Investigation

1
Investigation management of non-ethanol alcohol
poisoning

• Aoibhin Hutchinson
• April 27th 2007

2
Types of alcohol

• Beer
• Wine
• Spirits
• Vodka
• Gin
• Whiskey
• Rum

• Ethanol / Ethyl alcohol
• Methanol / Methyl alcohol
• Isopropanol / Isopropyl alcohol
• Ethylene glycol
• Propylene glycol
• Fusel oil

3
Non ethanol alcohols

• Methanol
• Ethylene glycol
• Poisoning
• Non accidental / suicide attempt
• Accidental
• Children
• Alcoholics

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Methanol CH3OH
Ethylene Glycol CH2OH-CHO
Alcohols
Alcohol dehydrogenase
Glyoxalate CH2OH-CHO
Formaldehyde HCHO
Aldehyde dehydrogenase
Metabolic acidosis
Formate HCOO-
Glycolate CH2OH-COO-
Acids
Blindness
Coma seizures
folate
Coma
Renal failure
Oxalate COO--COO- Ca2
CO2 H2O
Myocarditis
Hypocalcaemia
5
Methanol

• Initially
• Confusion
• Inebriation
• Ataxia

• After 6-30hrs (latency)
• Metabolic acidosis
• High anion / osmolar gap

6
Methanol

• Progression
• Severe headache
• Blurred vision
• (snow storm)
• Severe abdominal pain
• (acute pancreatitis)
• Vomiting
• Progressive neurology
• Seizures, coma

• Visual symptoms
• Initial early reversible retinal dysfunction,
• eventual irreversible optic neuropathy

7
Methanol acid base

• Initially may have no acid-base disorder due to
  long latent period while methanol is metabolised
• Later, typically develop a high anion gap
  metabolic acidosis -due to formic acid
• May also develop a respiratory acidosis secondary
  to CNS depression (with depression of respiratory
  centre and/or airway obstruction)
• May occasionally present with normal anion gap
  acidosis if smaller ingestion
• If patient is an alcoholic, there may other types
  of acidosis present as well
• eg alcoholic ketoacidosis, starvation
  ketoacidosis, lactic acidosis, respiratory
  acidosis due aspiration, respiratory alkalosis
  due chronic liver disease

8
Ethylene glycol

• Initially
• inebriation
• NV
• nystagmus, depressed reflexes
• Hypocalcaemia tetany
• Coma, seizures

• Anti freeze
• Added to car radiator fluid to prevent
  overheating / freezing
• Fluorescein added to identify leaks
• Tastes sweet

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Ethylene glycol

• By 24 - 48 hour
• Renal failure
• CVS collapse

• By 12-24 hours
• Metabolic acidosis
• High anion / osmolar gap
• Tachycardia
• Hypertension
• Pulmonary oedema
• Shock

30-60mls can be fatal
10
Isopropanol

• Rubbing alcohol
• Twice as potent an intoxicant as ethanol
• Severe gastritis
• Metabolised to acetone
• Modest anion gap acidosis
• (methanol high, ethylene glycol very high)

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Investigation (high index suspicion)

• Plasma concentration
• Metabolic acidosis
• The Gaps
• High anion gap
• High osmolar gap
• Lactate gap
• Calcium level
• Urine
• Urinalysis oxaluria (Calcium oxalate crystals)
• Woods lamp

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Calcium oxalate crystals
13
An ER Moment
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Osmolar Gap

• Exposure to ingested alcohol estimated by
  measuring osmolar gap
• Indicates appreciable quantities of low molecular
  weight substances
• Measured osmolality - Calculated osmolarity
• Calculated 1.86 x (Na, K) glucose urea
  (mmol/L)
• Calculated (1.86 x Na) glucose urea
  9
• Measured determined by freezing point depression

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Osmolar gap

• Alerts you to the diagnosis before the acidosis
  develops
• Osmolar gap presence of alcohols
• Anion gap presence of acid metabolites
• Early high OG, normal AG
• Late normal OG, high AG

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Osmolar gap

• Gap gt 10 mmol/L significant
• Can estimate serum level of toxic alcohol by
  conversion factor.
• Ethylene glycol 6.2
• Methanol 3.2
• ethanol 4.6
• Need to subtract ethanol contribution
• (To convert ethanol levels in mg/dl to mmol/l
  divide by 4.6.)

