Transcript 2008_01_17-Patterson - Calgary Emergency Medicine

Toxic Alcohols
and ASA
Heather Patterson
PGY-3
Jan 17, 2007
Objectives
• Review of:
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Toxicokinetics
Basic Pathophysiology
Clinical Features
Managment
Case 1:
• 18M
• Drinking with friends
– Brought to ED because he was having ++N/V and abdo
pain and seemed overly intoxicated
– Thought it was strange because he really hadn’t had that
much to drink
– Mixed their own drinks. But didn’t have enough booze
for “good” drinks. So they added a little of this, a little
of that – just to help out a bit.
Investigations
• Usual toxic w/u
• Labs
– Lytes, including Ca
– Anion and osmolar gaps
– Urine for crystals
Case
• Osmolar gap: 12
• Anion gap: 14
• What is your DDx for anion + osmolar
gap?
– Methanol
– Ethylene glycol
– Propylene glycol
– Alcoholic or starvation ketoacidosis
– DKA
– Acteonitrile
Case
• With toxic alcohol ingestions:
– What causes an osmolar gap?
– What causes an anion gap?
Toxic Alcohol
(Osmol Gap)
Toxic Metabolite
(Anion gap)
Case
• Who is the sickest?
– Patient A: wide osmolar gap, minimal AG
– Patient B: smaller osmolar gap, high AG
OsmolarDdx
Gap
of DDx
Osmolar Gap
P
Proteins
A
Alcohols (EtOH, methanol, ethylene glycol,
isopropanol, propylene glycol, diethylene glycol, triethylene
glycol)
S
Sugars (mannitol, glycerol, sorbital)
C
Contrast dyes
A
Acidosis (ketoacidosis, lactic acidosis)
L
Lipids
A
Acetone
Osmolar Gap
•Osmolality
– Solute/kg of
solvent
Lab measures
• Osmolarity
– Solute/liter of
solution
– You calculate!
Osmolality
Osmolarity Formulas
• Other formulas…….
Osmolality
Formulas
Osmolarity
Formulas
• Calgary
– 1.86Na + BUN + glucose + 9
– 1.86:
• 93% is in Na+, Cl- (ionized form) and the remainder
is in the NaCl (nonionized form)
– +9 factor:
• Accounts for other osmotially active molecules ie K,
Ca, proteins
– Thought to be the best formula: Dorwat Clin Chemistry
1975.
Case
Case 1
• Intoxicated male
• Na 140, BUN 5, Gluc 5, EtOH 75
• Osmolality = 385
Does he have a gap?
How does EtOH effect osmolar gaps?
EtOH
andand
Osmolar
Gap Gap
Ethanol
the Osmolar
• 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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Geller 1986:
Galvan 1992:
Synder 1992:
Hoffman 1993:
Pappas 1985:
Britten 1972:
Glasser 1973:
1.20
1.14
1.20
1.09
1.12
1.74
1.1
EtOH and Osmolar Gap
• Purssell. Ann Emerg Med 2001: 38: 653659.
– Derived a formula to account for the
relationship between ethanol and osmolar
gap
– Prospectively validated
– Best formula = EtOH (mmol/L) X 1.25
Case
• 35 yo male
• Took a swig of a mug
that had antifreeze
• Osmolarity = 321
Na 140
Gluc 5
EtOH 25
• What is a normal osmolar
gap?
BUN 5
HCO3 24
Osmolality 321
• No anion gap
Osmolar Gap
• Case 2: osmolar gap = 0
Can osmolar gaps be used to rule out toxic
alcohol ingestions?
Is there a “cutoff” where toxic alcohols
should be routinely measured?
Normal Osmolar Gap:
Hoffman. J Toxicol Clin Toxicol. 1993
2Na + BUN + Gluc + EtOH
-14
-8
-2
+4
+10
Osmolar Gap
• When should we measure toxic alcohols?
• Calgary (1.86Na + BUN + Gluc + EtOH +9)
– Osmolar gap > 10: measure methanol and
ethylene glycol
• Edmonton (2Na + BUN + Gluc + EtOH)
– Osmolar gap > 2: measure ethylene glycol
– Osmolar gap > 5: measure methanol
Can these cut offs r/o a significant toxic
alcohol ingestion?
-14
0
• Baseline -14
• Osm gap 0
• Methanol
level of 14!!!
Osmolar Gap
• Additional problems/questions:
– What is the normal distribution for the formula
that we use in Calgary for osmolarity?
– What is the true effect of EtOH?
