Understanding Toxic Alcohols & ASA

1. Toxic Alcohols and ASA Heather Patterson PGY-3 Jan 17, 2007

2. Objectives • Review of: • Toxicokinetics • Basic Pathophysiology • Clinical Features • Managment

3. Case 1: • 18M • Drinking with friends • Brought to ED because he was having ++N/V and abdo pain and seemed overly intoxicated • Thought it was strange because he really hadn’t had that much to drink • Mixed their own drinks. But didn’t have enough booze for “good” drinks. So they added a little of this, a little of that – just to help out a bit.

4. Investigations • Usual toxic w/u • Labs • Lytes, including Ca • Anion and osmolar gaps • Urine for crystals

5. Case • Osmolar gap: 12 • Anion gap: 14 • What is your DDx for anion + osmolar gap? • Methanol • Ethylene glycol • Propylene glycol • Alcoholic or starvation ketoacidosis • DKA • Acteonitrile

6. Case • With toxic alcohol ingestions: • What causes an osmolar gap? • What causes an anion gap?

7. Case • Who is the sickest? • Patient A: wide osmolar gap, minimal AG • Patient B: smaller osmolar gap, high AG

8. Osmolar Gap DDx Ddx of Osmolar Gap

9. Osmolar Gap • Osmolality • Solute/kg of solvent • Lab measures • Osmolarity • Solute/liter of solution • You calculate!

10. Osmolality Osmolarity Formulas • Other formulas…….

11. Osmolality Formulas Osmolarity Formulas • Calgary • 1.86Na + BUN + glucose + 9 • 1.86: • 93% is in Na+, Cl- (ionized form) and the remainder is in the NaCl (nonionized form) • +9 factor: • Accounts for other osmotially active molecules ie K, Ca, proteins • Thought to be the best formula: Dorwat Clin Chemistry 1975.

12. Case Case 1 • Intoxicated male • Na 140, BUN 5, Gluc 5, EtOH 75 • Osmolality = 385 Does he have a gap? How does EtOH effect osmolar gaps?

13. EtOH and Osmolar Gap Ethanol and the Osmolar Gap • 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

14. EtOH and 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

15. 35 yo male Took a swig of a mug that had antifreeze Na 140 BUN 5 Gluc 5 HCO3 24 EtOH 25 Osmolality 321 Osmolarity = 321 No anion gap What is a normal osmolar gap? Case

16. Osmolar Gap • Case 2: osmolar gap = 0 Can osmolar gaps be used to rule out toxic alcohol ingestions? Is there a “cutoff” where toxic alcohols should be routinely measured?

17. Normal Osmolar Gap:Hoffman. J Toxicol Clin Toxicol. 19932Na + BUN + Gluc + EtOH -14 +10 +4 -2 -8

18. Osmolar Gap • When should we measure toxic alcohols? • 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!!! -14 0

20. Osmolar Gap • Additional problems/questions: • 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. Osmolar Gap • So how do we use this most effectively? • 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 • Remember: osmolar gaps are irrelevant when the patient has an AGMA from toxic metabolites

22. Methanol • What products contain methanol? • Paint remover, varnish, washer fluid, antifreeze, carborator fluid, glass cleaner, gasoline substitute, canned heating products, wood spirits/alcohol • What is a toxic dose: • Blindness: 4ml of 40% • Lethal: 15ml of 40% • Peak levels and half life? • 30-90 min • T ½ = 14-20 h for small ingestions • T ½ = 24-30h for large ingestions

23. Methanol Metabolism

24. Methanol • Why is the half life longer with higher doses of methanol? • Clue – what is first order kinetics vs zero order kinetics?

25. Basic Pathophysiology • Formic acid: • High affinity for iron • Indirectly inhibits cytochrome oxidase enzymes • Leads to ATP depletion, anaerobic metabolism, lactic acidosis • Ocular injury: • Myelin damage  axonal disruption • Acidosis  increased diffusion of formic acid into neurons  increased acidosis etc etc

26. Basic Pathophysiology • Basal Ganglia: • Uncertain why the affinity for the basal ganglia – especially the putamen • Hemorrhage, necrosis, cysts

27. Methanol: clinical features • Onset: • May be delayed 18+ hours especially if coingested with EtOH • Vitals: • CVS normal unless preterminal (hypotension, dysrhythmias) • Tachypnea – Kussmauls is uncommon

28. Methanol: clinical features • Cardinal Presentation: GI + Ocular + CNS • GI: • N/V/ abdo pain, pancreatitis with increased amylase • Due to mucosal irritation • Ocular (50%): • Most common: “Snow field: or dense central scotoma • Diplopia, blurred vision, photophobia, fixed dilated pupils, retinal edema/hyperemia • LOOK AT THE RETINA • Changes occur 18-48h

29. Methanol: clinical features • CNS • This is a spectrum • Headache, dizziness/vertigo, ataxia, confusion, sz, coma • May be difficult to assess if they have coingestants or are significantly altered

30. Case • You send a urine sample from your intoxicated teenager. • Lab report: • Many octahedral crystals • Urine fluoresces under wood’s lamp • If the urine didn’t fluoresce can you r/o EG toxicity?

