Transcript Toxicology Anion & osmolar gap (Toxic alcohols)

Toxicology
Anion Gap, Osmolar
Gap & Toxic Alcohols
Christine Kennedy
Pediatric Emergency Fellow
Oct 15, 2009
Objectives
1)
2)
3)
Review the causes of an anion gap
Review the causes of an osmolar gap
Review the “toxic alcohols”
Methanol
2) Ethylene Glycol
3) Isopropyl Alcohol
1)
4)
Discuss the evidence for Fomepizole
Anion Gap
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
AG = Na - (Cl + HCO3). Is it this simple?
AG = Measured cations - measured anions
 Na is the primary measured cation
 Cl & HCO3 are the primary measured anions
 What are the other cations & anions??

Normal plasma AG is 7-13 meq/L
 lab
dependant
 Interpret with caution
Anion Gap
Anion Gap
Anion Gap

AG= Unmeasured anions-unmeasured cations

An increase in the AG can be induced by:
a
fall in unmeasured cations

a
Hypocalcemia, hypomagnesemia, hypokalemia
rise in unmeasured anions
hyperalbuminemia due to volume contraction
 the accumulation of an organic anions in metabolic
acidosis

Anion Gap

Primarily determined by the negative
charges on the plasma proteins (albumin)

As a result, the expected normal values for
the AG must be adjusted downward in
patients with hypoalbuminemia
 AG
falls by 2.5 meq/L for every 10 g/L
reduction in the plasma albumin concentration
Anion Gap-The DDx we all learned
in medical school
Methanol
 Uremia
 DKA, SKA, AKA
 Paraldehyde
 Isoniazid/Iron
 Lactate
 Ethylene glycol
 Salicylates

Anion Gap-DDx
Now, this is an okay mnemonic…although
Tintinalli isn’t a fan of it
 If you use it, be aware that…

 There
are other things to include in your
Differential
 It doesn’t really tell you what causes the anion
gap
What causes the AG?

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Methanol ----> formate
Uremia--->Chronic renal failure
(GFR<20=impaired excretion of acids)
DKA, SKA, AKA---> Acetaldehyde  acetylCoA
B-hydroxybutyrate, acetoacetate
P
Isoniazide--->lactic acidosis 2o to seizure activity
Iron---> lactic acidosis (uncoupling of oxidative
phosphorylation)
Lactate
Ethylene glycol ----> glyoxylate, glycolate,
oxalate
Salicylates ----> ketones, lactate
Anion Gap

Other causes of AG (due to lactate)

Metformin
Phenformin
Propylene Glycol
Carbon Monoxide
Hydrogen sulfide
Cyanide
Methemoglobinemia
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Anion Gap-DDx
Methanol/Metformin/Methemoglobinemia
 Uremia
 DKA, SKA, AKA
 Paraldehyde/Phenformin/Propylene glycol
 Isoniazid/Iron
 Lactate……
 Ethylene glycol
 Salicylates

Osmolar Gap

Osmolar gap
 Measured
serum osmolality-calculated osmolarity
 should be <10 mmol/L

Plasma osmolarity
 Determined
by the concentration of the different
solutes in the plasma
 Posm = 2[Na] + [Glc] + [BUN] + 1.25[ethanol]
 Na multiplied by 2 to account for accompanying
anions
Osmolar Gap…which method to
use???
Osmolarity Formulas

Calgary
 1.86Na
+ BUN + glucose + 9
 Why 1.86?

93% is in Na+ & Cl- (ionized forms) and 7% is in the
nonionized forms (NaCl)
 Why +9?
 Intercept for multiple regression line
 NB:

EtOH is not automatically added!
Edmonton
 2Na
+ BUN + glc
 Serum is only 93% water: 1.86/0.93 = 2
DDx of elevated Osm Gap
With anion gap metabolic acidosis
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Methanol ingestion
End-stage renal disease (GFR <10)*
Diabetic ketoacidosis**
Alcoholic ketoacidosis**
Paraldehyde ingestion
Lactic acidosis**
Ethylene glycol ingestion
Formaldehyde ingestion
DDx of elevated Osm Gap
Without metabolic acidosis


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Ethylene glycol and Methanol*
EtOH**
Isopropanol ingestion---> acetone
Diethyl ether ingestion
Mannitol
Severe hyperproteinemia
Severe hyperlipidemia
Ethanol and the Osmolar Gap

