Carson R. Harris, MD, FAAEM, FACEP
Regions Hospital Clinical Toxicology Service
Emergency Medicine Department
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Objectives
 Discuss the toxicological effects of salicylate
overdose
 Identify key management issues
 Discuss the limitations of the Done nomogram
and how to avoid pitfalls of management
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History and Demographics
 Hippocrates – 5th century B.C.
▪ Powder from the willow bark
 1800s sodium salicylate for arthritis
▪ Abdominal pain
 Felix Hoffmann
▪ Acetylsalicylic acid (ASA)
 Introduced 100 years ago
▪ Antipyretic, analgesic, anti-inflammatory
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History and Demographics
 Decline in use, but…
▪ Prophylactic for migraine, colon ca
▪ Antiplatelet agent
▪ Decline in incidence of Reye’s
 Childproof caps – 1970s legislature
 OTC meds
▪ Combined with antihistamines, caffeine, barbs, and
opioids
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Salicylate formulations
 Oil of wintergreen: 98% methyl salicylate
▪ 1400 mg/mL
 Bismuth subsalicylate
 Aggrenox
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Therapeutic doses
 Pediatric 10-20 mg/kg
 Adults 650-1000 mg q 4-6 hrs
▪ Produce a serum level of 5-10 mg/dL
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Potential Toxic Acute dose > 150 mg/kg
Serious toxicity: 300-500 mg/kg
Chronic toxicity: >100 mg/kg/day
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Peak levels
 Therapeutic – 1-2 hours
 Therapeutic EC – 4-6 hours
 OD – 10-60 hours
▪ Reason for delay ? Concretions, contraction of the
pylorus or combination of drugs that delay gastric
emptying (opioids and anticholinergics)
 Liquids absorbed in 1 hr
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Distribution is facilitated by pH
Elimination dependent on dose
 First order kinetic to zero order
▪ From 4 hours to 15-29 hours
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A 24-year-old male presented to the ED with
nausea, vomiting, tinnitus, and tachypnea after
ingesting 100 aspirin tablets. His 4-hour salicylate
level was 78 mg/dL; Chem-8 revealed Na 143, Cl 105,
K 4.2, HCO3 17; the ABGs showed pH 7.38, pO2 107,
and pCO2 27 on room air. He was initially treated
with reasonable volume and admitted to the ward.
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Orders for sodium bicarbonate were given to
alkalinize the urine, but this was ineffective
in raising urine pH. Approximately 6 hours
later the attending was notified that the
patient had become confused.
He was transferred to the ICU where he was
sedated and intubated.

Approximately 20
minutes after
intubation, the
patient rapidly
deteriorated and
died.
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ASA is hydrolyzed to salicylic acid
 Responsible for therapeutic and toxic effects
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Direct stimulation of respiratory center
 Medulla
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Uncouples oxidative phosphorylation
 Increase in O2 consumption and CO2 production
▪ Increase respiration
▪ Respiratory alkalosis
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Renal excretion of bicarb, Na and K
 Metabolic acidosis
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Inhibition of mitochondrial respiration
 Increase pyruvate and lactic acid
▪ Metabolic acidosis
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Disruption of Krebs cycle metabolism and
glycolysis
 Hyperglycemia, ketonemia
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Dehydration
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Hyperpnea
Diaphoresis
Vomiting
Fever (increased muscle metabolism)
Vasoconstriction of auditory microvasculature
Enhance insulin secretion => hypoglycemia
Decrease peripheral glucose utilization =>
hyperglycemia
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Increase permeability of pulmonary
vasculature
Increase the production of leukotrienes
Stimulate medullary chemoreceptor trigger
zone
Hematologic effects
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ASPIRIN Mnemonic
 Altered mental status (lethargy – coma)
 Sweating/diaphoresis
 Pulmonary edema
 Increased vital signs (HTN, inc RR, inc T, tachycardia)
 Ringing in the ears
 Irritable
 Nausea and vomiting
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Early
 Nausea, vomiting, diaphoresis, tinnitus, deafness
▪ Level 25-30 mg/dL
 Hyperventilation
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Later
 Hypotension, NCPE, oliguria, acidemia, cerebral
edema, delirium, seizure, coma
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Classic acid-base disturbance
 AGMA
 Respiratory alkalosis with metabolic acidosis
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Acidemia
 Increases tissue distribution
▪ Brain, heart, lung
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Severe hypokalemia
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NCPE
 Older patients
 Smokers
 Levels >100 mg/dL
 Acidemia
 CNS involvement (hallucinations, sz)
 Chronic toxicity
Features
Acute
Chronic
Age
Young adult
Older adult/infants
Etiology
Overdose
RX misuse
Co-ingestions
Frequent
Rare
Mental status
Normal
Altered
Presentation
Early
Late
Mortality
Low w/ Rx
High
Serum levels
40 to >120
30 to >80
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Salicylate level
 Peak 4-6 hr
 EC and SR preparations late rise
 Every 2-4 hours until clearly decreasing
▪ Then q 4-6 until <30 mg/dL
 Always confirm units!
