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 850 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?

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Ethylene Glycol

• Pathophysiology
• Diagnostics
• Treatment modalities

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30 excreted unchanged
6
Stages of Toxicity

• 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

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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

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Case

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

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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 doesnt tell you anything
  if you dont see it

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Anion Gap

• Na - HCO3 Cl
• Normal 7 /- 4
• Detects toxic metabolites expect it to be normal
  in the early period following ingestion

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Anion Gap

• 141 - 10721 13
• What does this tell you?
• What if he had an AG of 28 and an EthOH level of
  40?

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Osmol Gap

• To Calculate
• 2 Na Glu BUN EthOH x 1.2
• Calculated - Measured
• A difference gt 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 dont contribute to the osmol gap

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Anion Gap Osmol Gap
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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

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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

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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.

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Treatment

• Options
• Gut Decontamination?
• Hemodialysis
• Bicarb
• Cofactors
• Ethanol
• Fomepazole
• Memory Aid
• 4 As block ADH, Alkalinize, Accelerate, Adjunct

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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

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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

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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.

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Treatment

• NaHCO3
• Recommendations
• UpToDate
• 1-2 meq/kg bolus with maintenance infusion for
  patients with pH lt 7.3
• Micromedex Poison Index
• NaHCO3 should NOT be routinely administered
  prophylactiallyor 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)

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Treatment

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

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Treatment

• Hemodialysis
• Indications
• Deteriorating vital signs
• Unresponsive significant MA (pH lt 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

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Treatment

• Hemodialysis
• Recommendations from European Conference

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Treatment

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

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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?

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Treatment

• ADH Inhibition MOA
• N Engl J Med 1999

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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 soln
• 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)

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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

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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

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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 dont require ICU
• Safe, minimal side effects
• Cons
• Expensive
• Expensive
• Expensive

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Treatment

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

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Back to the Case

• His EthOH level was only 8, not protective
• He doesnt have an AG
• He does have an osmol gap
• Based on what weve reviewed how do you want to
  treat him?

36
Case

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

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Proposed Treatment Algorithm
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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

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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).