Salicylates

SALICYLATE TOXICITY Rif ASA toxicity Objec0ves: •  Review the basics •  5 CORE things to know about ASA toxicity: 1. 
2. 
3. 
4. 
5. 
Role of low pH and bicarb Role of glucose supplementa0on Intuba0on piEalls Sources of ASA Dialysis and piEalls of chronic ASA toxicity Rif ASA Basics •  Use declining (Reye syndrome, other meds) •  S0ll relevant as a source of toxicity! •  Are we more uncomfortable with ASA toxicity? Rif Basics •  Chemoreceptor trigger zone in medulla = nausea and vomiGng •  Respiratory center in medulla = hypervenGlaGon and resp alkalosis •  Cellular toxin = high AG metabolic acidosis and hyperthermia •  MOST SEVERE ASA OVERDOSES ARE VOLUME DEPLETED Rif 1. Low pH is the KILLER Progression of BADNESS Resp.
alkalosis
N bicarb
Low pCO2
high pH
Mixed resp
alkalosis +
metabolic
acidosis
Low bicarb
Low pCO2
N/high pH
Rif Resp and
metabolic
acidosis
Low bicarb
High pCO2
Low pH
PREDEATH
1. Low pH is the KILLER CATS
Predominantly
non ionized ASA
at low pH
RATS
Rif 1. Low pH is the KILLER •  Animal studies: increased mortality with increased CNS ASA concentra0on. •  Serum ASA ≠ CSF ASA at low pH •  low pH = more non-­‐ionized ASA (HA) driven into the “lipophilic” brain 1. Low pH is the KILLER •  Treatment: urine alkaliza0on pH 7.5-­‐8 •  Non-­‐ionized ASA Ionized ASA + H+ •  Respiratory alkalosis not a contraindica0on to urine alkaliza0on 1. Low pH is the KILLER Treatment •  Urinary alkaliniza0on = treatment endpoint –  reduces diffusion of ASA anions into the brain –  traps ASA anions in renal tubule –  Avoid hypokalemia Low K prevents good
urine alkalinization
Rose, BD et al, 2013
Rif 2. Role of glucose supplementa0on •  Poor correla0on between serum and CSF glucose concentra0ons: Other studies
showed
improved
survival with
glucose
supplementation
Rif 2. Role of glucose supplementa0on •  Uncoupling of oxida0ve phosphoryla0on = increase in cerebral glycolysis à Glucose u0liza0on > delivery •  Treatment: 0.5-­‐1 g/kg dextrose bolus, then D10 drip, maintain serum glucose at 7-­‐8 mmol/L Rif 1 + 2. Watch the pH & serum glucose CSF glucose
Plasma glucose
CSF ASA
Plasma ASA
Assess serum ASA in
light of the pH!
Rif 3. Intuba0on PiEalls Pearls •  Low pH = non-­‐ionized ASA “flooding” the brain •  Hyperven0la0on keeps pH up •  Apnea during intuba0on = drop in pH = death •  Intubate quickly to avoid sudden PaCO2 rise! •  Avoid post intuba0on hypoven0la0on •  Increase pH with bicarb: urine pH 7.5-­‐8; serum pH 7.45-­‐7.5 Rif 4. Sources of Salicylate Toxicity •  Not JUST aspirin CALL POISON
CENTER!
Rif 5. PiEalls of Chronic Toxicity •  Therapeu0c range in acute inges0on: 1.1-­‐2.2 mmol/L •  Acute toxicity: symptoms above 2.9 mmol/L •  ACUTE TOXICITY: •  150-­‐300 mg/kg: moderate •  300-­‐500 mg/kg: severe •  > 500 mg/kg: poten0ally lethal Rif 5. PiEalls of Chronic Toxicity •  75F with ARF, confusion, ataxia, CHF, WBCs on urinalysis, ASA level 2.2, pH 7.3, metabolic acidosis. Rest nega0ve. •  Would you dialyze? a.  Yes b.  No way Rif Chronic ASA Toxicity is a Great “Pretender” Vitals
ENT
Neuro
Acid-base
abn
Cardiac
Resp
Heme
GI
Glucose
metabolism
Sepsis? Delirium? CHF? Stroke?
Rif 5. HD and PiEalls of Chronic ASA Toxicity: When to dialyze? ACUTE
Very high ASA level >7.2
mmol/L, or 5.5 (mortality
in studies)
CHRONIC
Regardless of level if low
pH, end-organ damage
End-organ damage, levels
not dropping
Call Poison Centre!
Rif 18
☠  Summary = 5 Things to Know 1. 
2. 
3. 
4. 
5. 
