toxicology of aspirin

8/13/2019 Toxicology of Aspirin

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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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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

toxicology of aspirin

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