ToxicologyAnion Gap, Osmolar Gap & Toxic Alcohols

Christine Kennedy

Pediatric Emergency Fellow

Oct 15, 2009

Objectives

1) Review the causes of an anion gap

2) Review the causes of an osmolar gap

3) Review the “toxic alcohols” 1) Methanol

2) Ethylene Glycol

3) Isopropyl Alcohol

4) Discuss the evidence for Fomepizole

Anion Gap

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

Hypocalcemia, hypomagnesemia, hypokalemia

a 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 hypoalbuminemiaAG 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? 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

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 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 Ethylene glycol and Methanol* EtOH** Isopropanol ingestion---> acetone Diethyl ether ingestion Mannitol Severe hyperproteinemia Severe hyperlipidemia

Ethanol and the Osmolar Gap

Case 1 Intoxicated maleNa 140, BUN 5, Glc 5, EtOH 75Osmolality 385Osmolarity = ____Osm gap = ____

Ethanol and the Osmolar Gap

Case 1 Intoxicated maleNa 140, BUN 5, Glc 5, EtOH 75Osmolality 385Osmolarity 2(140) + 5 + 5 + 75 = 365Osm 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 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: 653-659.Derived a formula to account for the

relationship between ethanol and then osmolar gap

Prospectively validatedBest 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 labO-Gap (absence of toxic Alc)

0

20

40

60

80

100

120

140

160

180

200

0 50 100 150 200

Ethanol mmol/L

O-G

AP

, mo

smo

L

This supports the 1.25 EtOH conversion

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

What is the normal osmolar gap?

Normal Osmolar gap

Hard to define because it depends onLab method of osmolality determinationOsmolarity formula usedLab error of Na, BUN, Glc, EtOHEtOH 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 GapHoffman. J Toxicol Clin Toxicol. 1993

-14 -8 -2+4

+10

Mean Osm gap= -2

SD 6.1

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

EdmontonOsm gap >2: measure ethylene glycolOsm 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/LMethanol 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)

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/kgLethal dose of methanol: 1.2cc/kgLethal 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

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 21BUN 10, Cr 190, glc 6, pH 7.35Osmolality 329EtOH 8.3 mmol/LEthylene Glycol, methanol, isopropanol-pending

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

GirlVery sedated, vomited at triageVitals: T37.8, HR 112, BP 115/70, RR 28O/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

GuyObnoxious, ongoing slurring and swearingVitals: T37.9, HR 110, RR 18, BP 120/80O/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 acidOxalic 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) CNS depression (inebriation, hallucinations, coma, seizures)

Phase 2 (12-24 hours post ingestion) Cardiopulmonary phase (tachycardia, tachypnea, mild

hypertension, CHF, ARDS, cardiomegaly, circulatory collapse)

Phase 3 (24-72 hours post ingestion) Nephrotoxicity (CVA tenderness, oliguria, ATN)

Phase 4 (6-12 days) Delayed CNS (Cranial neuropathies, motor deficits, cognitive

deficits)

Methanol

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 presentationCNS depressionSeizuresVisual disturbancesAbdominal painNauseaVomitingAG metabolic acidosisOsmolar gap

EG & Methanol Tx Approach

ADH blockage (Ethanol or Fomepizole) Alkalinize (If acidotic) Accelerate Elimination (Dialysis) Adjuncts

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: Arterial pH <7.3 Bicarb <20 mEq/L Osm gap >10 Urinary oxalate crystals

EtOH

Load 7.6-10ml/kg of 10% solution IV in D5W over 30 min

Maintenance 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 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 15mg/kg IV in 250 cc NS or D5W over 30 min

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)

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 case42 year old male drank 1.5 L of antifreeze and

presented 4.5 hours after ingestion.EG level 51mmol/LLoading dose of EtOH, then fomepizoleComplete recovery without dialysisCJEM 2002

Fomepizole-How good is it?

Retrospective case seriesFomepizole 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

acidemiaclinical course complicated by an MIDied 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 injuryEG levels as high as 71.9mmol/LpH levels as low as 7.16Glycolic 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 & 7.01Formic acid levels 43 & 28 mmol/L

Fomepizole for the treatment of methanol poisoning. N Engl J Med. 2001

9 survivedpH’s as low as 6.9Methanol levels as high as 191 mmol/LVisual 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

Coma, extreme agitation, cardiovascular 2/42 (5%) of Fomepizole treated pts

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 ratesadverse 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 reactionNone reported

Fomepizole-When to stop

Previous guidelines*EG<3.2mmol/LMethanol < 6.2mmol/L

NEJM 2009**Exact point not definedStates “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; 360:2216-23.

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

RecommendationsUTD: 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 IV

Folic acid 50mg 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…

1. 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)

Ethylene Glycol--->Formate

Total of 9 resources3 do not mention formate6 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 recommendationsSevere or refractory metabolic acidosisDeteriorating vital signsOnset of acute renal failure/visual symptomsEG >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 considerationsFomepizole is dialyzableEuropean 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, Cr 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

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/LCBG 7.35/35/55/21/-4AG 12, Osm gap 2U/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 dose250 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--->comaNausea, vomiting, abdominal painFruity 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) Review the causes of an anion gap

2) Review the causes of an osmolar gap

3) Review the “toxic alcohols” 1) Methanol

2) Ethylene Glycol

3) Isopropyl Alcohol

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