Case 1
 Intoxicated
male
 Na 140, BUN 5, Glc 5, EtOH 75
 Osmolality 385
 Osmolarity = ____
 Osm gap = ____
Ethanol and the Osmolar Gap

Case 1
 Intoxicated
male
 Na 140, BUN 5, Glc 5, EtOH 75
 Osmolality 385
 Osmolarity 2(140) + 5 + 5 + 75 = 365
 Osm gap = 20
 So
how does EtOH affect the osm gap?
Ethanol and the Osmolar Gap


Several Studies have noted the increase in osmolar gap
with rising EtOH in a non 1:1 relationship
Many different EtOH conversion factors have been
developed
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Britten 1972: 1.74
Glasser 1973: 1.1
Pappas 1985: 1.12
Geller 1986: 1.20
Galvan 1992: 1.14
Synder 1992: 1.20
Hoffman 1993: 1.09
Ethanol and the Osmolar Gap

Purssell. Ann Emerg Med 2001; 38: 653659.
 Derived
a formula to account for the
relationship between ethanol and then
osmolar gap
 Prospectively validated
 Best formula = EtOH (mmol/L) X 1.25
Explanation for EtoH X 1.25
Ethanol has a “non-ideal” osmotic
behaviour because molecules form
physiochemical bonds with other
molecules
 Results in an effect on osmolarity that is
non-uniform

Data from Calgary lab
O-Gap (absence of toxic Alc)
This supports the
1.25 EtOH
conversion
200
180
O-GAP, mosmoL
160
140
120
100
80
60
40
20
0
0
50
100
Ethanol m m ol/L
150
200
Case 1


Intoxicated male
Using 1:1 EtOH
 Osmolality
= 385
 Osmolarity = 2(140) + 5 + 5 + 75 = 365
 Osm gap = 20



Redo this with EtOH X 1.25 = 94
Osmolarity = 2(140) + 5 + 5 + 94 = 384
Osm gap = 1
Case 2
35 year male
 Took a swig of a mug that had antifreeze
 Na 140, Cl 106, BUN 5, Glc 5, EtOH 25,
 HCO3 24
 Osmolality 321
 Normal anion gap (10)
 Osmolarity = ___
 Osmolar gap = ___

Case 2
Osmolarity=2(140) + 5 + 5 + 1.25(25)=321
 Osmolar gap = 321 – 321 = 0
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What is the normal osmolar gap?
Normal Osmolar gap

Hard to define because it depends on
 Lab
method of osmolality determination
 Osmolarity formula used
 Lab error of Na, BUN, Glc, EtOH
 EtOH conversion factor used

Few studies documenting what normal
osmolar gaps are in the population
Normal Osmolar gap

Traditionally normal osmolar gap is <10

In case #2 the osm gap was 0
Can osmolar gaps be used to rule out
toxic alcohol ingestions?
 Is there a cut off where toxic alcohols
should be routinely measured?

Normal Osmolar Gap
Hoffman. J Toxicol Clin Toxicol. 1993
Mean Osm gap= -2
SD 6.1
-14
-8
-2
+4
+10
Can you still miss toxic levels?
-14
0
Baseline -14
Osm gap 0
Methanol level
14!!!
When should toxic alcohols be
measured? AMA guidelines

Calgary
 Osm
gap >10: measure methanol and
ethylene glycol

Edmonton
 Osm
gap >2: measure ethylene glycol
 Osm gap >5: measure methanol
When should toxic alcohols be
measured? AMA guidelines
Where do the 5 & 2 come from?
 “Classically” EG & methanol ingestions
needed treatment at levels of 20 mg/dL in
nonacidotic patients
 This translates to

 EG
level of 3.2 mmol/L
 Methanol level of 6.24mmol/L
Analyzed all published case reports of
MeOH poisoning to determine the
applicability of the 20mg/dL (6.24mmol/L)
threshold for treatment
 329 articles analyzed (2433 patients)
 70 articles met inclusion criteria (173 pts)



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Only 22 pts presented for care within 6 hours of
ingestion
All but 1 patient was treated with an ADH
inhibitor
A clear acidosis developed only with a methanol
level of >126mg/dL (39.4mmol/L)
There were cases of acidosis after only a few
hours of ingestion

Conclusions

There are no useful data available to create
treatment recommendations for the MeOH
exposed pt who presents early, prior to
development of toxicity