– What is a significant toxic alcohol level?
• Nobody really knows!
• Evidence for when to dialyze based on case series and case
reports.
• Are you willing to miss a methanol level of 5, 10, or 15
mmol/L?
Osmolar Gap
• So how do we use this most effectively?
– Osmolar gaps are NOT 100% reliable to exclude
treatable toxic alcohol ingestions
– Low suspicion ------ check osmolar gap
– High suspicion ------ low threshold to check toxic
alcohol levels regardless of osmolar gap
• Remember: osmolar gaps are irrelevant when the
patient has an AGMA from toxic metabolites
Methanol
• What products contain methanol?
– Paint remover, varnish, washer fluid, antifreeze,
carborator fluid, glass cleaner, gasoline substitute,
canned heating products, wood spirits/alcohol
• What is a toxic dose:
– Blindness: 4ml of 40%
– Lethal: 15ml of 40%
• Peak levels and half life?
– 30-90 min
– T ½ = 14-20 h for small ingestions
– T ½ = 24-30h for large ingestions
Methanol Metabolism
Methanol
• Why is the half life longer with higher
doses of methanol?
• Clue – what is first order kinetics vs
zero order kinetics?
Basic Pathophysiology
• Formic acid:
– High affinity for iron
– Indirectly inhibits cytochrome oxidase enzymes
– Leads to ATP depletion, anaerobic metabolism, lactic
acidosis
• Ocular injury:
– Myelin damage  axonal disruption
– Acidosis  increased diffusion of formic acid into
neurons  increased acidosis etc etc
Basic Pathophysiology
• Basal Ganglia:
– Uncertain why the affinity for the basal ganglia –
especially the putamen
– Hemorrhage, necrosis, cysts
Methanol: clinical features
• Onset:
– May be delayed 18+ hours especially if coingested with
EtOH
• Vitals:
– CVS normal unless preterminal (hypotension,
dysrhythmias)
– Tachypnea – Kussmauls is uncommon
Methanol: clinical features
• Cardinal Presentation: GI + Ocular + CNS
• GI:
– N/V/ abdo pain, pancreatitis with increased amylase
– Due to mucosal irritation
• Ocular (50%):
– Most common: “Snow field: or dense central scotoma
– Diplopia, blurred vision, photophobia, fixed dilated
pupils, retinal edema/hyperemia
– LOOK AT THE RETINA
• Changes occur 18-48h
Methanol: clinical features
• CNS
– This is a spectrum
– Headache, dizziness/vertigo, ataxia, confusion, sz, coma
– May be difficult to assess if they have coingestants or are
significantly altered
Case
• You send a urine sample from your
intoxicated teenager.
• Lab report:
– Many octahedral crystals
– Urine fluoresces under wood’s lamp
• If the urine didn’t fluoresce can you
r/o EG toxicity?
EG: Pathophysiology
EG: Pathophysiology
• Multiple toxic metabolites – oxalate is the
most toxic
• Mechanism for tissue toxicity not fully
understood.
• Tissues targeted:
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CNS
Kidney
Lung
Muscle including cardiac
Retinal
EG: Clinical
• Stage 1: Acute neurological (1-12h)
– Inebriated, ataxic
– Hallucinations, sz, coma, death
– Fundi N
•Occular abnormalities not seen in pure
ingestion
EG: Clinical
• Stage 2: Cardiopulmonary (12-24h)
– Tachy, mild HTN, tachypnea
– Arrhythmias secondary to ↓Ca
– ARDS, CV collapse, Cardiomegaly
EG: Clinical
• Stage 3: Nephrotoxicity (24-72h)
– Urine crystals
•Ca oxalate 50%
•Dihydrate or monohydrate
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Hematuria, proteinuria
Flank/CVA tenderness
ATN
Oliguric or anuric ARF
EG: Clinical
• Stage 4: Delayed Neuro Sequelae (6-12days)
– CN palsies
•VII, VIII common
– Multiple possible neurological findings
• focal and cognitive deficits
Mangement: Approach
• The 5 A’s
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ABCs and supportive care
Alkalinize
Alcoholize
Accelerate Elimination – Dialysis
Adjuncts
• Goals:
– Correct acidosis
– Block alcohol dehydrogenase
– Remove parent alcohol
Mangement: Decontamination
• Is charcoal indicated with toxic alcohol ingestion?