▪ Mg/dL vs. mg/L
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Done Nomogram (Pediatrics 1960)
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NOT USEFUL for
 Chronic ingestions
 Liquid preparations
 EC or SR
 Acidemia
 Renal failure
 Unknown time of
ingestion
 Methylsalicylate
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Severity of ingestion
 Serum levels
 Acid-base status
 Acuteness of ingestion
 Mental status
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Bedside Tests
 Trinder’s reagent – 10% ferric chloride
 Ames phenistix
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Chemistry Panel
 Q 4-6 h
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LFTs
Coagulation studies
ABGs
APAP
Consider: CT, Serum osm, ketones, LP, CO,
serum Fe, blood cultures
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Gastric lavage / WBI
Activated charcoal - MDAC
Hydration and electrolyte replacement
 Correct hypokalemia aggressively
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Urine alkalinization
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Increase salicylate excretion
1-2 mEq/kg NaHCO3 bolus IV
Then 150 mL in 850 ml D5W run 1.5-2 times maintenance
Caution in elderly and chronic
Monitor UO
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Dialysis
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Serum levels > 100 in acute
Levels > 60 in chronic
Pulmonary edema
Renal failure
CHF
Poor response to standard Rx
AMS and acidemia
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Enteric Coated aspirin
 Can cause delayed symptom onset
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Don't wait for clinical deterioration.
 Alert you nephrology team early and call the
poison center even earlier.
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Serial salicylate levels are imperative.
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One teaspoon of methyl salicylate contains 7,000 mg
of salicylate which is equivalent to approximately 21
regular strength aspirin tablets!
The presence of fever is a poor prognostic sign in
adults!
Cerebrospinal fluid salicylate levels correlate with
symptoms better than blood levels
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The Done nomogram, has limited usefulness
Be aware of the proper unit of measure
 (mg/dL not mg/L or µg/L or mmol/L)!
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Start potassium supplementation early (in
the absence of renal insufficiency) because
hypokalemia makes urinary alkalization
impossible!
Multiple-dose activated charcoal and
alkalinization are currently the most popular
methods of treatment.
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Be aggressive. Dialyze early if signs of
toxicity are evident.
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ASA and elderly
 Impaired renal function
▪ Decreased elimination
 Impaired hepatic function
 The risk of salicylate nephrotoxicity is increased
with age,
 Upper gastrointestinal bleed is associated with
increased mortality in older age groups.
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Mortality and Epidemiology
 From 15% to 1.7% in 1977
 Second leading cause of death from overdose in
US (Analgesics first).
