Toxicology Anion Gap, Osmolar Gap & Toxic Alcohols - PowerPoint PPT Presentation

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Toxicology Anion Gap, Osmolar Gap & Toxic Alcohols
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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?