• CHILE:
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Caustics
Hydrocarboms
Iron
Lead, Li
Ethanol/methanol/ethylene glycol
Mangement: Alkalinize
• Goal:
– pH 7.45-7.5
• Rationale?:
– Normalizing pH ioninzes formic acid/oxalic acid and
limits its movement into CNS/eyes
– Helpful in those with cardiovascular instability
• Method?
– Bolus: 1-2 mEq/kg
– Maintenance: 1.5-2x mainenance
Management: Alcoholize
• When to start an antidote?
• AACT Consensus statements
– Strong suspicion of ingestion and 2 of:
• Osmole gap > 10,
• pH < 7.3, or
• Bicarb < 20, or
• Urinary oxalate crystals (EG)
– Documented ingestion and OG > 10
– Me >6 mmol/L, EG > 3 mmol/L
Management: Alcoholize/Antidote
• What options do you have?
• EtOH vs Fomepizole?
• EtOH:
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Cheap
Difficult to dose
Metabolic effects
Toxic effects
• Fomepizole:
– Expensive
– Easy q12h dosing
– No drunk and rowdy pt
Management: Alcoholize
• EtOH infusion (10% solution):
– Loading dose: 10cc/kg
– Maintenance: 1cc/kg/hr
– Goal: 20-30mmol/L
– Dosing in alcoholics?
– Dosing during dialysis?
• Often infusion runs for 2-3 days
• What can you use if no IV EtOH available?
Managment: Antidote
• Fomepizole:
– Loading: 15 mg/kg load
– Maintenance 10 mg/kg q12hr
X4, then 15 mg/kg q12hr
– Continue treatment until
methanol level is acceptable, pt
asymptomatic, and normal pH
Managemt: Adjuncts
• How do the treatment of Methanol and Ethylene
glycol differ?
Methanol: Adjuncts
• Folate:
– Cofactor in conversion of
formic acid to H20 and
CO2
– Dose: 50mg IV q4h x 2
days
EG: Adjunts
• Dosing:
– Thiamine 100mg IV q6h
– Mg 2-4g IV
– Pyridoxine 50 IV q6h x 2days
EG: Managment
• What about the hypocalcemia?
– MUST be replaced
– Calcium chloride (10%) 10 mls
– Follow levels and EKG
Real Case
• You are the STARs doc-on call
• Called from Taber
• 14month old M found on the floor with small
container that used to hold fuel for a model car
– 80% Methanol
• 60 mins post suspected ingestion
• Not curretly showing symptoms/signs of intoxication
Real Case
• 30 minutes later, the child starts looking a bit
intoxicated
– It is also WAY past his bedtime
– Parents say he always “walks like that”
Case
• 52M found on park bench altered LOC
• Bottle of rubbing alcohol beside him
– It is half full
Isopropyl Alcohol
• Not so tasty
• Found in:
– Rubbing alcohol, disinfectants, solvents,
hair products, jewelry cleaners, dtergtents,
paint thinners, some antifreeze
• Has 2x the CNS depressant activity of
EtOH
Toxicokinetics
• Absorption:
– GI
– Resp
– Dermal
• Peak levels
– 30min-3h
– T ½ 3-7h
• Toxic Dose:
– 1ml/kg of 70%
• Lethal dose:
– 2-3ml/kg
– (less in kids)
Isopropyl: Pathophysiology
• Ketosis WITHOUT acidosis
Isopropyl: Pathophysiology
• Mechanism of CNS depression not well understood
• Acetone:
– Direct myocardial depressant
– Peripheral vasodilatation
Isopropyl: Clinical features
• General:
– Intoxicated
– Smells like acetone
• Vitals:
– Normal
– Sinus tach
– Possible – hypotension, ↓RR
Isopropyl: Clinical features
• GI:
– N/V, pain
– +/- hematemesis – hemorrhagic gastritis
• CNS
– Altered  confusion coma
– Loss DTR and corneals, +babinski
– Nystagmus
Isopropyl: Investigations
• Labs:
– Helpful trid:
• Minimal acidosis + ketonuria (no glucosuria) + osmolar gap
– Elevated Isopropyl Alcohol
– Others:
• ARF
• Hepatic failure
• Hypoglycemia
• Hemolysis
• Rhabdo
Isopropyl: Management
• How would you like to manage this patient?
• Decontamination?
• Alkalinization?
• Alcoholization?
• Accelerated Elimination?
Isopropyl: Management
• What if the patient has a GCS of 7?
• What if the patient has a pressure of 78/40?
Isopropyl: Management
• What are the indications for dialysis?
