glucose + 9 • Why 1.86? • 93% is in Na+ & Cl- (ionized forms) and 7% is in the nonionized forms (NaCl) • Why +9? • Intercept for multiple regression line • NB: EtOH is not automatically added! • Edmonton • 2Na + BUN + glc • Serum is only 93% water: 1.86/0.93 = 2

  16. DDx of elevated Osm Gap Withanion gap metabolic acidosis • Methanol ingestion • End-stage renal disease (GFR <10)* • Diabetic ketoacidosis** • Alcoholic ketoacidosis** • Paraldehyde ingestion • Lactic acidosis** • Ethylene glycol ingestion • Formaldehyde ingestion

  17. DDx of elevated Osm Gap Withoutmetabolic acidosis • Ethylene glycol and Methanol* • EtOH** • Isopropanol ingestion---> acetone • Diethyl ether ingestion • Mannitol • Severe hyperproteinemia • Severe hyperlipidemia

  18. Ethanol and the Osmolar Gap • Case 1 • Intoxicated male • Na 140, BUN 5, Glc 5, EtOH 75 • Osmolality 385 • Osmolarity = ____ • Osm gap = ____

  19. Ethanol and the Osmolar Gap • Case 1 • Intoxicated male • Na 140, BUN 5, Glc 5, EtOH 75 • Osmolality 385 • Osmolarity 2(140) + 5 + 5 + 75 = 365 • Osm gap = 20 • So how does EtOH affect the osm gap?

  20. Ethanol and the Osmolar Gap • Several Studies have noted the increase in osmolar gap with rising EtOH in a non 1:1 relationship • Many different EtOH conversion factors have been developed • Britten 1972: 1.74 • Glasser 1973: 1.1 • Pappas 1985: 1.12 • Geller 1986: 1.20 • Galvan 1992: 1.14 • Synder 1992: 1.20 • Hoffman 1993: 1.09

  21. Ethanol and the Osmolar Gap • Purssell. Ann Emerg Med 2001; 38: 653-659. • Derived a formula to account for the relationship between ethanol and then osmolar gap • Prospectively validated • Best formula = EtOH (mmol/L) X 1.25

  22. Explanation for EtoH X 1.25 • Ethanol has a “non-ideal” osmotic behaviour because molecules form physiochemical bonds with other molecules • Results in an effect on osmolarity that is non-uniform

  23. Data from Calgary lab This supports the 1.25 EtOH conversion

  24. Case 1 • Intoxicated male • Using 1:1 EtOH • Osmolality = 385 • Osmolarity = 2(140) + 5 + 5 + 75 = 365 • Osm gap = 20 • Redo this with EtOH X 1.25 = 94 • Osmolarity = 2(140) + 5 + 5 + 94 = 384 • Osm gap = 1

  25. Case 2 • 35 year male • Took a swig of a mug that had antifreeze • Na 140, Cl 106, BUN 5, Glc 5, EtOH 25, • HCO3 24 • Osmolality 321 • Normal anion gap (10) • Osmolarity = ___ • Osmolar gap = ___

  26. Case 2 • Osmolarity=2(140) + 5 + 5 + 1.25(25)=321 • Osmolar gap = 321 – 321 = 0 • What is the normal osmolar gap?

  27. Normal Osmolar gap • Hard to define because it depends on • Lab method of osmolality determination • Osmolarity formula used • Lab error of Na, BUN, Glc, EtOH • EtOH conversion factor used • Few studies documenting what normal osmolar gaps are in the population

  28. Normal Osmolar gap • Traditionally normal osmolar gap is <10 • In case #2 the osm gap was 0 • Can osmolar gaps be used to rule out toxic alcohol ingestions? • Is there a cut off where toxic alcohols should be routinely measured?

