Interesting Case Rounds

1. Interesting Case Rounds Chris McCrossin Special Thanks to Dr Vicas and Paul Tourigny

2. Case • 21 yo M presents to ED at 8:50 AM • Drank 1 glass of antifreeze at 2am, was “tired of life” • Vomited immediately after the ingestion • Now he wants to live so he thought he should get checked out in the ED • Vitals • T 37.2, HR 129, RR 18, BP 138/96 • O/E • CVS, Resp, Neuro, Abdo all unremarkable

3. Case • Are you worried? • He tells you he vomited “right away”, does this change anything? • What if you are a rural doc with access only to basic to labs?

4. Ethylene Glycol • Pathophysiology • Diagnostics • Treatment modalities

5. ~ 30% excreted unchanged

6. Acute CNS Within 12 h Slurred Speech Ataxia Altered mental status AG, Oxalate crystalluria Cardiopulmonary 12 - 24 h HTN Tachycardia CHF Renal Failure 24-72 h Oliguria Flank Pain Azotemia Delayed CNS 6-12 days Cranial neuropathies Motor deficits Cognitive deficits Stages of Toxicity

7. Toxic Levels • What ingested dose do you start to worry about EG toxicity? • Minimum Lethal Dose: • 1-2 ml/kg (ie 70 cc in 70 kg adult = 1/3 cup) • 30-60 ml can result in death or severe impairment • What serum level do you worry about EG toxicity? • Not reliable, especially if late presenting; metabolites that are toxic (EG may be low in presence of high [metabolites]) • Will talk about more specifics with treatment

8. Case • Labs • Na 141, K 3.6, Cl 107, CO2 21 • EthOH 8.3 mmol/L • Ethylene Glycol 10 mmol/L • Isopropanol, methanol undetectable

9. Case • What do you want to do? • More labs? • Treatment? • Start ethanol drip? • Start fomepazole? • Start dialysis?

10. Urinalysis • Crystalluria is only seen in ~ 15-50% of cases • Hematuria and proteinuria are more common • Helpful if you see oxalate crystals in the unknown overdose but it doesn’t tell you anything if you don’t see it

11. Anion Gap • Na - [HCO3 + Cl] • Normal 7 +/- 4 • Detects toxic metabolites; expect it to be normal in the early period following ingestion

12. Anion Gap • 141 - [107+21] = 13 • What does this tell you? • What if he had an AG of 28 and an EthOH level of 40?

13. Osmol Gap • To Calculate • 2 Na + Glu + BUN + [EthOH x 1.2] • Calculated - Measured • A difference > 10 suggests a gap is present • Primary use is as a screening test for the presence of toxic alcohols • Detects presence of parent alcohol; toxic metabolites don’t contribute to the osmol gap

14. Anion Gap & Osmol Gap

15. Osmol Gap • Our patient: • Calculated Osmol • 2(141) + 5.3 + 6.4 + 1.2(8.3) = 303 • Measured Osmol • 321 • Osmol Gap • 18 • Irrelevant in this case

16. Osmol Gap • Limitations • Only estimates molar quantity of uncharged molecules (ie measures only the parent compound, not the toxic metabolites {glycolate, glyoxylate, and oxalate}) therefore insensitive for late presentations • Can see a gap in ketoacidosis, lactic acidosis, and chronic renal failure* • Gap is not sensitive enough to rule out small ingestions* • Cannot distinguish between the alcohols • Large quantities of Alcohol raise the gap more than expected based on its molecular weight

17. Osmol Gap • Conclusion • An abnormal gap may be helpful in identifying toxic alcohol ingestion, however, a normal gap does not rule out the diagnosis, nor does an abnormal gap confirm the diagnosis.

18. Treatment • Options • Gut Decontamination? • Hemodialysis • Bicarb • Cofactors • Ethanol • Fomepazole • Memory Aid: • 4 A’s: block ADH, Alkalinize, Accelerate, Adjunct

19. Treatment • Gastric Lavage or Charcoal? • EG is very rapidly absorbed • Activated charcoal does not absorb significant amounts of alcohol • Gastric lavage may be beneficial only within the 1st hour after ingestion and before toxic symptoms develop

20. Treatment • Cofactors • Thiamine & Pyridoxine • MOA • Involved in the metabolism of glyoxylic acid to non-toxic substrates • Theoretical benefit with some indirect evidence • Cheap therefore use them

21. Treatment • NaHCO3? • Rationale • EG is metabolized to glycolate, glyoxalate, and oxalate. Acidemia leads to protonation of these metabolites and making them more likely to penetrate end-organ tissues (ie kidney). Tx with bicarb deprotonates metabolites making them less toxic. • However • No clear evidence exists to determine how bicarb should be given.

