Non Ethanol

8/23/2019 Non Ethanol

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Investigation & management

of non-ethanol alcoholpoisoning

Reviewed byDIDI CANDRADIKUSUMA

Tropical Disease Infection DivisionInternal Medicine Department

Saiful Anwar General Hospital


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Types of alcohol

Beer

Wine

Spirits Vodka

Gin

Whiskey

Rum

Ethanol / Ethyl alcohol

Methanol / Methylalcohol

Isopropanol / Isopropylalcohol

Ethylene glycol

Propylene glycol

Fusel oil


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Non ethanol alcohols

Methanol

Ethylene glycol

Poisoning: Non accidental / suicide attempt

Accidental Children

Alcoholics


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MethanolCH3OH

Ethylene GlycolCH2OH-CHO

FormaldehydeHCHO

GlyoxalateCH2OH-CHO

FormateHCOO-

GlycolateCH2OH-COO

-

CO2 + H2OOxalateCOO--COO-

+ Ca2+

Alcohols

Metabolic acidosis

Blindness

Coma

Coma & seizures

Renal failure

Myocarditis

Hypocalcaemia

Alcohol dehydrogenase

Aldehyde

dehydrogenase

folate

Acids


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Methanol

Initially:

Confusion

Inebriation Ataxia

After 6-30hrs (latency)

Metabolic acidosis

High anion / osmolargap


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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 irreversibleoptic neuropathy


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Ethylene glycol

Initially

inebriation

N&V nystagmus,

depressed reflexes

Hypocalcaemia;

tetany Coma, seizures

Anti freeze

Added to car radiator

fluid to preventoverheating / 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

Pulmonaryoedema

Shock

30-60mls can be fatal


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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


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An ER Moment


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Osmolar Gap

Exposure to ingested alcohol estimated by measuringosmolar 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 > 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 divideby 4.6.)


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Anion Gap

([Na+] + [K+]) - ([Cl-] + [HCO3-])

Measures the difference between conc ofunmeasured 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 careanalysers: 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 essentialDelays lead to

Renal failure

Death


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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


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Recommended management1. Supportive care: ABC

2. 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 hospitalisation4. NaHCO3 IVI

Correct metabolic acidosis (pH


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Initial management

Supportive :ABC

IV access & Bloods: U&E, Ca, Mg, ABG

Fluids IV crystalloids 250-500ml/hr: increaserenal clearance

HCO3 if pH < 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 confirmedefficacy(2,3)

1. Megarbane B, Borron SW, Trout H et al. treatment of acute methanol poisoning withfomepizole. Intensive Care Med. 2001. 27:1370-1378

2. Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of ethylene glycolpoisoning. NEJM. 1999. 340:832-838

3. Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of methanolpoisoning. NEJM. 2001. 344:424-429


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Fomepizole: dosing regime

Loading dose 15mg/kg

Then 10mg/kg every 12 hours until

alcohol level


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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

Acetaldehyde(more toxic: hangover)

Acetic acid

Alcohol dehydrogenase

Acetaldehyde dehydrogenase

(glutathione)

oxidation

oxidation


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Treatment with ethanol

Competitively inhibits ADH, thus reducing toxicmetabolite 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 toethanol

Reliable therapeutic concentrationsachieved with dosing regimes

BD dosing No severe CNS / liver toxicity

No hypoglycaemia

No monitoring of conc required


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Current recommendations for treatment of severe toxic alcoholpoisonings. Intensive care med. 2005

Fomepizole

Due to efficacy & safety profile

Recommended as 1st line antidote in confirmedethylene glycol / methanol poisoning

Also recommend initial fomepizole dose Suspicion of toxic alcohol ingestion

In presence of metabolic acidosis with elevatedanion gap unexplained by equivalent increase inserum lactate


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Haemodialysis

Considered integral part of treatment

Expediate removal of alcohol & toxicmetabolites

Reduces necessary duration of antidotaltreatment

Both ethylene glycol & methanol effectivelycleared by HD

End point: alcohol conc


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HD & Ethylene Glycol poisoning

Severe or refractory metabolic acidosis

EG conc >0.5g/L (8.1mmol/L) considered

symptom independent indication for HD


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Starting HD after fomepizole

NEJM 1999, Brent et al

Started after initial loading dose if: pH 0.05 despite IV HCO3 pH 5mmol/L HCO3 despite IV HCO3 Creatinine >265mol/L, or increase >88mol/L

Initial ethylene glycol conc >50mg/dL (8.1mmol/L)


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Fomepizole & HD

US: reduction in dosage interval from12hrs to 4hrs

Europe: Initial loading dose & then IVI at1-1.5mg/kg/hr for duration HD(intermittent)

Unknown in CVVHD


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Overview of toxic ingestions

General rule: actively investigate for toxicingestion if pt has high anion gap acidosis inabsence of ketoacidosis, lactic acidosis or renal

failure. Treatment can be life saving if early.

High index suspicion esp if pt appearsintoxicated +/- 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.


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References

Megarbane B, Borron S.W, Baud F.J. Current recommendations fortreatment 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 elevatedpoint 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 ofthe errors of all of these measurements.

Many formulae to calculate osmolarity: variability innumber.

Osmolar gap: wide normal range in population

Widely quoted abnormal value of > 10mmol/L has a lowsensitivity

May be normal in EG ingestion because of its higherMW (compared to methanol)

As toxic alcoholc metabolised osmolar gap decreases,so normal value may be late presentation.

C ti d d f f th l (f t)

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Non Ethanol

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