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Anion Gap

• (Na K) - (Cl- HCO3-)
• Measures the difference between conc of
  unmeasured anions cations
• Normal 12-18mmol/L
• High anion gap
• Ketoacidosis
• Lactic acidosis
• Renal failure
• Poisoning paracetamol,methanol, ethylene glycol,
  salicyclates,paraldehyde, formaldehyde,toluene

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Anion gap Osmolar gap

• Anion Gap
• A Alcohol
• T Toluene
• M Methanol
• U Uraemia
• D DKA
• P Paraldehyde
• I Iron, Isoniazid
• L Lactic acidosis
• E Ethylene glycol
• S Salicylates

• Osmolar gap
• M Methanol
• E Ethanol
• D Diuretics
• I Isopropanol
• E Ethylene glycol

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Lactate Gap

• False positive elevation in point of care
  analysers Radiometer analyser.
• Most lactate analysers use lactate oxidase.
• This cross reacts with EG metabolites.
• Useful in late presentation.
• Could indicate when dialysis can stop.

Canadian medical association journal, April 10th
2007
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Treatment is time dependent

• Early suspicion treatment essential
• Delays lead to
• Renal failure
• Death

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Indications for treatment

• Ethylene glycol level gt 20mg/dL
• Definite history of ingestion osmolal gap
  gt10mosm/L
• Suspicion of intoxication plus at least 2 of
• pHlt7.3
• HCO3 lt20mmol/L
• Osmol gap gt10
• Oxaluria

22
Recommended management

• Supportive care ABC
• Antidotes Block mechanism
• Ethanol (competitive ADH substrate)
• Fomepizole (ADH inhibitor)
• Haemodialysis Remove agent
• Remove the toxic alcohol its metabolites
• Correct acidosis
• ARF
• Methanol Shortens hospitalisation
• NaHCO3 IVI
• Correct metabolic acidosis (pHlt7.2)
• Increase renal excretion of glycolate formate
• Inhibit precipitation of calcium oxalate

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Initial management

• Supportive ABC
• IV access Bloods UE, Ca, Mg, ABG
• Fluids IV crystalloids 250-500ml/hr increase
  renal clearance
• HCO3 if pH lt 7.2
• Pyridoxine thiamine
• Cardiac monitoring
• Urinary catheter
• Osmolar anion gap

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Fomepizole

• 4-methylpyrazole (4MP)
• Potent inhibitor of ADH
• Has an affinity for ADH x 500-1000 of ethanol
• Limited toxicity
• Safely used in France since 1981(1)
• 2 US multi centre prospective trials confirmed
  efficacy(2,3)

• Megarbane B, Borron SW, Trout H et al. treatment
  of acute methanol poisoning with fomepizole.
  Intensive Care Med. 2001. 271370-1378
• Brent J, McMartin K, Phillips S et al. Fomepizole
  for the treatment of ethylene glycol poisoning.
  NEJM. 1999. 340832-838
• Brent J, McMartin K, Phillips S et al. Fomepizole
  for the treatment of methanol poisoning. NEJM.
  2001. 344424-429

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Fomepizole dosing regime

• Loading dose 15mg/kg
• Then 10mg/kg every 12 hours until alcohol level
  lt0.2g/L (BD dosing)
• Subsequent doses tapered

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Problems

• Expensive (esp if used empirically)
• CI allergy, pregnancy
• Headache 12
• Nausea 11
• Dizziness 7
• Injection site irritation
• Usual rash, vertigo, fever, transient LFT
  derangement, eosinophilia

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Ethanol metabolism

• 1 unit / hour

Ethanol
Alcohol dehydrogenase
oxidation
Acetaldehyde (more toxic hangover)
Acetaldehyde dehydrogenase (glutathione)
oxidation
Acetic acid
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Treatment with ethanol