Low pH kills by “flooding” the brain with ASA, alkalinized urine is your “sink” for ionized ASA. CNS hypoglycemia: supplement with dextrose Beware of apnea / hypoven0la0on during / post intuba0on Mul0ple sources of ASA = call Poison Control when in doubt Chronic toxicity: great mimicker, the syphilis of toxicology, remember when to dialyze your pa0ent Rif Oil of Wintergreen Inges0on Rif Ques0ons? Rif UP THE CREEK WITHOUT A TOX LAB: TOXIC ALCOHOLS IN RURAL SETTINGS Rif Methanol and Ethylene Glycol Objec0ves: 1.  Iden0fy sources of methanol and ethylene glycol 2.  Compare and contrast the differences & similari0es 3.  Define the toxic dose 4.  Iden0fy the piEalls of osmolar and anion gap / other labs 5.  Discuss treatment op0ons including dialysis Rif 1. Sources of Toxic Alcohols •  Mul0ple... Rif 2. Different Alcohols, Different Toxic Metabolites Non toxic; osm gap+
Toxic; anion gap+
acidosis
Rif 2. Different Alcohols, Different Toxic Metabolites Half-life of
3-9 hours if
ADH not
blocked
Eliminate 3
mmol/L/hr
if ADH not
blocked
Elimination
half-life of 14
hours with
blocked ADH
Elimination
half-life of
48-54 hours
with blocked
ADH
Rif 2. Different Alcohols, Different Toxic Metabolites Retinal
toxicity
Basal
ganglia
hemorrhage
HypoCa
Tetany
Renal
failure
Rif 2. Clinical Similari0es “Drunk”, comatose
Profound metabolic acidosis
MILD lactate elevation
Increased anion gap
Seizures
Morgan TJ, et al. Artifactual elevation of measured plasma L-lactate
concentration in the presence of glycolate. Crit Care Med 1999; 27;2177
Rif 3. What is the Toxic Dose? Methanol
Ethylene glycol
Toxic dose, mmol/L
≥ 6
≥ 3
50% vol/vol solution
0.4 g/cc
0.6 g/cc
1 g/kg
1 g/kg
Lethal dose Small amounts can kill
Rif What is the lethal dose in a 20 kg child? 50% EG? a. 
b. 
c. 
d. 
33 cc’s 5 cc’s 200 cc’s 500 cc’s 3. What is the Toxic Dose? Small Amounts Kill! •  Let’s do a bit of math: –  A toddler, 20kg, 50% solu0on of EG (0.6 g/ml) –  Lethal dose = 20 grams = only 33 mls! = 2 tablespoons! –  Now do this for an average 70 kg adult... 70 g / 0.6 g/ml = 117 mls = less than ½ cup!
Rif A normal osm gap early on rules out a lethal toxic alcohol inges0on a.  True b.  False 4. PiEalls of Osm & Anion Gap AG
mEq/L
mOsm
osm gap
time from ingestion
Rif 4. PiEalls of Osm & Anion Gap •  AG and OG by themselves are NOT sufficient to RULE in or RULE out a toxic alcohol inges0on! •  OG insensi0ve to late presenters; AG insensi0ve to early presenters! •  Even early presenters can have a toxic concentra0on with a normal osmolar gap Steinart, B. Case report: severe ethylene glycol intoxication with normal
osmolar gap - a “chilling thought”. J Emerg Med 1990; 8:583.
Rif Treatment 1.  Bicarb -­‐-­‐> avoid penetra0on of toxic acids into organs (e.g. re0na) 2.  Inhibit ADH: ETOH or fomepizole (preferred, but $$$) 3.  Hemodialysis 4.  Cofactors: –  Folic acid 50 mg IV q 6hrs(for methanol), thiamine 100 mg IV q 6 hrs and pyridoxine (ques0onable for EG) Rif Indica0ons for HD •  Symptoma0c pa0ents: end organ damage, low pH, high AG •  Large methanol inges0ons (long t½ ) •  Toxic alcohol level? Not available in rural sexng •  Can get away with just fomepizole in EG inges0ons that are not acido0c with normal AG Rif What would you do? •  3 year old girl, accidentally drank 2 sips of an0freeze 1 hour ago, pH normal •  30 year old male, suicidal inges0on of 3 cups of windshield washer fluid 2 hours ago, pH 7.3, bicarb 16 •  46 year old female, acido0c with intractable Torsade: Which toxic alcohol did she ingest? Rif Summary ☠  EG and Methanol themselves are NOT toxic ☠  Toxic metabolites are responsible for acidosis and end organ damage ☠  Alkalinize if low pH ☠  Fomepizole is easier to use ☠  HD for all “sick” pa0ents ☠  Consider HD for predicted long t½ of elimina0on: cost effec0veness analysis, etc. ☠  PiEalls of osmolar and anion gap ☠  Always discuss with Poison Centre Rif Rif Ques0ons? Rif