Understanding Toxic Alcohols in Emergency Medicine

1. Toxic Alcohols John Kashani D.O. Attending, St. Joseph’s Emergency Department Staff Toxicologist, New Jersey Poison Center

2. Case • An 18 year old male is brought into the ED by his mother when he was difficult to awaken in the AM • He was partying the night before, he is not able to provide a history • He becomes progressively more obtunded while in the ED

3. Case • A 22 year old frustrated medical student drinks a bottle of formaldehyde he stole from gross anatomy lab • He complains of throat and esophageal irritation and has had multiple episodes of emesis

4. Case • A 65 year old man is found comatosed • His wife states that he has been depressed recently and has been drinking heavily • An empty bottle of antifreeze was found in his kitchen garbage can

5. Case • A 17 year old female ingests a bottle of rubbing alcohol • She appears drunk, has multiple episodes of emesis and complains of abdominal pain

6. Case • A 25 year old man presents to the ED with blurry vision • For the past few days he has been feeling “cruddy” • He admits to the ingestion of homemade everclear 3 days prior

7. Objectives • Outline the “toxic” alcohols and potentially toxic alcohols • Discuss the pharmacology, kinetics and pathophysiology of the toxic alcohols • Discuss the clinical manifestations, diagnosis and management of patients poisoned by these agents

8. Introduction • Alcohols are hydrocarbons that contain a hydroxyl group • A compound with two hydroxyl groups is called a diol or a glycol • Toxic alcohols commonly refer to methanol, ethylene glycol and isopropyl alcohol

9. Introduction • Less common but potentially toxic alcohols include diethylene glycol, benzyl alcohol and the glycol ethers

11. Ethylene Glycol • Coolant mixtures • Antifreeze • Air craft de-icing solutions • Solvent (inks, pesticides and adhesives) • Brake fluid • Heat exchangers and condensers • Glycerin substitute

12. Propylene glycol • Commonly used as a diluent for parental preparations • Environmentally safe alternative to ethylene glycol antifreeze

13. Benzyl alcohol +

14. Methanol • Antifreeze (window washer fluid) • Anti icing agent • Octane booster • Ethanol denaturant • Extraction agent • Solvent • Fuel source

15. Methanol • Varnish and paint removers • Industrial solvent • Manufacture of acetic acid, formaldehyde and inorganic acids

16. Isopropanol • Synthesis of acetone, glycerin • Solvent for oils, gums and resins • Deicing agent • Rubbing alcohol • Hair care products, skin lotion and aerosols

17. Diethylene glycol • Solvent • Sprinkler antifreeze • Paints, cosmetics HEAA +

18. Glycol ethers • Solvents • Semiconductor industry • Fingernail polishes and removers • Dyes, ink, cleaners, degreasers • Brake fluid, car wax, injector cleaner • Various household cleaning products

19. Pharmacology and Kinetics • Exposure may occur dermally, pulmonary and GI • Pulmonary absorption depends on vapor pressure • Rapidly absorbed by the gastrointestinal route

20. Pharmacology and Kinetics • Time to peak concentration • Ethylene glycol = 1 - 4 hrs • Methanol, isopropyl alcohol = 30 - 60 minutes • VD is 0.6L/kg

21. Pharmacology and Kinetics • Ethylene glycol and methanol are metabolized by alcohol dehyrogenase and aldehyde dehydrogenase • Isopropanol is metabolized by alcohol dehydrogenase • Binding affinities for • ethanol>methanol>ethylene glycol

22. Pharmacology and Kinetics • Methanol metabolism may be delayed (up to 72 hours) • The volatility of methanol contributes to its pulmonary excretion (10-20%) • Ethylene glycol is metabolized over 3 – 8 hours • Undergoes multiple oxidations

23. Pharmacology and Kinetics • Ethylene glycol is not appreciably excreted by the lungs • Isopropanol is rapidly metabolized to acetone via alcohol dehyrogenase • 20% is excreted unchanged • Acetone is predominantly renally excreted