• Competitively inhibits ADH, thus reducing toxic
  metabolite production.
• Requires PO or IVI administration
• Requires intoxicating doses
• Accepted target 100-125mg/dL
• Risks with Rx
• Intoxicated require close monitoring
• Hypoglycaemia
• Potential hepatotoxicity
• Kinetics unpredictable requires monitoring
  adjustment

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Advantages of fomepizole compared to ethanol

• Reliable therapeutic concentrations achieved with
  dosing regimes
• BD dosing
• No severe CNS / liver toxicity
• No hypoglycaemia
• No monitoring of conc required

30
Current recommendations for treatment of severe
toxic alcohol poisonings. Intensive care med. 2005

• Fomepizole
• Due to efficacy safety profile
• Recommended as 1st line antidote in confirmed
  ethylene glycol / methanol poisoning
• Also recommend initial fomepizole dose
• Suspicion of toxic alcohol ingestion
• In presence of metabolic acidosis with elevated
  anion gap unexplained by equivalent increase in
  serum lactate

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Haemodialysis

• Considered integral part of treatment
• Expediate removal of alcohol toxic metabolites
• Reduces necessary duration of antidotal treatment
• Both ethylene glycol methanol effectively
  cleared by HD
• End point
• alcohol conc lt0.2g/L
• Resolution acid base balance
• Resolution anion gap
• ?Resolution of lactate gap

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HD Ethylene Glycol poisoning

• Severe or refractory metabolic acidosis
• EG conc gt0.5g/L (8.1mmol/L) considered symptom
  independent indication for HD

33
Starting HD after fomepizole

• NEJM 1999, Brent et al
• Started after initial loading dose if
• pH lt7.1
• pH decrease of gt0.05 despite IV HCO3
• pH lt7.3 despite IV HCO3
• decrease gt5mmol/L HCO3 despite IV HCO3
• Creatinine gt265?mol/L, or increase gt88?mol/L
• Initial ethylene glycol conc gt50mg/dL (8.1mmol/L)

34
Fomepizole HD

• US reduction in dosage interval from 12hrs to
  4hrs
• Europe Initial loading dose then IVI at
  1-1.5mg/kg/hr for duration HD (intermittent)
• Unknown in CVVHD

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Overview of toxic ingestions

• General rule actively investigate for toxic
  ingestion if pt has high anion gap acidosis in
  absence of ketoacidosis, lactic acidosis or renal
  failure.
• Treatment can be life saving if early.
• High index suspicion esp if pt appears
  intoxicated /- neuro symptoms
• Always check osmolar gap
• gt 10 suspect EG, methanol, ethanol
• Dont be put off by a normal AG or OG as both can
  occur even in life threatening ingestion.

36
References

• Megarbane B, Borron S.W, Baud F.J. Current
  recommendations for treatment of severe toxic
  alcohol poisonings.Intensive Care Med (2005)
  31189-195
• Brent J, McMartin K, Phillips S et al. Fomepizole
  for the treatment of ethylene glycol poisoning.
  NEJM (1999) 340 (11)832-838
• Brent J, McMartin K, Phillips S et al. Fomepizole
  for the treatment of methanol poisoning. NEJM
  (2001) 344424-429
• Brindley P.G, Butler M.S, Cembrowski G, Brindley
  D.N. Falsely elevated point of care lactate
  measurement after ingestion of ethylene glycol.
  Canadian Medical Association Journal (2007)
  176(8)1097-1099

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Limitations of osmolar gap

• Calculation depends on measurement of 3
  substances an osmolality measurement so the
  error is the sum of the errors of all of these
  measurements.
• Many formulae to calculate osmolarity
  variability in number.
• Osmolar gap wide normal range in population
• Widely quoted abnormal value of gt 10mmol/L has a
  low sensitivity
• May be normal in EG ingestion because of its
  higher MW (compared to methanol)
• As toxic alcoholc metabolised osmolar gap
  decreases, so normal value may be late
  presentation.
• Correction needed for presence of ethanol
  (frequent)