Investigation & management of non-ethanol alcohol poisoning

Reviewed by DIDI CANDRADIKUSUMA

Tropical Disease Infection Division Internal Medicine Department Saiful Anwar General Hospital

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

Non ethanol alcohols

Methanol Ethylene glycol

Poisoning:
Non accidental / suicide attempt Accidental

Children Alcoholics

Methanol CH3OH

Alcohols

Ethylene Glycol CH2OH-CHO

Alcohol dehydrogenase

Formaldehyde HCHO
Metabolic acidosis

Aldehyde dehydrogenase

Glyoxalate CH2OH-CHO

Blindness Coma

Formate HCOOfolate

Acids

Glycolate CH2OH-COOComa & seizures Renal failure

CO2 + H2O

Oxalate COO--COO+ Ca2+

Myocarditis

Hypocalcaemia

Methanol
Initially:
Confusion Inebriation Ataxia

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

Methanol
Progression: Severe headache Blurred vision

(snow storm) (acute pancreatitis)

Severe abdominal pain

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

Vomiting Progressive neurology Seizures, coma

Ethylene glycol

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

Initially

inebriation N&V nystagmus, depressed reflexes Hypocalcaemia; tetany Coma, seizures

Ethylene glycol

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

By 24 - 48 hour: Renal failure CVS collapse

30-60mls can be fatal

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)

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

Calcium oxalate crystals

An ER Moment

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

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

Osmolar gap

Gap > 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.)

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

Anion gap & Osmolar gap

Anion Gap

Osmolar gap

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

M: Methanol E: Ethanol D: Diuretics I: Isopropanol E: Ethylene glycol

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

Treatment is time dependent

suspicion & treatment essential Delays lead to
Renal failure Death
Early

Indications for treatment

Ethylene glycol level > 20mg/dL Definite history of ingestion & osmolal gap >10mosm/L Suspicion of intoxication plus at least 2 of:

pH<7.3 HCO3 <20mmol/L Osmol gap >10 Oxaluria

Recommended management
1.

2.

Supportive care: ABC Antidotes: Block mechanism

Ethanol (competitive ADH substrate) Fomepizole (ADH inhibitor)

3.

Haemodialysis: Remove agent

Remove the toxic alcohol & its metabolites Correct acidosis ARF Methanol: Shortens hospitalisation

4.

NaHCO3 IVI
Correct metabolic acidosis (pH<7.2) Increase renal excretion of glycolate & formate Inhibit precipitation of calcium oxalate

Initial management

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

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. 27:1370-1378 Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of ethylene glycol poisoning. NEJM. 1999. 340:832-838 Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of methanol poisoning. NEJM. 2001. 344:424-429

1.
2. 3.

Fomepizole: dosing regime

Loading dose 15mg/kg

Then 10mg/kg every 12 hours until alcohol level <0.2g/L (BD dosing)

Subsequent doses tapered

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

Ethanol metabolism

1 unit / hour

Ethanol
oxidation

Alcohol dehydrogenase

Acetaldehyde
oxidation

(more toxic: hangover) Acetaldehyde dehydrogenase (glutathione)

Acetic acid

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

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

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

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 <0.2g/L Resolution acid base balance Resolution anion gap Resolution of lactate gap

HD & Ethylene Glycol poisoning

Severe or refractory metabolic acidosis EG conc >0.5g/L (8.1mmol/L) considered symptom independent indication for HD

Starting HD after fomepizole

NEJM 1999, Brent et al Started after initial loading dose if:

pH <7.1 pH decrease of >0.05 despite IV HCO3 pH <7.3 despite IV HCO3 decrease >5mmol/L HCO3 despite IV HCO3 Creatinine >265mol/L, or increase >88mol/L Initial ethylene glycol conc >50mg/dL (8.1mmol/L)

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

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

> 10 suspect EG, methanol, ethanol

Dont be put off by a normal AG or OG as both can occur even in life threatening ingestion.

References

Megarbane B, Borron S.W, Baud F.J. Current recommendations for treatment of severe toxic alcohol poisonings.Intensive Care Med (2005) 31:189-195 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); 344:424-429 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

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 > 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)