Transcript Alcohol Poisoning

Dr / Essam M. Hafez
Lecturer consultant of clinical toxicology
M.D, clinical toxicology
30 March 2017
1
 Alcohols
are hydrocarbons that
contain a hydroxyl group
 A compound with two hydroxyl
groups is called a diol or a glycol
 Toxic alcohols commonly refer to
methanol, ethylene glycol and
isopropyl alcohol
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H
Primary alcohol as methanol CH3OH
and ethanol C2H5OH
H H
(H – C – C - OH)
H
methanol
(H – C – OH)
H
H
Ethanol
Secondary alcohol as isopropyl alcohol C3H7OH
H HO H
(H – C – C – C - H)
H H H
Tertiary alcohol as tert butyl alcohol (CH3)3COH
Ethylene glycol as ethanol attached with other
hydroxyl group CH2OHCH2OH
H
H
OH – C – C - OH
H
H
Ethanol (ethyl alcohol)
It is available as
beverages
Ingredient of
Food extract
Cough and
cold
Medication
Methanol ( methyl alcohol)
It is widely used as an
industrial marine solvent and paint remover
photocopying fluid and wind shield-washing fluid
Mouth
washes
Isopropanol (isopropyl alcohol)
Used as
disinfectant
solvent
skin lotion
Ethylene glycol
Is used in many manufacturing process
and as antifreeze
mouth washes

Alcohol is absorbed directly into the blood stream
through the lining of the mouth and the tissue that lines
the stomach and small intestine. Food, water, and fruit
juice help to slow this absorption. Carbonated beverages
speed the absorption of alcohol, which means that the
drinker feels the effects sooner.
Once alcohol (or ethanol, the chemical in
alcoholic beverages) is in your bloodstream, it
is carried to the brain and all the organs of
your body within 90 seconds. The affects of
alcohol vary according to the individual’s sex,
body size, amount of body fat, the amount of
alcohol consumed, the situation, and the
amount of food in the stomach.
The liver is the largest glandular organ in the body. It is
responsible for filtering 95% of ingested alcohol out of the
body. An important fact to remember is that the body will
eliminate 7-10 gm/h. So the more you drink, the longer
the alcohol will remain in the body.
When the amount of alcohol consumed exceeds the
liver’s ability to break down the alcohol, the
concentration of alcohol in the bloodstream (the
proportion of alcohol to blood in the body)
increases. Increased blood alcohol concentrations
(higher proportions of alcohol to blood) impair
thought processes and coordination, and slow
automatic functions such as breathing. Excessive
blood alcohol concentration can lead to coma or
possibly death.
Methanol
Ethylene Glycol
Alcohol
Dehydrogenase
Acetaldehyde
(hangover, flushing)
Aldehyde
Dehydrogenase
Acetic Acid
CO2 + H20
Formaldehyde
Glycoaldehyde
Formic Acid
Glycolic Acid
(blindness, cerebral
oedema)
(metabolic acidosis)
Lactate dehydrogenase or
glycolic acid oxidase
(
)
(metabolic acidosis)
Glycoxylate (lactic
acidosis)
Lactate dehydrogenase or
aldehyde oxidase
Oxalate
(cerebral &
renal damage, hypocalcaemia)
Although effects will vary from person to person,
the following are some short-term effects that may be experienced
after moderate to light drinking:
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Distorted vision, hearing, and coordination
Altered perceptions and emotions
Anxiety
Slowed Breathing
Mental confusion
Memory loss
Increased aggression
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Alcohol Dependence
Liver disease
Heart disease and stroke
Brain cell death
Stomach ailments
Sexual impotence
Central Nervous System damage
Death
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The legal system uses a more scientific method for
determining when a person is drunk, Blood Alcohol
Concentration (BAC,) the percentage of alcohol in the
blood (or proportion of alcohol to blood in the body) as
someone drinks.

In most states, a BAC of .08% is considered legally
drunk, which means that for every 1000 milliliters of
blood, the body contains 8/10ths of a milliliter of
alcohol.
1.
BAC = .02 = Drinkers begin to feel moderate effects.
2. BAC = .04 = Most people begin to feel relaxed, mildly euphoric,
sociable, and talkative.
3. BAC = .05 = Judgment, attention, and control are somewhat
impaired. Ability to drive safely begins to be limited. Sensorymotor and finer performance are impaired. People are less able
to make rational decisions about their capabilities (for example,
about driving.)
4. BAC = .08 = This is legal level for intoxication in some states.
There is a definite impairment of muscle coordination and
driving skills.
5. BAC = .10 = This is legally drunk in most states. There is a clear
deterioration of reaction time and control.