31. EG: Pathophysiology

32. EG: Pathophysiology • Multiple toxic metabolites – oxalate is the most toxic • Mechanism for tissue toxicity not fully understood. • Tissues targeted: • CNS • Kidney • Lung • Muscle including cardiac • Retinal

33. EG: Clinical • Stage 1: Acute neurological (1-12h) • Inebriated, ataxic • Hallucinations, sz, coma, death • Fundi N • Occular abnormalities not seen in pure ingestion

34. EG: Clinical • Stage 2: Cardiopulmonary (12-24h) • Tachy, mild HTN, tachypnea • Arrhythmias secondary to ↓Ca • ARDS, CV collapse, Cardiomegaly

35. EG: Clinical • Stage 3: Nephrotoxicity (24-72h) • Urine crystals • Ca oxalate 50% • Dihydrate or monohydrate • Hematuria, proteinuria • Flank/CVA tenderness • ATN • Oliguric or anuric ARF

36. EG: Clinical • Stage 4: Delayed Neuro Sequelae (6-12days) • CN palsies • VII, VIII common • Multiple possible neurological findings • focal and cognitive deficits

37. Mangement: Approach • The 5 A’s • ABCs and supportive care • Alkalinize • Alcoholize • Accelerate Elimination – Dialysis • Adjuncts • Goals: • Correct acidosis • Block alcohol dehydrogenase • Remove parent alcohol

38. Mangement: Decontamination • Is charcoal indicated with toxic alcohol ingestion? • CHILE: • Caustics • Hydrocarboms • Iron • Lead, Li • Ethanol/methanol/ethylene glycol

39. Mangement: Alkalinize • Goal: • pH 7.45-7.5 • Rationale?: • Normalizing pH ioninzes formic acid/oxalic acid and limits its movement into CNS/eyes • Helpful in those with cardiovascular instability • Method? • Bolus: 1-2 mEq/kg • Maintenance: 1.5-2x mainenance

40. Management: Alcoholize • When to start an antidote? • AACT Consensus statements • Strong suspicion of ingestion and 2 of: • Osmole gap > 10, • pH < 7.3, or • Bicarb < 20, or • Urinary oxalate crystals (EG) • Documented ingestion and OG > 10 • Me >6 mmol/L, EG > 3 mmol/L

41. Management: Alcoholize/Antidote • What options do you have? • EtOH vs Fomepizole? • EtOH: • Cheap • Difficult to dose • Metabolic effects • Toxic effects • Fomepizole: • Expensive • Easy q12h dosing • No drunk and rowdy pt

42. Management: Alcoholize • EtOH infusion (10% solution): • Loading dose: 10cc/kg • Maintenance: 1cc/kg/hr • Goal: 20-30mmol/L • Dosing in alcoholics? • Dosing during dialysis? • Often infusion runs for 2-3 days • What can you use if no IV EtOH available?

43. Managment: Antidote • Fomepizole: • Loading: 15 mg/kg load • Maintenance 10 mg/kg q12hr X4, then 15 mg/kg q12hr • Continue treatment until methanol level is acceptable, pt asymptomatic, and normal pH

44. Managemt: Adjuncts • How do the treatment of Methanol and Ethylene glycol differ?

45. Methanol: Adjuncts • Folate: • Cofactor in conversion of formic acid to H20 and CO2 • Dose: 50mg IV q4h x 2 days

46. EG: Adjunts • Dosing: • Thiamine 100mg IV q6h • Mg 2-4g IV • Pyridoxine 50 IV q6h x 2days

47. EG: Managment • What about the hypocalcemia? • MUST be replaced • Calcium chloride (10%) 10 mls • Follow levels and EKG

48. You are the STARs doc-on call Called from Taber 14month old M found on the floor with small container that used to hold fuel for a model car 80% Methanol 60 mins post suspected ingestion Not curretly showing symptoms/signs of intoxication Real Case

49. 30 minutes later, the child starts looking a bit intoxicated It is also WAY past his bedtime Parents say he always “walks like that” Real Case

50. Case • 52M found on park bench altered LOC • Bottle of rubbing alcohol beside him • It is half full