This is a time-dependent disease (which is not
accounted for in the “classic” treatment
recommendations)
So….what is the utility of osm gap?
Osmolar gaps are not 100% reliable to
exclude treatable toxic alcohol ingestions
 Low suspicion-----check osmolar gap
 High suspicion----check toxic alcohol
levels regardless of osmolar gap

Toxic Alcohols

“Toxic”
 Generally
reserved for any alcohol other than
ethanol

A few mouthfuls can kill:
 Average
adult mouthful: 0.42cc/kg
 Lethal dose of methanol: 1.2cc/kg
 Lethal dose of ethylene glycol: 1.4-1.6cc/kg
How does EtOH affect methanol &
ethylene glycol metabolism
EtOH competes for the enzyme alcohol
dehydrogenase
 Minimizes the metabolism of methanol and
ethylene glycol to their toxic metabolites
 Takes longer to form an AG in methanol or
ethylene glycol ingestion if there is
concurrent EtOH ingestion

Case 3
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21 year male presents at 7 am
Drank 1 glass of antifreeze at 3 am, “was tired of
life”
Had been drinking EtOH earlier in the night
Vomited immediately after ingestion
Now he wants to live so came to ED
O/E
T
37.2, HR 129, RR 18, BP 138/96
 Neuro: inebriated
 CVS, resp, abdo all unremarkable
Case 3
What investigations would you like?
 Labs

 Na
141, K 3.6, Cl 107, CO2 21
 BUN 10, Cr 190, glc 6, pH 7.35
 Osmolality 329
 EtOH 8.3 mmol/L
 Ethylene Glycol, methanol, isopropanolpending

Is there a benefit of testing the urine?
Case 3

What would you like to do for this patient?
Case 3
Ethylene Glycol-7 mmol/L
 Methanol-undetectable
 Isopropyl Alcohol-undetectable

Does this change your treatment plan?
 How about if the EG level was 9mmol/L?

Case 4
17 male and his 13 year old girlfriend
present to ACH ED at 3am
 Male is obviously intoxicated, slurring his
words and swearing at the triage nurse
 Presenting complaint…. “my girlfriend
can’t see”
 Couple came from a party
 Heavy drinking and marijuana
consumption at the party

Case 4

Girl
 Very
sedated, vomited at triage
 Vitals: T37.8, HR 112, BP 115/70, RR 28
 O/E:
Eye exam: mydriasis, but uncooperative
 CVS normal, resp normal, abdo tender diffusely


Labs???
Case 4
Labs on girl
 Glc 5
 Na 142, K 4.0, Cl 105, CO2 15
 CBG 7.25/30/55/15/-10 lactate 4
 BUN 8, Cr 55
 Osmolality 320
 EtOH 19mmol/L

Case 4

Guy
 Obnoxious,
ongoing slurring and swearing
 Vitals: T37.9, HR 110, RR 18, BP 120/80
 O/E
Diaphoretic
 H&N normal
 CVS, Resp, GI normal


Labs???
Case 4
Labs
 Glc 4.5
 Na 138, K 4.0, Cl 105, CO2 21
 CBG 7.35/35/55/21/-4 lactate 2
 BUN 7, Cr 70
 Osmolality 395
 EtOH 85mmol/L
 U/A: +ketones

Case 4
What’s the girl’s diagnosis?
 What do you want to do for her?

What’s the guy’s diagnosis?
 What do you want to do for him?

Case 4
Further history….girl showed up at the
party at 7pm, clearly intoxicated
 Rumours that prior to the party she had
experimented with windshield wiper fluid in
order to “get drunk fast”, as did another girl
 At the party, she consumed 5 beer
 At 2 am she started to complain of blurred
vision
 Methanol level 16mmol/L

Case 4

Does this change what you want to do for
her?
Ethylene Glycol
Coolant
 Peak levels in 1-4 hours
 Toxicity is a result of the metabolites

 Glycolic
acid---->glyoxylic, oxalic acid
 Oxalic acid produces calcium oxalate
crystalluria**
Ethylene Glycol Metabolism
Metabolic
acidosis
Ethylene Glycol
Urine sediment under polarized light showing calcium oxalate
monohydrate crystals
Ethylene Glycol
Calcium oxalate monohydrate and envelope-shaped
calcium oxalate dihydrate crystals
Stages of EG toxicity