Methanol
 Ethylene glycol
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Poisoning:
 Non
accidental / suicide attempt
 Accidental
 Children
 Alcoholics
Methanol
CH3OH
Alcohols
Ethylene Glycol
CH2OH-CHO
Alcohol dehydrogenase
Formaldehyde
HCHO
Aldehyde
dehydrogenase
Glyoxalate
CH2OH-CHO
Metabolic acidosis
Blindness
Coma
Formate
HCOO-
Acids
Glycolate
CH2OH-COOComa & seizures
folate
Renal failure
CO2 + H2O
Oxalate
COO--COO+ Ca2+
Myocarditis
Hypocalcaemia
Also known as “wood alcohol”
 Used in industrial production, windshield
wiper fluid, model airplane fuel and as a
cleaning solvent
 Sold as a mixture of ethanol and methanol
in hardware stores in many countries
 Approximately 1000 – 2000 cases of
methanol intoxication per year
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•
Methanol itself is non-toxic
• Formaldehyde inhibits retinal oxidative
phosphorylation but is rapidly metabolized to
formic acid
•
Formic acid damages the optic disk leading to the
characteristic visual impairments
• Intoxication can occur with as little as 30 cc of
ingestion
• Often coingested with ethanol which makes
diagnosis difficult and requires high index of
suspicion
• Formic acid causes high anion gap metabolic
acidosis and CNS depression causes a respiratory
acidosis
• Methanol causes an elevated osmolar gap
• Methanol levels can be slow to obtain and not
available in many labs. Levels > 20 mg/dL are
associated with symptomatic presentations.
Levels > 150 mg/dL are almost always fatal
•
Visual impairment common and often
can lead to permanent blindness
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Photophobia and abdominal pain are
other common symptoms
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Other signs of CNS depression including
depressed respiratory rate, obtundation,
and coma
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Slow hepatic metabolizing can delay
toxic effects for up to 24 hours after
ingestion
Peripapillary edema, not shown Hyperemia
of the optic disks and reduced papillary
response to light,
putaminal necrosis = rigidity, tremor, masked faces, and monotonous speech;
direct toxicity of formic acid on the brain and decreased cerebral flow
Mortality rates of 8-36% overall
• Mortality of 50-80% if pH < 7.1 on
presentation
 Visual defects persist in 20-25% of
surivivors
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Colorless, odorless, sweet tasting solvent
Used in antifreeze, heat transfer fluids and
runway deicers
Itself is non toxic
Approximately 5800 cases of poisonings yearly
Metabolized to glycolic acid and oxalic acid
(excreted in urine)
Ingestion of as little as 30 cc can be fatal
Mortality rate of 1-22%
•
Can present with intoxication like symptoms without
odor
• Anion gap metabolic acidosis with elevated osmolal gap
• Hypocalcemia from deposition of calcium oxalate in
tissues
• Within 12 hours of ingestion nausea, vomiting,
hypocalcemia and CNS depression can occur
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This is followed by tachycardia and tachypnea from 1224 hours of ingestion
• Renal failure typically occurs around 24 hours post
ingestion
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Clinical history
Elevated osmolal gap
Anion gap acidosis with or without the presence of lactic
acid
Calcium oxalate crystals in the urine which present 4
hours after ingestion
Crystals are initially envelope shaped dihydrate crystals
and later are needle shaped monohydrate crystals
Urine can be tested with UV light to test for sodium
flourescein
Confirmation with serum ethylene glycol level
Colorless liquid with bitter taste
 Used in rubbing alcohol, nail-polish remover,
glues, and in industrial solvents
 Toxic dose of 2-4 mL/kg (approximately 200 mL
of rubbing alcohol for an adult)
 11,216 exposures to isopropanol occurred in
1998
 Metabolized in liver by alcohol dehydogenase to
acetone
 20-50% excreted unchanged in the urine
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Presents with symptoms of intoxication, respiratory
depression, nausea, vomiting, gastritis
 Fruity breath from acetone production is characteristic of
ingestion
 Symptoms occur within 1 hour of ingestion
 Metabolically presents with ketosis without acidosis
 An elevated osmolal gap will be present
 Hypoglycemia common due to inhibition of gluconeogenesis
 Ethanol drip and fomepizole have no role no toxic
metabolites are formed
 Hemodialysis indicated for isopropanol levels > 400 mg/dL
or with significant CNS depression or renal failure
 Severe overdose can result in coma or death, but mortality
occurring in < 0.05% of all exposure
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Plasma concentration
 Metabolic acidosis
 The Gaps:
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 High
anion gap
 High osmolar gap
 ‘Lactate gap’
Calcium level
 Urine:
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 Urinalysis:
oxaluria (Calcium oxalate crystals)
 Wood’s lamp
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Exposure to ingested alcohol estimated by measuring
osmolar gap
Indicates appreciable quantities of low molecular weight
substances
Measured osmolality - Calculated osmolality
Calculated = 1.86 x (Na, K) + glucose + urea (mmol/L)
Calculated = (1.86 x [Na]) + [glucose] + [urea] + 9
Measured: determined by freezing point depression
Ethylene glycol ingestion
 Methanol ingestion
 Formaldehyde ingestion
 Paraldehyde ingestion
 DKA
 Alcoholic ketoacidosis
 Lactic acidosis
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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
Gap > 10 mmol/L significant
 Can estimate serum level of toxic alcohol
by conversion factor.
