Toxicology Anion Gap, Osmolar Gap & Toxic Alcohols Christine Kennedy Pediatric Emergency Fellow Oct...
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Transcript of Toxicology Anion Gap, Osmolar Gap & Toxic Alcohols Christine Kennedy Pediatric Emergency Fellow Oct...
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