Phase 1 (1-12 hours post ingestion)
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Phase 2 (12-24 hours post ingestion)
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Cardiopulmonary phase (tachycardia, tachypnea, mild
hypertension, CHF, ARDS, cardiomegaly, circulatory
collapse)
Phase 3 (24-72 hours post ingestion)

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CNS depression (inebriation, hallucinations, coma, seizures)
Nephrotoxicity (CVA tenderness, oliguria, ATN)
Phase 4 (6-12 days)
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Delayed CNS (Cranial neuropathies, motor deficits, cognitive
deficits)
Methanol

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
Paint removers, solvents, varnishes, windshield
washing fluid
Well absorbed from the GI tract
Peak levels 30-90 minutes after ingestion
Presentation may be delayed 12-18 hours
(longer if EtOH co-ingested)
Toxicity is the result of the metabolites
 Formaldehyde & formate
 Cause optic papillitis and retinal edema---> blindness
 Inhibits mitochondrial respiration---> lactic acidosis
Methanol Metabolism
Methanol Metabolism
Retinal & optic
nerve damage
Methanol

Clinical presentation
 CNS
depression
 Seizures
 Visual disturbances
 Abdominal pain
 Nausea
 Vomiting
 AG metabolic acidosis
 Osmolar gap
EG & Methanol Tx Approach
ADH blockage (Ethanol or Fomepizole)
 Alkalinize (If acidotic)
 Accelerate Elimination (Dialysis)
 Adjuncts

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Supportive treatment
Seizures
 IV Calcium for symptomatic hypocalcemia

GI decontamination
EG/Methanol are very rapidly absorbed
 Activated charcoal does not absorb
significant amounts of alcohol---no role
 Gastric aspiration via NG tube may be
beneficial only within the first hour after
ingestion, prior to symptoms

ADH Inhibition



Prevents conversion of parent alcohol to it’s
toxic metabolites
ADH inhibition doesn’t help once the toxic
metabolites are formed
2 options
 EtOH


65X more affinity for ADH than EG
10-20X more affinity for ADH than methanol
 Fomepizole

500-1000 X more affinity for ADH than EtOH
ADH Inhibition

MOA
N Engl J Med 1999;340:832-8
ADH Inhibition

AACT practice guidelines
 Toxic
alcohol concentration >3.2mmol/L (EG),
>6.2mmol/L (methanol)
OR
 Documented recent history of ingesting toxic amounts
of EG/methanol with osm gap >10
OR
 Strong clinical suspicion of EG/methanol poisoning
with at least 2 of:



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Arterial pH <7.3
Bicarb <20 mEq/L
Osm gap >10
Urinary oxalate crystals
EtOH

Load


Maintenance







7.6-10ml/kg of 10% solution IV in D5W over 30 min
Average drinker: 1.39 mL/kg/h
Chronic drinker: 1.95 mL/kg/h
Non drinker: 0.83 mL/kg/h
With dialysis: 3 mL/kg/h
Monitor levels q1h
Goal: 22-28 mmol/L EtOH level
Continue until EG/methanol levels are undetectable


T1/2 is increased with ethanol
EG 11-18h, Methanol 30-52 h
EtOH

Complications of infusion

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Hypotension
Respiratory depression (with supratherapeutic concentrations)
Flushing
Hypoglycemia
Hyponatremia
Pancreatitis
Gastritis
Inebriation

Patients receiving IV ethanol require ICU monitoring

Orally administered ethanol is effective, and may be
considered when ICU is unavailable

rural areas where there may be a significant delay in getting the
patient to another hospital
Fomepizole (4-methylpyrazole)

Load


Maintenance





10mg/kg IV q12h X 4 doses
Then 15mg/kg q12h until EG/methanol levels <3.2mmol/L
Don’t need to monitor levels & no ICU monitoring
Expensive (~$1000 per 1.5g vial)


15mg/kg IV in 250 cc NS or D5W over 30 min
Average 4 vials per patient
Previous EtOH intake does not decrease efficacy
T1/2 is increased

EG 20h; methanol 54h
Fomepizole-How good is it?

Anecdotal case
 42
year old male drank 1.5 L of antifreeze and
presented 4.5 hours after ingestion.
 EG level 51mmol/L
 Loading dose of EtOH, then fomepizole
 Complete recovery without dialysis
 CJEM 2002
Fomepizole-How good is it?