 Approximately 500,000 overdoses annually
 Female, age 20-29, single, employed, no history
of drug abuse
 Approximately 70% die pre-hospital
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Indications
 Depression
 Chronic pain syndromes
 OCD
 Panic and Phobic disorders
 Migraine prophylaxis
 Peripheral neuropathies
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Acute Toxic Doses
 Fatal ingestions range 10-210 mg/kg
 2-4 mg/kg is therapeutic, 20 mg/kg is potentially
fatal
 Variable response
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Absorption
 Rapidly and completely absorbed
 Massive OD delays absorption
 Enterohepatic re-circulation secretes 30%
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Distribution
 Wide range in Vd (15-40 L/kg)
▪ Genetic variation
▪ Lipophilic
▪ Elderly has higher Vd
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Distribution (cont’d)
 Tissue levels usually 10 times plasma levels
 Protein binding usually exceeds 90% with some
variations
▪ pH dependent
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Elimination
 Genetic component
 Metabolism influenced by other drugs
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Therapeutic effects
 Not completely understood
 Blocks serotonin and NE uptake
 Anticholinergic effects
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Cardiac Effects
 Sinus tachycardia, dysrhythmias
▪ Na channel blockade – quinidine effect
 Hypotension
▪ Alpha adrenergic blockade and NE depletion
 Conduction delays / blocks
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CNS
 Anticholinergic
▪ Excitation, confusion, hallucination, ataxia
 Seizures
 Coma
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Respiratory
 Pulmonary edema
 ARDS
 Aspiration pneumonia
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Gastrointestinal
 Delayed gastric emptying
 Decreased motility
 Prolonged transit time
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Case #1
 25 year-old man ingested 60 tablets of Elavil 50 mg
each. He presented to the ED about 45 minutes post
ingestion agitated and confused. Possibly
hallucinating. BP 145/94, P 112, R22, T99.6. He
became more agitated and combative and was
intubated, lavaged and given AC.
 EKG revealed QRS 108 with rate 114
 What are the critical ECG changes?
 Prolongation of the QRS complex:
▪ Blockage of fast sodium channels slows phase 0
depolarization of the action potential.
▪ Ventricular depolarization is delayed, leading to a
prolonged QRS interval. Patients with QRS intervals
>100 ms are at risk for seizures and patient with QRS
intervals >160 ms are at risk for arrhythmias.
▪ QRS interval is evaluated best using the limb leads.
 R wave in aVR >3 mm:
▪ greater selectivity and toxicity to the distal conduction system of
the right side of the heart.
▪ effect can be observed as an exaggerated height of the R wave aVR.
▪ may be more predictive of seizure and arrhythmia than
prolongation of the QRS complex.
 R/S ratio >0.7 in aVR
 QT interval prolongation
 Arrhythmias
 How do you treat this?
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ABCs
 Activated Charcoal: 30-50 gm
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Sodium Bicarbonate
 Dose
 Endpoint
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What is the mechanism?
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Alkalinization
 appears to uncouple TCA from myocardial sodium
channels.
 Alkalinization may increase protein binding
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Increases the extracellular sodium
concentration
 improves the gradient across the channel.
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The initial bolus of 1-2 mEq/kg
A constant infusion of sodium bicarbonate
 commonly accepted clinical practice without any
controlled studies validating the optimum
administration
 100 to 150 mEq of sodium bicarbonate to each
liter of 5% dextrose,
▪ the resulting solution is hypotonic or nearly isotonic.
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What if NaHCO3 doesn’t work?
 may require treatment with lidocaine and/or
magnesium sulfate.
 Class Ia and Ic agents contraindicated
 Beta blockers and CCB
▪ Worsen or potentiate hypotension
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Hypotension, Persistent
 Direct acting alpha agonists, such as norepinephrine and
phenylephrine
 Dopamine may not be as effective
▪ Require release of endogenous catecholamines that may be
depleted during TCA toxicity.
 Dopamine or dobutamine alone may result in unopposed
beta-adrenergic activity due to TCA induced alpha
blockade and, therefore, may worsen hypotension.
 Vasopressin (ADH)
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What about Seizures from TCA
 Usually brief (<1 min)
 self-limiting
 acidosis increase cardiovascular toxicity.
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Benzodiazepines
Phenytoin is no longer recommended
 limited efficacy and possible prodysrhythmic.
 Phenobarbital may be used as a long-acting
anticonvulsant.
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Agitation from TCA
 Anticholinergic effects
 Benzodiazepines are also the treatment of choice
 Physostigmine is contraindicated in TCA overdoses
▪ May cause bradycardia and asystole in the setting of TCA
cardiotoxicity.
 Flumazenil is contraindicated even in the presence of a
benzodiazepine co-ingestion.
▪ Several case reports - seizures
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Emergency department discharge criteria
 At least 6 hour observation period
 No significant sign of toxicity during observation
period, including normal follow-up ECG prior to
discharge
 Accidental ingestion
 Appropriate follow-up measures in place
 Adequately supervised home environment