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 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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([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
 A: Alcohol
 T: Toluene
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Osmolar gap
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M: Methanol
 U: Uraemia
 D: DKA
 P: Paraldehyde
 I: Iron, Isoniazid
 L: Lactic acidosis
 E: Ethylene glycol
 S: Salicylates
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M: Methanol
E: Ethanol
D: Diuretics
I: Isopropanol
E: Ethylene glycol
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.
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Canadian medical association journal, April 10th 2007
Early suspicion & treatment essential
Delays lead to
Renal
failure
Death
Ethylene glycol level > 20mg/dL
 Definite history of ingestion & osmolal gap
>10mosm/L
 Suspicion of intoxication plus at least 2 of:
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 pH<7.3
 HCO3
<20mmol/L
 Osmol gap >10
 Oxaluria
1.
2.
3.
4.
Supportive care: ABC
Antidotes: Block mechanism
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Ethanol (competitive ADH substrate)
Fomepizole (ADH inhibitor)
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Remove the toxic alcohol & its metabolites
Correct acidosis
ARF
Methanol: Shortens hospitalisation
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Correct metabolic acidosis (pH<7.2)
Increase renal excretion of glycolate & formate
Inhibit precipitation of calcium oxalate
Haemodialysis: Remove agent
NaHCO3 IVI
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Ethanol:
ethanol is a strong competitive inhibitor of
methanol at the alcohol dehydrogenase
enzyme
4- Methyl-Pyrazole: (4-MP=
fomepizole)
Action: alcohol dehydrogenase inhibitor.
Folic acid and folinic acid:( Leucoverin)
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converts formic acid to CO2 and water i.e. it
enhance methanol elimination.
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
Ethanol is a competitive inhibitor of ADH. It’s
affinity for ADH is 10-20 times greater than that
of methanol. Ethanol slows the rate of
methanol’s conversion to formaldehyde and
formic acid, allowing the body time to excrete
methanol in the breath and urine.
Methanol
ADH
Formaldehyde
-
-
Ethanol
Formic
Acid
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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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1.
2.
3.
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
CH3OH
Fompepizole
X
AD
CH2O
H
Methanol
Ethanol
Formaldehyde
ADH
CHOOH
Formic Acid
Folate
CO2 + H2O
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Fomepizole…
30 March 2017
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
Loading dose 15mg/kg
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Then 10mg/kg every 12 hours until
alcohol level <0.2g/L (BD dosing)
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Subsequent doses tapered
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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:
- Oral or IV
- CNS depression
- Difficult titration
- Frequent levels
- Hypoglycemia
30 March 2017
Fomepizole:
- IV
- No CNS depression
- Easy dosing
- No levels to monitor
- More predictable
pharmacokinetcs
- No Hypoglycemia
- Cost
57
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
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
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End point:
alcohol conc <0.2g/L
 Resolution acid base balance
 Resolution anion gap
 ?Resolution of lactate gap

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 >265mol/L, or increase >88mol/L.
 Initial ethylene glycol conc >50mg/dL
(8.1mmol/L)
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Fomepizole should be administered to slow down
conversion of methanol to formic acid
Ethanol (when fomepizole is unavailable) administered via
central line to competitively inhibit metabolism of
methanol (required serum ethanol concentration of at
least 100 mg/dL)
Hemodialysis effectively removes methanol
During dialysis, ethanol and fomepizole is also removed
which can increase the levels of formic acid unless
adjusted for
Folic acid supplement to enhance the metabolism of
formic acid
American Academy of Clinical Toxicology recommends dialysis for
severe metabolic acidosis, presence of visual symptoms, serum
methanol concentration > 50 mg/dL, or severe electrolyte
disturbances
Confirmed history of ingestion of more than 30 cc (0.4 mg/kg body
weight) also used as an indication for dialysis
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Activated charcoal ineffective
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Gastric lavage only effective within 1 hour of ingestion
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Ethanol infusion if fomepizole not available (loading
dose of 0.6 g ethanol/kg followed by constant infusion to
target levels 100-200 mg/dL)
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Fomepizole now used to competively inhibit metabolism
Bicarbonate to correct acidosis
Volume expansion increases excretion of ethylene glycol
and may prevent crystal induced renal failure
 Hemodialysis effectively removes ethylene glycol with
mean clearance rate of 145-230 ml/min
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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
Don’t be put off by a normal AG or OG as both can occur
even in life threatening ingestion.
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Elevated osmolal gap can be suggestive of
toxic alcohol ingestions
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Serum levels of toxic alcohols are often too
slow to aide in guiding therapy
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Fomepizole is a safe and effective adjunct to
hemodialysis to limit toxicity associated with
methanol and ethylene glycol ingestion
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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