Retrospective case series
 Fomepizole
in the treatment of uncomplicated
EG poisoning. Lancet 1999.
 Treatment of acute methanol poisoning with
fomepizole. Intensive Care Med 2001.
Fomepizole-How good is it?

Multi-center prospective clinical trials
 Fomepizole
for the treatment of ethylene glycol
poisoning. Methylpyrazole for Toxic Alcohols Study
Group. N Engl J Med. 1999
 Fomepizole
for the treatment of methanol poisoning.
N Engl J Med. 2001
Fomepizole for the treatment of ethylene
glycol poisoning. N Engl J Med. 1999
Enrolled 23 patients (19 met criteria for EG
poisoning)
 18 patients survived
 1 death occurred in a pt with severe
acidemia

 clinical
course complicated by an MI
 Died of cardiogenic shock on the day of
admission
Fomepizole for the treatment of ethylene
glycol poisoning. N Engl J Med. 1999

All 10 pts who had normal renal fcn at
presentation showed no subsequent
kidney injury
 EG
levels as high as 71.9mmol/L
 pH levels as low as 7.16
 Glycolic acid levels under 10.5mmol/L

Pts needed median of 3.5 doses [range 1-7]
Fomepizole for the treatment of methanol
poisoning. N Engl J Med. 2001
11 patients
 2 died

 Both
pts comatose with signs of anoxic brain
injury on admission
 pH 6.9 & 7.01
 Formic acid levels 43 & 28 mmol/L
Fomepizole for the treatment of methanol
poisoning. N Engl J Med. 2001

9 survived
 pH’s
as low as 6.9
 Methanol levels as high as 191 mmol/L
 Visual deficits (only able to count fingers)
 Formic acid levels no higher than 21.7mmol/L
All regained baseline visual acuity
 Pts needed median of 4 doses [range 1-10]

When does Fomepizole win?





Rural areas without adequate lab support
Patients prone to hypoglycemia
Liver failure
Children
Patients who are going to be admitted to the
ward and dialysis is not imminent (i.e. those
without acidosis or end-organ damage)
Fomepizole-Adverse Effects?
Adverse Drug Events Associated with the
Antidotes for Methanol and EG poisoning: A
Comparison of Ethanol and Fomepizole




Cohort study of pts 13 years and older
Hospitalized patients 1996-2005
Methanol or EG poisoning treated with
fomepizole or ethanol
Primary outcome
 At least one adverse drug event
 Adverse drug event rate per person-day

of antidote tx
Secondary outcomes
 Severe
& serious adverse drug events
Lepik et al. Annals of Emergency Medicine 2009; 53(4): 439-50
Adverse Drug Events Associated with the
Antidotes for Methanol and EG poisoning: A
Comparison of Ethanol and Fomepizole


223 charts reviewed, 172 analyzed
Toxicologists identified at least 1 AE in
 74/130
(57%) EtOH treated pts
 5/42 (12%) Fomepizole treated pts

CNS symptoms accounted for most AE
 48%
of all patients treated with EtOH
 2% of all patients treated with Fomepizole
Lepik et al. Annals of Emergency Medicine 2009; 53(4): 439-50
Adverse Drug Events Associated with the
Antidotes for Methanol and EG poisoning: A
Comparison of Ethanol and Fomepizole

Severe AE (Poison Severity Score severity threshold)

26/130 (20%) of EtOH treated pts


2/42 (5%) of Fomepizole treated pts


Coma, extreme agitation, cardiovascular
Coma, cardiovascular
Serious AE (WHO criteria)

11/130 (8%) EtOH treated pts


Resp depression, hypotension
1/42 (2%) Fomepizole treated pts

Hypotension, bradycardia
Lepik et al. Annals of Emergency Medicine 2009; 53(4): 439-50
Adverse Drug Events Associated with the
Antidotes for Methanol and EG poisoning: A
Comparison of Ethanol and Fomepizole

Median adverse drug event onset was
within 3 hours of the start of the antidote

Adverse drug event rates
 adverse
drug events per treatment-day
0.93 EtOH
 0.13 Fomepizole

Lepik et al. Annals of Emergency Medicine 2009; 53(4): 439-50
Fomepizole-Any contraindications?