– >66mmol/L
– Refractory hypotension
**** Coma is NOT an indication for dialysis ****
Isopropyl: Management
• Your patient has now been stable for some time. There
are no ongoing signs of intoxication, no hypotension or
hypoglycemia.
• Can this patient go home?
Isopropyl: Management
• Key things to remember:
– ABCs!
– Evaluate for hypoglycemia
– Watch for GI bleeding
– Dialysis when indicated
Thanks Rob and Ingrid!
Thanks Rob and Ingrid!
Case
• 55F
• Brought in by EMS
• Called by neighbours who
saw her confused and acting
bizarrely.
• PMHx
– DM2
– HTN
– GERD
• Meds:
– Adalat
– Gluconorm
– Pantoloc
Case
• Vitals:
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38.0
HR 90s
RR 16
BP 130/80
95% RA
CS 9.5
• Physical exam:
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CVS N
Chest clear
Abdo soft
GCS 13, no focal findings
• EKG:
– Sinus tach
Case
• Video here…
Case
• What some of the key features of this
presentation?
– Clue: breathing and LOC
• Based on this, what would you like to do
next?
Case
ASA
• Common drug – multiple preparations
• Highest mortality rate of OTC analgesics in
OD (~0.5%)
• Most fatalities for single drug OD in Ontario
in ’83-’84
ASA
• GI absorption
– Speed of absorption:
•Liquids > plain ASA > EC or SR preps
•Pylorospasm with large ingestions
•Concretions due poor solubility in gastric secretions
•Ionic form binds albumin and other proteins
ASA: Toxicokinetics
• Plasma levels:
– Detectible at 30 min
– Peak levels 2-4 hours
ASA: Toxicokinetics
• Toxicity:
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<150mg/kg = non toxic
150-300mg/kg = mild to mod toxicity
300-500mg/kg = severe toxicity
>500mg/kg = lethal
ASA
• Elimination:
– Therapeutic doses – first order kinetics
– Toxic doses – zero order kinetics
•Hepatic mechanism overwhelmed
•Excretion is renal
• Half life:
– Increases with toxic levels to 15-30h
ASA – Pharmacokinetics
HA  H+ + A• Weak organic acid – 99.99% ionized at pH 7.4
– pKa low therefore most of ASA is in ionic form at
physiological pH
• Only non-ionized form can cross membranes
ASA – Clinical features
• Correlation of symptoms with increasing ASA levels
• Symptoms do NOT allow you to r/o significant
toxicity
What is the usual progression of symptoms?
(ie what systems are affected in which order)
• GI  Metabolic  CNS  Renal and Respiratory
ASAS–+Clinical
features Toxicity
S of Salicylate
S
A
L
I
C
Y
L
A
T
E
C
O
N
C
• Renal / Respiratory failure
• Coma, Seizures
• CNS (confusion, irritability, delirium,
visual hallucinations, lethargy)
• Metabolic Acidosis
• Dehydration / Electrolyte Abnormalities
• Hyperventilation / Resp alkalosis
• Nausea + Vomiting
• Fever, Diaphoresis
• Tinnitus, Hearing Changes
• Asymptomatic
ASA – Clinical features: GI
• Gastritis
– local effects
• Vomiting
– Stimulation of cerebral chemoreceptors
– Decreased gastric motility
– Pylorospasm
ASA – Clinical features: Metabolic
• How does ASA affect oxidative phosphorylation?
• What are the effects on cellular metabolism?
ASA – Clinical features: Metabolic
• ASA uncouples oxidative phosphorylation and
prevents production of ATP
• Increased anaerobic metabolism
• Catabolic state
– Lipolysis
– Proteolysis
– Glycogenolysis and gluconeogenesis
ASA – Clinical features: Metabolic
• Tinnitis:
– Occurs before hearing loss
– Due to metabolic changes in the endolymph
• Pyrexia:
– Due to uncoupling of oxidative phosphorylation
ASA – Clinical features: Metabolic
• Alterations in glucose homeostasis:
– Hyperglycemia early
– Hypoglycemia late
– Paradoxical CNS hypoglycemia
• Cerebral glycolysis
• Hypokalemia:
– Due to GI losses
– Direct increase in renal excretion
– Cellular shift with bicarb
ASA – Clinical features: Metabolic
• What is the common progression of the acid-base
disturbances in the course of ASA toxicity?
– Respiratory alkalosis
– Resp alkalosis, met acidosis
– Resp alkalosis but pCO2 increasing, met acidosis
ASA – Clinical features: Metabolic
• What are the 4 mechanisms for metabolic acidosis in
ASA toxicity?
