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

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

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?

Ethylene Glycol Pathophysiology Diagnostics Treatment modalities

~ 30% excreted unchanged Toxic metabolites in red. Oxalic acid combines with calcium to form calcium oxalate crytals (watch out for hypocalcemia) which was originally thought to be the primary toxic insult, however rat studies have shown CNS, cardiac, and renal toxic effects secondary to glycoaldehyde, glycolic acid, and glyoxylic acid independent of oxalate crystal formation. Green Arrow: Glycolic acid is the primary reason why patients with EG poisoning get a metabolic acidosis.

Stages of Toxicity Acute CNS Cardiopulmonary Renal Failure Delayed 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 Cranial neuropathies: facial diplegia, dysarthria, dysphagia, visual deterioration, ophthalmoplegia Motor: ataxia, chorea, coma Cognitive: personality changes

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

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

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

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 From Rosen’s We don’t do glycolic acid levels here, but would potentially be helpful in the unknown overdose with a metabolic acidosis and normal osmolar gap

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

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? He doesn’t have a gap therefore no toxic metabolite formation yet EthOH is protective, toxic alcohol unlikely if ethoh level > 20

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

Anion Gap & Osmol Gap

Osmol Gap Our patient: Calculated Osmol Measured Osmol Osmol Gap 2(141) + 5.3 + 6.4 + 1.2(8.3) = 303 Measured Osmol 321 Osmol Gap 18 Irrelevant in this case Irrelevant in this case given we have 24 h access to measuring the toxic alcohols

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 *Pathophys unknown *ie if a patient has a normal gap of -5, and now they have a gap of 10 it is within normal limits. From UpToDate (articles: “Osmol Gap” and “Methanol and ethylene glycol intoxication”)

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.

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

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

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

Treatment NaHCO3? Rationale However 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.

Treatment NaHCO3 Recommendations UpToDate Micromedex Poison Index 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)” Discussed with Dr Vickas: People with EG metabolic acidosis won’t correct the way a DKA’er would once you fix the inciting problem. In general if you have a patient with a low pH (<7.2 or 7.3) with a bicarb of 15 or less you should be thinking about it.

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

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 Serum glycolic acid may be a better measure for need for hemodialysis, however, it isn’t available in calgary

Treatment Hemodialysis Recommendations from European Conference

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

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? Methanol elimination is extremely slow when you give an ADH inhibitor

Treatment ADH Inhibition: MOA N Engl J Med 1999

Treatment

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) Can also give orally: Loading dose: 1 ml/kg of 95% ethanol solution Maintenance: 0.15 ml/kg hourly, diluted to a 20% solution Note Loading dose does not change if you have a chronic alcoholic, however the maintenance dose will be higher (you have to titrate)

Treatment Fomepazole How to give it (CJEM 2002) Cost 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 The reason for the bump from 10 mg/kg to 15 mg/kg is because after repeated dosing Fomepazole induces CYP450 and increases its own elimination.

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

Treatment Ethanol Fomepazole Pros Pros Cons Cons Cheap Effective 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 There have not been any head to head comparisons between these two treatments

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

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?

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

Proposed Treatment Algorithm Substiture EthOH for Fomepazole?

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

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).