22. Treatment • NaHCO3 • Recommendations • UpToDate • 1-2 meq/kg bolus with maintenance infusion for patients with pH < 7.3 • Micromedex Poison Index • “NaHCO3 should NOT be routinely administered prophylactially…or for the tx of mild to mod acisosis” • Tx should be reserved for temporizing measure in manageing cases of severe and life-threatening acidosis prior to hemodialysis • CJEM 2002 • “MA should be treated aggressively with NaHCO3 to bring the serum pH back to within normal limits (7.35-7.45)”

23. Treatment • Hemodialysis • Best method to rapidly remove both parent alcohols and their toxic metabolites • May be avoidable with early administration of an ADH inhibitor

24. Treatment • Hemodialysis • Indications • Deteriorating vital signs • Unresponsive significant MA (pH < 7.3) • Renal failure, fluid, or electrolyte disturbances not responsive to the usual therapy • A serum ethylene glycol concentration of greater than 8 mmol/L is traditionally an indication for dialysis • Micromedix, CJEM 2002

25. Treatment • Hemodialysis • Recommendations from European Conference

26. Treatment • Hemodialysis Endpoints • Serum pH is normal • Parent alcohol concentration is less than 3.2 mmol/L • Resolution of the osmolar gap

27. Treatment • ADH Inhibitors • Prevents conversion of parent alcohol into its toxic metabolites • Two options: • EthOH (65 x more affinity for ADH than EG) • Fomepazole (500-1000 x more affinity for ADH than EthOH) • ADH inhibitors do nothing once the toxic metabolites have formed (other than prevent further parent alcohol from forming) • May prevent need for HD even in large ingestions; same is not true for Methanol • WHY?

28. Treatment • ADH Inhibition: MOA • N Engl J Med 1999

29. Treatment

30. Treatment • Ethanol • How to give it (CJEM 2002) • ADH is effectively saturated at 22-33 mmol/L • IV loading dose • 7.6- 10 ml/kg as 10% sol’n • IV maintenance dose • 1-2 ml/kg hourly • Draw levels hourly • Higher doses required for dialysis • Continue until EG levels are undetectable (1/2 life is increased when ADH inhibitor is given)

31. Treatment • Fomepazole • How to give it (CJEM 2002) • Loading dose • 15 mg/kg IV (oral is effective but not available in Canada) • Maintenance • 10 mg/kg every 12 hours for 4 doses; then 15 mg/kg every 12 hours until EG levels are below 3.2 mmol/L* • Shortened dosing interval or infusion recommended if patient is undergoing hemodialysis • Cost • $1075 per 1.5 gram vial (avg 4 vials per patient) • Restricted access to PADIS

32. Treatment • How good is Fomepazole? • Anecdotal cases with ingestions between 100-300 mL presenting 1-12 h post ingestion. All treated with fomepazole, no dialysis, complete recovery. • 42 yo M with 1.5 L of antifreeze presented 4.5 h post ingestion, EG 51 mmol/L. Received initial loading dose of ethanol, then fomepazole. Complete recover without dialysis. • CJEM 2002

33. Ethanol Pros Cheap Effective Cons Notoriously difficult to titrate (easy to over/under shoot) S/E of hypoglycemia Risk of aggressive behaviour Peds require ICU Admit Need to monitor levels Need to be on an infusion (oral difficult to titrate) Fomepazole Pros Effective No levels required Long 1/2 life Easy dosing Peds don’t require ICU Safe, minimal side effects Cons Expensive Expensive Expensive Treatment

34. Treatment • When to consider Fomepazole over Ethanol? • Rural areas without adequate lab support • Pediatrics (decrease ICU admissions) • Patients prone to hypoglycemia • Liver failure

35. Back to the Case • His EthOH level was only 8, not protective • He doesn’t have an AG • He does have an osmol gap • Based on what we’ve reviewed how do you want to treat him?

36. Case • He was started on an EthOH drip and titrated to a level > 20 mmol/L and maintained on the drip until his EG level became undetectable and his Osmol gap cleared

37. Proposed Treatment Algorithm

38. Summary • EG is rapidly absorbed and toxic in small amounts • A low/neg EG level and osmol gap can be misleading in late presenters • Expect AG to be normal in early presenters • Significant metabolic acidosis suggests presence of toxic metabolites of which our only definitive therapy is dialysis • ADH inhibitors are used to prevent further metabolization of the parent alcohol

39. References • Scalley, RD et al. Treatment of ethylene glycol poisoning. Am Fam Phys 2002; 66(5): 807-12. • Megarbane, B et al. Current recommendations for treatment of severe toxic alcohol poisonings. Intensive Care Med 2005; 31: 189-95. • Glaser, DS. Utility of the serum osmol gap in the diagnosis of methanol or ethylene glycol poisoning. Ann Emerg Med 1996; 27(3): 343-46 • Hall, T. Fomepazole in the treatment of ethylene glycol poisoning. CJEM 2002; 4(3): 199-204 • Micromedix Poison Index: Ethylene Glycol. Accessed June 29, 2008. • Sivilotti, ML. Methanol and ethylene glycol intoxication. UpToDate Accessed June 29th, 2008 (updated Feb 14, 2008).