  29. Normal Osmolar GapHoffman. J Toxicol Clin Toxicol. 1993 Mean Osm gap= -2 SD 6.1 -14 -2 +10 -8 +4

  30. Can you still miss toxic levels? 0 Baseline -14 Osm gap 0 Methanol level 14!!! -14

  31. When should toxic alcohols be measured? AMA guidelines • Calgary • Osm gap >10: measure methanol and ethylene glycol • Edmonton • Osm gap >2: measure ethylene glycol • Osm gap >5: measure methanol

  32. When should toxic alcohols be measured? AMA guidelines • Where do the 5 & 2 come from? • “Classically” EG & methanol ingestions needed treatment at levels of 20 mg/dL in nonacidotic patients • This translates to • EG level of 3.2 mmol/L • Methanol level of 6.24mmol/L

  33. Analyzed all published case reports of MeOH poisoning to determine the applicability of the 20mg/dL (6.24mmol/L) threshold for treatment • 329 articles analyzed (2433 patients) • 70 articles met inclusion criteria (173 pts)

  34. Only 22 pts presented for care within 6 hours of ingestion • All but 1 patient was treated with an ADH inhibitor • A clear acidosis developed only with a methanol level of >126mg/dL (39.4mmol/L) • There were cases of acidosis after only a few hours of ingestion

  35. Conclusions • There are no useful data available to create treatment recommendations for the MeOH exposed pt who presents early, prior to development of toxicity • This is a time-dependent disease (which is not accounted for in the “classic” treatment recommendations)

  36. So….what is the utility of osm gap? • Osmolar gaps are not 100% reliable to exclude treatable toxic alcohol ingestions • Low suspicion-----check osmolar gap • High suspicion----check toxic alcohol levels regardless of osmolar gap

  37. Toxic Alcohols • “Toxic” • Generally reserved for any alcohol other than ethanol • A few mouthfuls can kill: • Average adult mouthful: 0.42cc/kg • Lethaldose of methanol: 1.2cc/kg • Lethal dose of ethylene glycol: 1.4-1.6cc/kg

  38. How does EtOH affect methanol & ethylene glycol metabolism • EtOH competes for the enzyme alcohol dehydrogenase • Minimizes the metabolism of methanol and ethylene glycol to their toxic metabolites • Takes longer to form an AG in methanol or ethylene glycol ingestion if there is concurrent EtOH ingestion

  39. Case 3 • 21 year male presents at 7 am • Drank 1 glass of antifreeze at 3 am, “was tired of life” • Had been drinking EtOH earlier in the night • Vomited immediately after ingestion • Now he wants to live so came to ED • O/E • T 37.2, HR 129, RR 18, BP 138/96 • Neuro: inebriated • CVS, resp, abdo all unremarkable

  40. Case 3 • What investigations would you like? • Labs • Na 141, K 3.6, Cl 107, CO2 21 • BUN 10, Cr 190, glc 6, pH 7.35 • Osmolality 329 • EtOH 8.3 mmol/L • Ethylene Glycol, methanol, isopropanol-pending • Is there a benefit of testing the urine?

  41. Case 3 • What would you like to do for this patient?

  42. Case 3 • Ethylene Glycol-7 mmol/L • Methanol-undetectable • Isopropyl Alcohol-undetectable • Does this change your treatment plan? • How about if the EG level was 9mmol/L?

  43. Case 4 • 17 male and his 13 year old girlfriend present to ACH ED at 3am • Male is obviously intoxicated, slurring his words and swearing at the triage nurse • Presenting complaint…. “my girlfriend can’t see” • Couple came from a party • Heavy drinking and marijuana consumption at the party

  44. Case 4 • Girl • Very sedated, vomited at triage • Vitals: T37.8, HR 112, BP 115/70, RR 28 • O/E: • Eye exam: mydriasis, but uncooperative • CVS normal, resp normal, abdo tender diffusely • Labs???

  45. Case 4 • Labs on girl • Glc 5 • Na 142, K 4.0, Cl 105, CO2 15 • CBG 7.25/30/55/15/-10 lactate 4 • BUN 8, Cr 55 • Osmolality 320 • EtOH 19mmol/L

  46. Case 4 • Guy • Obnoxious, ongoing slurring and swearing • Vitals: T37.9, HR 110, RR 18, BP 120/80 • O/E • Diaphoretic • H&N normal • CVS, Resp, GI normal • Labs???

  47. Case 4 • Labs • Glc 4.5 • Na 138, K 4.0, Cl 105, CO2 21 • CBG 7.35/35/55/21/-4 lactate 2 • BUN 7, Cr 70 • Osmolality 395 • EtOH 85mmol/L • U/A: +ketones

  48. Case 4 • What’s the girl’s diagnosis? • What do you want to do for her? • What’s the guy’s diagnosis? • What do you want to do for him?

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