Toxicology of Salicylates

William L. Enslow, DO CPT, MC, USA Darnall Army Community Hospital Fort Hood, Texas

Government Services Chapter

American College of Emergency Physicians

Salicylates
Pharmacologic uses:
Analgesic/Anti-inflammatory Antiplatelet Sunscreen preparations Keratolytics Topical pain relievers
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Salicylates
Forms:
Tablets Capsules/ 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, gastric mucous production, others effects

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Pharmacokinetics
Rapidly absorbed from GI tract
2/3 in first hour Peak plasma level in 3-4 hours Large doses decrease GI motility
Pylorospasm Prolonged absorption

Bound to serum albumin

Once saturated, small doses will greatly increase free drug levels
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Metabolism/Clearance
SA is conjugated in liver with:
Glycine Glucuronic 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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Pathophysiology
Acid/Base Disturbances Fluid/Electrolyte Disturbances

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Acid/Base Disturbances
Hallmark of ASA toxicity: Mixed respiratory alkalosis with metabolic acidosis Children <2 years: metabolic acidosis predominates Older children/adults: respiratory alkalosis predominates
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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 production also increases tissue glucolysis
Potential for hypoglycemia Cerebral glucose levels can be low even with 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 first abnormality, 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+ GSACEP (C) 2005

Renal dysfunction
Due to decreased renal blood flow or direct nephrotoxicity Can progress to oliguric renal failure, especially when compounded by dehydration
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Pulmonary Edema
SA toxicity causes increased alveolar capillary permeability Can progress to acute pulmonary edema
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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

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 Failure Hemorrhage-rare even with antiplatelet properties

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Diagnosis
Clinical suspicion is most important part of diagnosis Labs
BMP for K+ levels, anion gap Serum aspirin level[SA] at 6 hours post ingestion
Nontoxic range (<30mg/dL) re-measure in 2 hrs Toxic range (begins at >30 mg/dL, but levels approaching 100 are 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 goals
1. Decrease absorption of ASA 2. Correct fluid/electrolyte/acid-base problems 3. Maintain blood glucose levels 4. Decrease tissue [SA] burden 5. Increase elimination of ASA

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 large overdose 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 2-3 mL/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 worsen acidosis If patient is protecting airway, consider avoiding intubation

Decreasing tissue [SA] burden

Increasing urinary clearance Hemodialysis

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Increase Clearance/Excretion
Optimum urine pH to enhance SA clearance is 7.5-8.0 NaHCO3 1-2 mEq/kg IV over two hours, titrate to goal pH. Important to ensure prior or concomitant potassium replacement Closely monitor ABG-maintain serum pH 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 imbalance Failure 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 excessive dosing/topical applications/unusual formulations Adult cases usually in elderly due to decreased metabolism/clearance
Often 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 with hyperpnea/mixed acid/base picture and neurologic symptoms, regardless of serum [SA]

Symptom severity/ lab abnormalities determine need for hospitalization Infants: May need emergency exchange transfusion GSACEP (C) 2005

Disposition
Discharge pending documented decreasing levels and clinical improvement Otherwise admit to ICU
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