Previous allergic reaction
 None
reported
Fomepizole-When to stop

Previous guidelines*
 EG<3.2mmol/L
 Methanol

< 6.2mmol/L
NEJM 2009**
 Exact
point not defined
 States “undoubtedly safe to discontinue
therapy when the EG level is <4.8mmol/L &
methanol <9.4mmol/L
Great review article

Fomepizole for EG and Methanol
Poisoning. N Engl J Med 2009; 360:221623.
NaHCO3

Rationale
 EG
metabolized to glycolate, glyoxalate & oxalate
 Methanol metabolized to formate
 Acidemia leads to protonation of these metabolites &
makes them more likely to penetrate end-organ
tissues
 Bicarb deprotonates them, making them less toxic

Issues
 No
clear evidence for how bicarb should be given
NaHCO3

Recommendations
 UTD:
1-2 mEq/kg bolus for pH < 7.3, then
infusion (133meq NaHCO3 in 1L D5W) to
maintain pH >7.35


American Academy of Clinical Toxicology Practice
Guidelines on the treatment of Ethylene Glycol Poisoning. J
Toxicol Clin Toxicol 1999
American Academy of Clinical Toxicology Practice
Guidelines on the treatment of Methanol Poisoning. J
Toxicol Clin Toxicol 2002
Adjuncts

Thiamine & Pyridoxine
 MOA:
involved in the metabolism of glyoxylic
acid to non-toxic substrates
Theoretical benefit with
some indirect evidence
Cheap! So use them!
Dose:
Thiamine 100mg IV
Pyridoxine 100 mg IV
Adjuncts

Folinic acid
 50mg

Folic acid
 50mg


IV
IV q6h for
methanol
How about for EG?
Perhaps a better question
is….Does ethylene glycol
metabolism produce
formate?
Which
pathway
is
correct???
Ethylene Glycol--->Formate

EVIDENCE AGAINST:
 NONE
OF THE FOLLOWING MENTION FORMATE
AS A POSSIBLE METABOLITE FROM ETHYLENE
GLYCOL….
1. Medical Toxicology. 3rd edition. R. Dart.
2. Clinical Toxicology. Ford, Ling, Delaney,
Erickson.
3. Goldfrank’s Toxicologic Emergencies. 5th
Edition.
Ethylene Glycol--->Formate
EVIDENCE FOR formate formation from the metabolism of ethylene
glycol…
Critical Care Toxicology: Diagnosis and Management of the
Critically Poisoned Patient. Brent, Wallace, Burkhart, Phillips,
Donovan.
2. Haddad and Winchester’s Clinical Management of Poisoning and
Drug Overdoses. Shannon, Berron, Burns.
3. Emergency Toxicology 2nd Edition. Peter Viccellio.
4. Current Occupational and Environmental Medicine. Joseph La
Dou.
5.
Poison Management Manual. 4th Edition. D. Kent. G. Willis. K
Lepik.
6.
6. W. Henderson and J. Brubacher. Methanol and Ethylene Glycol
Poisoning: A case study and review of the current literature.
CJEM. Vol 4. (2002)
1.
Ethylene Glycol--->Formate

Total of 9 resources
3
do not mention formate
 6 mention formation of formate

Of the 6, only 1 (#3) suggested treatment with folic
acid. Yet the reference quoted suggested “other
metabolites (including formate) are deemed to be
negligible.”
Hemodialysis
Best method to rapidly remove parent
alcohols and their toxic metabolites
 General recommendations

 Severe
or refractory metabolic acidosis
 Deteriorating vital signs
 Onset of acute renal failure/visual symptoms
 EG >8.1mmol/L; Methanol > 15.6mmol/L*

evidence for HD based on levels alone is almost
nonexistent
Hemodialysis

Intensive Care Med (2005) 31: 189-195
Hemodialysis

Intensive Care Med (2005) 31: 189-195
Hemodialysis

Intensive Care Med (2005) 31: 189-195
Hemodialysis


Special considerations
 Fomepizole is dialyzable
 European recommendation: continuous
infusion 1mg/kg/h
 USA manufacturer recommends q4h
administration
Endpoints
 Serum
pH normal
 Parent alcohol concentration <3.2mmol/L
 Resolution of the osmolar gap
Back to the cases….

Case 3
 21 year male drank antifreeze (&EtOH)
 AG 13, osm gap 21, pH 7.35, EtOH 8.3mmol/L,
190, Na 141, K 3.6, Cl 107, CO2 21
 Ethylene Glycol: 7 mmol/L
 Methanol and Isopropanol-undetectable





How would you treat him?
Fomipazole or Ethanol
NaHCO3 not needed at this time
Dialysis not needed
Adjuncts: Thiamine and Pyridoxine
Cr
Back to the cases….

