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Toxicology of Salicylates
William L. Enslow, DO
CPT, MC, USA
Darnall Army Community Hospital
Fort Hood, Texas
Government Services ChapterAmerican College of Emergency Physicians
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GSACEP (C) 2005
Salicylates
Pharmacologic uses:
Analgesic/Anti-inflammatoryAntiplatelet
Sunscreen preparations
KeratolyticsTopical pain relievers
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Salicylates
Forms:
TabletsCapsules/ Enteric coated (Aspirin)
Topical creams/ fluids
Oil of Wintergreen
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Mechanism of Action
Hydrolyzed to salicylic acid (SA) in tissues
Inhibits cyclooxygenase therefore:
Inhibits platelet thromboxane synthesis
Decreased platelet aggregation
Inhibits prostaglandin/prostacyclin synthesis
Decreased inflammation, renal blood flow, gastricmucous production, others effects
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Pharmacokinetics
Rapidly absorbed from GI tract2/3 in first hour
Peak plasma level in 3-4 hoursLarge doses decrease GI motility
Pylorospasm
Prolonged absorption
Bound to serum albuminOnce saturated, small doses will greatly
increase free drug levels
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Metabolism/Clearance
SA is conjugated in liver with:
GlycineGlucuronic Acid
Small amount is hydroxylated
All forms cleared by kidneys
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Clearance
Acute Toxicity: Liver conjugative
system is overwhelmed
Elimination of free SA dependant on
kidneys
Half life from 15-30 hours
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Clearance
Urine pH above 8.0 maintains SA
molecules in ionized form
Inhibits reabsorption across the renal
tubule
Increases renal clearance
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Salicylate Toxicity
Due to oral intake or absorption through
skin (usually pediatric)
Acute or Chronic
Acute toxicity usually in children, young adults
Chronic toxicity usually in elderly
Pediatric Chronic- due to over aggressive
dosing
Very dangerous
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Acid/Base Disturbances
Hallmark of ASA toxicity: Mixed
respiratory alkalosis with metabolic acidosis
Children
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Respiratory Alkalosis
SA in brain stimulates medullary respiratory
center causing hyperpnea
Increased alveolar ventilation
Increased depth of breaths
Results in panting dog breathing pattern
Decreases PaCO2 causes alkalosis
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Metabolic Acidosis
SA in cells inhibits Krebs cycle enzymes
Increases lactic, pyruvic acid levels
SA uncouples oxidative phosphorylation
Results in:
Wide Anion Gap Metabolic Acidosis
Increased metabolic rate
Increased body temp
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Metabolic Acidosis
Dysfunction in cell energy productionalso increases tissue glucolysis
Potential for hypoglycemia
Cerebral glucose levels can be low evenwith normal serum glucose
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Acid/Base Disturbances
Actual acid/base picture is dependant
on balance between respiratory and
metabolic influence
Respiratory alkalosis is usually firstabnormality, metabolic acidosis occurs
later
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Fluid/Electrolyte abnormalities
Dehydration
Hypokalemia/decreased K+ stores Renal dysfunction
Pulmonary Edema
Cerebral Edema
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Dehydration
Nausea/vomiting- SA triggers
medullary chemoreceptor zone
Increased body temp
Hyperpnea/ increased ventilation
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Potassium Losses
Vomiting
Increased renal losses due to increased
excretion
Compensating for respiratory alkalosis,kidneys excrete K+, Bicarbonate
SA makes renal tubules more permeable
to K+
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Renal dysfunction
Due to decreased renal blood flow ordirect nephrotoxicity
Can progress to oliguric renal failure,especially when compounded by
dehydration
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Pulmonary Edema
SA toxicity causes increased alveolarcapillary permeability
Can progress to acute pulmonaryedema
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Cerebral Edema
Rare but serious complication
Metabolic acidosis makes blood-brain
barrier more permeable to SA
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Hemorrhage
Rare complication
Due to:
Platelet dysfunction
Chronic ingestions can inhibit clotting