24. (CH2OH)2 Ethylene glycol ADH CH2OHCHO Glycoaldehyde ADH CH2OHCOOH Glycolic Acid ADH Glyoxylic Acid CHOCOOH thiamine B6 Mg++ Oxalic Acid Glycine + Benzoic Acid Alpha-hydroxy-beta-ketoadipic acid Hippuric Acid

25. CH3OH Methanol ADH Formaldehyde CH2O ADH CHOOH Formic Acid Folate CO2 + H2O

26. Isopropyl alcohol CH3CHOHCH3 ADH CH3COCH3 Acetone

27. The Usual Suspects

28. Formic acid • Metabolic acidosis • Inhibits cytochrome oxidase: • Decreased ATP production • Increased anaerobic glycolysis & lactate

29. NAD+ NADH + H+ R-OH ADH

30. NADH H+ NAD+ Lactate Pyruvate NAD+ CO2 NADH H+ NADH Acetyl-CoA NAD+

31. Clinical Manifestations • Clinical manifestations may be related to the parent compound or metabolites • There may be an initial asymptomatic period • Inebriation (unreliable) • Isopropyl>ethylene glycol>methanol

32. Clinical Manifestations • Vasodilation – hypotension and reflex tachycardia • Hypoglycemia • Anion gap acidosis • Methanol and ethylene glycol • Visual disturbances (”snow Field”) • Formic acid is a retinal toxin

33. Clinical Manifestations • ATN may develop secondary to calcium oxalate crystalluria • Cranial nerve deficits have been reported with ethylene glycol

34. Clinical Manifestations • Ispopropanol ingestion usually does not cause major toxicity unless a large amount is ingested • CNS depression, hemorrhagic gastritis and tracheobronchitis

35. Diagnosis • Both ethylene glycol and methanol result in an anion gap acidosis • Isopropyl alcohol usually does not result in an anion gap acidosis • Hypocalcemia may be seen in ethylene glycol intoxication • Chelation of calcium by oxalate – calcium oxalate crystals

36. Diagnosis • The absence of crystals is an unreliable finding • The urine of a patient with ethylene glycol ingestion may fluoresce • Short lived, unreliable

37. Calcium oxalate Crystals

38. The “Osmolar Gap” Measured Serum Osmolarity Minus Calculated Serum Osmolarity [ 2(NA) + BUN/2.8 + Glucose/18+Etoh/4.6]

39. * At 100 mg/dl

41. AG mOsm mEq/L OG 0 Time since Ingestion

42. Quantitative testing • If quantitative levels are readily available they can be used to determine proper management • Best method is gas chromatography with flame ionization • Subject to false positives

43. Management • ABC’s • +/---- NGT aspiration • AC/ipecac/lavage = Bad move • Thiamine and pyridoxine in the setting of ethylene glycol toxicity • Folic acid in the setting of methanol toxicity

44. Management • Sodium bicarbonate as needed • Inhibition of Alcohol dehydrogenase • Ethanol • Fomepizole

45. Ethanol: - Oral or IV - CNS depression - Difficult titration - Frequent levels - Hypoglycemia Fomepizole: - IV - No CNS depression - Easy dosing - No levels to monitor - More predictable pharmacokinetcs - No Hypoglycemia - Cost Ethanol vs Fompepizole

46. Fomepizole…because shit happens

47. (CH2OH)2 Ethylene glycol X ADH CH2OHCHO Glycoaldehyde ADH Glycolic Acid CH2OHCOOH ADH Glyoxylic Acid CHOCOOH Thiamine 100 mg IV/day B6 100 mg/day Mg++ Oxalic Acid Glycine + Benzoic Acid Alpha-hydroxy-beta-ketoadipic acid Hippuric Acid

48. CH3OH Methanol X ADH Formaldehyde CH2O ADH Formic Acid CHOOH Folate CO2 + H2O

49. Case • An 18 year old male is brought into the ED by his mother when he was difficult to wake up in the AM • Apparently he was partying the night before, he is not able to provide a history • He becomes progressively more obtunded while in the ED

50. Case • A 22 year old frustrated medical student drinks a bottle of formaldehyde he stole from gross anatomy lab • He complains of throat and esophageal irritation and has had multiple episodes of emesis