Case 4 (girl)
 Very sedated, “can’t see”, T37.8, HR 112, BP 115/70, RR 28
 CBG 7.25/30/55/15/-10, Na 142, K 4.0, Cl 105, CO2 15
 EtOH 19mmol/L, methanol 16mmol/L, BUN 8, Cr 55
 AG 22, Osm gap 1

Treatment?

ADH blockage-will it help her given that she has AG
already and no osm gap?
Dialysis indications:





Vision changes, MeOH>15mmol/L
NaHCO3
Adjuncts: Folate
Doesn’t the ethanol consumption protect her?
Back to the cases….

Case 4 (guy)
 Inebriated,
EtOH 85mmol/L
 CBG 7.35/35/55/21/-4
 AG 12, Osm gap 2
 U/A: +ketones
Treatment???
 No toxic alcohol exposure
 Treat as you would a drunk teenager

Proposed Treatment Algorithm
Intensive Care Med
(2005) 31:189–195
Isopropyl Alcohol
Disinfectant, solvent
 Typically comprises 70% “rubbing alcohol”
 When ingested, functions as a CNS
depressant and inebriant
 Fatality is rare
 Does NOT cause

 an
elevated anion gap acidosis
 retinal toxicity (as does methanol)
 renal failure (as does ethylene glycol)
Isopropyl Alcohol

Acetone
 Mild
CNS depressant
 Responsible for
marked ketosis
Isopropyl Alcohol

Lethal dose
 250
mL of 70% solution
Rapidly absorbed, peaks at 1-2 hours
 T1/2 = 2.5-8 hours (much slower when
ADH inhibitors are present)
 Absorption and toxicity are possible
following dermal exposure (in infants)

Isopropyl Alcohol

Clinical (Symptoms peak at 1 hour)
 Inebriation
w/ disinhibition--->sedation--->
stupor--->coma
 Nausea, vomiting, abdominal pain
 Fruity breath (acetone)

The metabolite (acetone) causes much
less sedation therefore expect clinical
improvement with time
Laboratory
Serum isopropyl alcohol levels & acetone
 Elevated osmolar gap
 Urine & serum ketones


Lytes, BUN, Cr, blood gas
Treatment

Supportive (ABC’s)
 Consider
intubation if patient unable to protect
airway
Decontamination: no real role
 ADH inhibition: no indication

Review of Objectives
1)
2)
3)
Review the causes of an anion gap
Review the causes of an osmolar gap
Review the “toxic alcohols”
Methanol
2) Ethylene Glycol
3) Isopropyl Alcohol
1)
4)
Discuss the evidence for fomepizole
Summary-Anion Gap

AG = Na - (Cl + HCO3) Simple way to calculate

AG=unmeasured anions-unmeasured cations

When considering the DDx, can use MUDPILES,
but need to consider what actually causes the
AG

In hypoalbuminemic patients, need to re-adjust
the “accepted” AG
Summary-Osmolar gap


Posm = 2[Na] + [Glc] + [BUN] + 1.25[ethanol]
Osmolar gap can not distinguish among ethanol,
isopropyl alcohol, methanol or ethanol

Osm gap increases only in the presence of the parent
alcohols

Osm gap is not sensitive enough to rule out small
ingestions

An unexlpained large osm gap (>25) is presumptive of a
recent methanol, ethylene glycol or isopropyl alcohol
exposure
Summary-EG & Methanol





Rapidly absorbed and toxic in small amounts
A low/neg EG/methanol level and osm gap can
be misleading in late presenters
Expect normal AG in early presenters
Significant met acidosis suggest toxic
metabolites---only definitive treatment is dialysis
ADH inhibitors are use to prevent further
metabolization of the parent alcohol
 Fomepizole
seems to be the recommendation!
Summary-Isopropyl Alcohol

Hallmark of isopropyl alcohol metabolism is marked
ketonemia and ketonuria in the absence of metabolic
acidosis

Isopropyl alcohol is rapidly and completely absorbed
following oral ingestion

Clinical presentation similar to ethanol intoxication

If ingested in isolation, no tx needed, but need to r/o
ingestion of more toxic alcohol