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

Stages of Toxicity1. Acute CNS

• Within 12 hI. Slurred SpeechII. AtaxiaIII. Altered mental status

• AG, Oxalate crystalluria

2. Cardiopulmonary• 12 - 24 h

I. HTNII. TachycardiaIII. CHF

3. Renal Failure• 24-72 h

I. OliguriaII. Flank PainIII. Azotemia

4. Delayed CNS• 6-12 days

I. Cranial neuropathiesII. Motor deficitsIII. Cognitive deficits

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

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?

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• 2(141) + 5.3 + 6.4 + 1.2(8.3) = 303

– Measured Osmol• 321

– Osmol Gap• 18

– Irrelevant in this case

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

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

1. Gut Decontamination?2. Hemodialysis3. Bicarb4. Cofactors5. Ethanol6. Fomepazole

• Memory Aid:1. 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• 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

– 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)”

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

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?

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)

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

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

– 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• 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

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).