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Lactic Acid
FFA
Amino Acids
Salicylic Acid, acetosalicylic acid
ABG analysis
ASA – Clinical features: Metabolic
• The ABG….
• Let’s work through our patient’s ABG
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1.
2.
3.
4.
5.
6.
Acidemia vs Alkalemia
Metabolic or respiratory
Anion gap
“Rule of 15”
Delta gap
Osmolar gap
ASA – Clinical features: Metabolic
7.34/15/62/8
Na 140
K 3.8
Cl 114
1.
2.
3.
4.
5.
6.
Acidemia vs Alkalemia
Metabolic or respiratory
Anion gap
“Rule of 15”
Delta gap
Osmolar gap
Rule of 15
• Creates a new set point for the pCO2
– pCO2 appropriate = normal compensation
– pCO2 too low = superimposed primary resp
alkalosis
– pCO2 too high = superimposed primary resp
acidosis
• Note: as HCO3 falls below 10 you need to use
the formula HCO3 x 1.5 + 8 = expected pCO2
Thanks Marc
ASA – Clinical features: Metabolic
• Respiratory compensation for Metabolic d/o
Compensation
PaCO2 : HCO3-
Metabolic Acidosis
1:1
Metabolic Alkalosis
1: 0.75
Thanks Marc
ASA – Clinical features: Metabolic
• Metabolic compensation for Respiratory d/o
Compensation
PaCO2 : HCO3-
Acute Resp Acidosis
Acute Resp Alkalosis
Chronic Resp Acidosis
Chronic Resp Alkalosis
10:1
10:2
10:3
10:4
Back to the case…
• How would you decontaminate the patient?
– AC/MDAC
– +/- WBI for EC/SR tabs
Case:
• What are the indications for bicarb?
– ASA level >2.5
– Suspected/known ingestion, symptomatic and levels
pending
Case:
• You have asked the nurses to
get some bicarb.
• How do you administer it?
• How does it work?
Ion trapping
HA
HA
HA
HA
pH=8
pKa=3.5
H+ + ABlood
A- + H+
Urine
Fig. 2a: Unionized molecules diffuse across renal
tubular membranes from blood to renal filtrate but
ionized ones cannot cross from one compartment into
the other.
H+ + ABlood:
lower pH
A- + H+
Urine:
higher pH
Fig. 2b: When urine is alkalinized, weak acids like salicylates
will dissociate into ions, become “trapped” and excreted in the
urine. Unionized parent molecules then diffuse down their
concentration gradient from blood into the urine.
Case:
• You have started your bicarb infusion
– Urine pH is NOT reaching the target
– What may inhibit the ability to alkalinize the urine?
•K
• Hypovolemia
• When would you stop the bicarb?
– Level <2.5 and declining
– Asymptomatic
– AG corrected
Case:
• She is now on 100% NRB and sats are 83%
• Her pCO2 is 30 (from 15) and pO2 is 50
• What do you think is going on?
ASA – Clinical features: Resp
• Pulmonary edema:
– Mechanism is unknown
– Non-cardiogenic
• Risk factors
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>30y
Smoker
Chronic toxicity
Met acidosis
ASA >2.9
Case:
• What would you like to do now?
• Do you have any concerns about intubating this
patient?
• What drugs would you use?
Case:
• As you are setting up to intubate your patient, she
has a generalized seizure.
• What drugs would you like to use in this situation?
• After 2 doses of benzos she is still seizing. The
nurses ask if you would like to load her with
dilantin?
Case:
• Does this patient need dialysis?
– Neurotoxicity
• Altered mental status, sz, cerebral edema
– Pulmonary edema
– Renal insufficiency that interferes with administration of
bicarb
– Fluid overload that interferes with administration of
bicarb
– ASA >7
– Clinical deterioration despite aggressive care
Summary of ASA management
• ABCDEs
• AC/MDAC or WBI with SR preps
• Bolus NaHCO3
• Bicarb infusion + 40 Meq KCl at 2-3x maintenance
• Replace K
• +/- dialysis
• Monitor:
– Urine pH q1h for pH 8
– K+ q2h
– Glucose
Case:
• 65M feeling unwell with viral infection for 1 week.
• Comes in with nausea and vomiting and his hearing
hasn’t been right
• Hasn’t changed or added any new meds
• No other symptoms
• Doesn’t like acetominophen or ibuprofen and so has
been taking “extra” ASA every day.
Case:
• How would you like to manage this patient?