factor production/function
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Salicylate Toxicity
Acute Toxic Exposure:
200-300 mg/kg
500 mg/kg or higher doses are potentially
fatal
Chronic Toxic Exposure:Toxicity may occur at much lower doses
Pediatric chronic exposure to excessive
doses can be very dangerous
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Clinical Features and
Presentation
Initial Symptoms:
Tinnitus/Impaired Hearing
Nausea and vomiting begin in 3-8 hours
Hyperthermia
Panting dog respiratory pattern
Dehydration
Impaired consciousness-children are more
predisposed this
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Clinical Features and
Presentation
More serious, but less common
symptoms:
Dyspnea due to pulmonary edema
High morbidity if not recognized
Oliguric Renal FailureHemorrhage-rare even with antiplatelet
properties
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Diagnosis
Clinical suspicion is most important part ofdiagnosis
Labs BMP for K+ levels, anion gap
Serum aspirin level[SA] at 6 hours post ingestion
Nontoxic range (30 mg/dL, but levels approaching 100are more likely to be dangerous)
Clinical picture drives management, not [SA]
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Ancillary Tests
ABG: watch pH, PaCO2
EKG: Signs of hypokalemia
CXR: ARDS
UA: pH, signs of renal failure along
with output
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Diagnosis
Done nomogram:Often misinterpreted
Not useful
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Management
SUPPORTIVE
5 goals1. Decrease absorption of ASA
2. Correct fluid/electrolyte/acid-base
problems3. Maintain blood glucose levels
4. Decrease tissue [SA] burden
5. Increase elimination of ASA
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Decreasing Absorption
Activated Charcoal: Initial dose
Pediatrics: 1g/kg in children
Adults: 50-100 g for adults
Repeat if vomited
Repeat dosing of AC for very largeoverdose
Enteric coated forms: Whole bowel
irrigation
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Contraindications to
Activated Charcoal
GI obstruction/ileus
Recent GI surgery
Hematemesis
Shock/Decreased tissue perfusion
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Correcting Fluid/Electrolyte
Status/Glucose
Goal of therapy is urine output of 2-3mL/kg/hr
Risk of pulmonary/cerebral edema with
over-hydration Initial rehydration
Correct K+ with IVF
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Ventilation
Hyperpnea induced alkalosis may be
important part of balancing acidosis
Be judicious in intubating patients-if
paralyzed and not adequately
mechanically ventilated, may worsenacidosis
If patient is protecting airway, consider
avoiding intubation
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Decreasing tissue [SA] burden
Increasing urinary clearance
Hemodialysis
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Increase Clearance/Excretion
Optimum urine pH to enhance SAclearance is 7.5-8.0
NaHCO3 1-2 mEq/kg IV over twohours, titrate to goal pH.
Important to ensure prior orconcomitant potassium replacement
Closely monitor ABG-maintain serumpH between 7.45-7.55
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Increase Clearance/Excretion
Indications for hemodialysis
AMS/Coma
Renal or hepatic failure
Pulmonary Edema/ARDS
Severe acid/base imbalanceFailure to respond to AC/Urine
alkalinization
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Special Considerations
Pregnancy
Chronic Exposure
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Pregnancy
Fetus is more susceptible
Toxicity associated with fetal demise
Consider delivery if fetus is viable
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Toxicity from Chronic Ingestion
25% mortality
Can be associated with a therapeutic [SA]
Pediatric cases usually due to excessivedosing/topical applications/unusualformulations
Adult cases usually in elderly due to
decreased metabolism/clearanceOften insidious onset, difficult to diagnose
Consider in altered elder pt taking ASA
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Toxicity from Chronic Ingestion
Adults: Mental status changes/CNS effects
more frequent.
Consider chronic salicylism in any patient withhyperpnea/mixed acid/base picture and
neurologic symptoms, regardless of serum [SA]
Symptom severity/ lab abnormalitiesdetermine need for hospitalization
Infants: May need emergency exchange
transfusion
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Disposition
Discharge pending documenteddecreasing levels and clinical
improvement
Otherwise admit to ICU