1. Osmolar Gaps: How does EtOH contribute to osmolar gaps? Can osmolar gaps be used to rule out toxic alcohols? Rob Hall PGY4 Lab Rounds Jan 15, 2004

2. Why review? Osmolar gaps aren’t perfect thus why use? Routine measurement of toxic alcohols is impractical – Labor intensive – Long turn around time – Only measured in tertiary care centers Osmolar gaps thus likely have some role and we need to know the major limitations

3. Osmolar Gap = Osmolality - Osmolarity Osmolality – Solute/kg of solvent – L ab measures Osmolarity – Solute/liter of solution – You calculate!

4. Ddx of Osmolar Gap PProteins AAlcohols (EtOH, methanol, ethylene glycol, isopropanol, propylene glycol, diethylene glycol, triethylene glycol) SSugars (mannitol, glycerol, sorbital) CContrast dyes AAcidosis (ketoacidosis, lactic acidosis) LLipids AAcetone

5. Osmolar Gaps Which formula is best?

6. Osmolarity Formulas Other formulas…….

7. Osmolarity Formulas Calgary – 1.86Na + BUN + glucose + 9 – Why 1.86: 93% is in Na+, Cl- (ionized form) and the remainder is in the NaCl (nonionized form) – Why +9 factor: intercept for multiple regression line – Thought to be the best formula: Dorwat. Clin Chemistry 1975. – NB: EtOH is not automatically added! Edmonton – 2Na + BUN + glucose – Serum is only 93% water: 1.86/0.93 = 2

8. Case 1 Intoxicated male Na 140, BUN 5, Gluc 5, EtOH 75 Osmolality = 385 Osmolarity = 2(140)+5+5+75 = 365 Osm gap = 20 How does EtOH effect osmolar gaps?

9. 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… – Geller 1986: 1.20 – Galvan 1992: 1.14 – Synder 1992:1.20 – Hoffman 1993:1.09 – Pappas 1985:1.12 – Britten 1972:1.74 – Glasser 1973: 1.1

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

11. Explanation for EtOH X 1.25 Ethanol has a “non-ideal” osmotic behavior Ethanol has a non-ideal osmotic behavior because molecules form physiochemical bonds with other molecules resulting in an effect on osmolarity that is non-uniform

12. Data from our own Lab! This data supports the 1.25 EtOH conversion

13. Case 1 With EtOH of 75: – Osm gap = 20 With EtOH 75 X 1.25 – Osm gap = 1

14. Case 2 35 yo male Took a swig of a mug that had antifreeze Na 140, BUN 5, Gluc 5, EtOH 25 Osmolality = 321 NO anion gap (HCO3 24) Osmolarity = 2Na + BUN + Gluc + EtOH X 1.25 = 321

15. Case 2 Osmolar gap = 321 - 321 = 0 What is a normal osmolar gap? Does this rule out a significant toxic alcohol ingestion?

16. What is a “ Normal ” Osmolar Gap? Traditional normal gap is < 10 It is not that simple!!!!! Depends on……….. – Lab method of osmolality determination – Osmolarity formula used – Lab error of Na, BUN, Gluc, EtoH – EtOH conversion factors used There are few studies documenting what normal osmolar gaps are in the population

17. Normal Osmolar Gap: Hoffman. J Toxicol Clin Toxicol. 1993 2Na + BUN + Gluc + EtOH -8 -2 +4 +10 -14

18. Case 2: osmolar gap = 0, should we measure toxic alcohols? AMA guidelines Calgary (1.86Na + BUN + Gluc + EtOH +9) – Osmolar gap > 10: measure methanol and ethylene glycol Edmonton (2Na + BUN + Gluc + EtOH) – Osmolar gap > 2: measure ethylene glycol – Osmolar gap > 5: measure methanol

19. Can these cut offs r/o a significant toxic alcohol ingestion? Baseline -14 Osm gap 0 Methanol level of 14!!! -140

20. Additional problems What is the normal distribution for the formula that we use in Calgary for osmolarity? What is the true effect of EtOH? What is a significant toxic alcohol level? – Nobody really knows! – Evidence for when to dialyze based on case series and case reports. – Are you willing to miss a methanol level of 5, 10, or 15 mmol/L?

21. So what is the utility of the osmolar gap?

22. Conclusions 1 EtOH has contributes more to osmolarity than expected: EtOH X 1.25 is likely the best conversion factor Which formula to use for osmolarity? – It doesn’t really matter, just be aware of suggested cut offs for toxic alcohol measurement and the inherent limitations of such cut offs

23. Conclusions 2 Remember: osmolar gaps are irrelevant when the patient has an AGMA from toxic metabolites Osmolar gaps are NOT 100% reliable to exclude treatable toxic alcohol ingestions Low suspicion ------ check osmolar gap High suspicion ------ low threshold to check toxic alcohol levels regardless of osmolar gap

24. REMINDER: how often to measure levels Dialysis of Methanol [Methanol] vs time to level < 6 mmol/L – 16012hrs – 10010hrs – 558hrs – 306hrs – 154hrs – 73hrs Ethanol therapy alone for Methanol – ADH is blocked by EtOH; excretion by pulmonary/renal – T1/2 increases A LOT – T ½ 30-70hrs – Don’t measure levels q 4hrs!