Agents

• Acetylsalicylic Acid (see Acetylsalicylic Acid, [[Acetylsalicylic Acid]])
• Oil of Wintergreen
• Salicylic Acid

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Adverse Effects

Pulmonary Adverse Effects

• Aspirin-Intolerant Asthma (see Asthma, [[Asthma]])
  • Epidemiology
    • Up to 5% of asthmatics are sensitive to ASA
  • Physiology: unknown -> may involve COX inhibition resulting in decreased production of bronchodilator PGE2 and increased production of leukotrienes
    • Not dose-related -> can occur with even small doses of ASA
  • Clinical
    • Samter’s Syndrome: ASA-sensitivity + asthma + nasal polyps
    • Commonly associated are rash and GI side effects
    • ASA may cause fatal bronchospasm
• Pulmonary Infiltrates with Eosinophilia (see Drug-Induced Pulmonary Eosinophilia, [[Drug-Induced Pulmonary Eosinophilia]])
  • Epidemiology: appears to be more frequent with naproxen than other NSAID’s

Gastrointestinal Adverse Effects

• Acute Pancreatitis (see Acute Pancreatitis, [[Acute Pancreatitis]]): probable association
• Asymptomatic Elevation of Hepatic Transaminases (Isolated Transaminitis) (see Drug-Induced Hepatotoxicity, [[Drug-Induced Hepatotoxicity]])
• Hepatic Steatosis (see Drug-Induced Hepatotoxicity, [[Drug-Induced Hepatotoxicity]])
• Peptic Ulcer Disease (PUD) (see Peptic Ulcer Disease, [[Peptic Ulcer Disease]])

Renal Adverse Effects

• Acute Kidney Injury (see Acute Kidney Injury, [[Acute Kidney Injury]])

Pseudo-Sepsis Syndrome

• Epidemiology: associated with chronic salicylate ingestion
• Diagnosis: elevated salicylate level
• Clinical
  • Fever (see Fever, [[Fever]])
  • Leukocytosis
  • Hypotension (see Hypotension, [[Hypotension]])
  • Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS, [[Acute Lung Injury-ARDS]])
  • Multiple Organ Failure
• Treatment: as for salicylate intoxication

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Salicylate Intoxication

Epidemiology

• Safety packaging has decreased incidence of salicylate toxicity in children
• Salicylate intoxication may occur with either acute or chronic overdosage
• More common in elderly smokers than in younger non-smokers
• Associated with serum salicylate level >40 mg/dL -> indicative of salicylate intoxication

Physiology

• Rapid absorption from stomach and GI tract (except methylsalicylate in Oil of Wintergreen)/absorption may continue for 24 hrs or longer after OD
• Rapid transformation to salicylic acid: cellular penetration is enhanced in acidic environment (this is the rationale for use of bicarbonate)
• Protein Binding: 50-80%
• Metabolism: mostly hepatic with rapid renal excretion of metabolites (with half-life: 3-6 hrs) under normal circumstances
  • Prolonged half-life (20-36 hrs) due to hepatic pathways being saturated in overdose, with resulting significant amounts of free salicylic acid renally excreted (renal excretion is enhanced with higher GFR and in presence of alkaline urine)

Effects of Salicylate Intoxication

• Direct CNS stimulation (degree depends on brain salicylate levels): brain levels are increased in presence of acidic environment
• Uncoupling of oxidative phosphorylation (later in course): leads to increased glucose and oxygen utilization/increased heat production
  • Accumulation of mixed organic acids (salicylate/lactic acid/etc) -> AG metabolic acidosis
• GI mucosal irritation/Inhibition of cyclooxygenase/platelet inhibition:
• Allergic reaction: asthmatic-type reactions may occur in some cases
• Acute Lung Injury: mechanism unknown -> possible direct effect on alveolar-capillary membrane with increased alveolar-capillary permeability vs neurogenic edema vs direct effect on platelets or prostaglandins

Diagnosis

• CXR/Chest CT Patterns
  • Pulmonary edema:
• KUB: may demonstrate radio-opaque pills in GI tract
• ABG Patterns
  • Respiratory Alkalosis with Metabolic Acidosis (40-50%): respiratory alkalosis (due to CNS stimulation with hyperventilation, early in course) with AG metabolic acidosis (due to accumulation of salicylic acid, pyruvic acid, lactic acid, and keto acids caused by uncoupled oxidative phosphorylation)
  • Isolated Respiratory Alkalosis (20%):
  • Isolated Metabolic Acidosis (20%):
  • Mixed Respiratory and Metabolic Acidosis (5-10%):
• Urinalysis: proteinuria is common
  • Alkaline urine (with urine pH >6) may be seen in early toxicity
  • Acidic urine (pH <6) seen in later toxicity
• CHEM: hyperkalemia, hypernatremia, hypoglycemia (may all be seen)
  • Elevated AG: usually 15-20
• CBC: leukocytosis
• INR: may be prolonged
• LFT’s: transminases may be elevated (but significant hepatotoxicity is rare)
• Salicylate Level: therapeutic level is 10-20 mg/dL
  • Toxicity at level >30 mg/dL (levels must be correlated to time of ingestion)
  • Blood levels correlate poorly with severity of intoxication (severity is based mostly on clinical features): in general, level >100 is suggestive of severe toxicity
  • In chronic toxicity, symptoms may occur at levels only slightly above the therapeutic range

Clinical Manifestations

Cardiovascular Manifestations

• Sinus Tachycardia (see Sinus Tachycardia, [[Sinus Tachycardia]])
• Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])

Endocrinologic Manifestations

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Neurologic Manifestations

• N/Vv (due to CNS effects): dehydration may occur
• Tinnitus:
• Headache:
• Altered MS:
• Seizures:
• Cerebral Edema

Pulmonary Manifestations

• Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS, [[Acute Lung Injury-ARDS]])

Renal Manifestations

• Anion Gap Metabolic Acidosis (AGMA) (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]])
• Normal Osmolal Gap
• Acute Kidney Injury (see Acute Kidney Injury, [[Acute Kidney Injury]]): usually pre-renal

Other Manifestations

• Fever (due to uncoupling of oxidative phosphorylation, with increased heat production):
• Coagulopathy (38% of cases): GI bleeding, etc. due to decreased platelet aggregation and some hepatocyte damage with prolonged PT

Treatment

• Alkaline diuresis: IVF with HCO3
• GI Decontamination (may be useful even 12-24 hrs after ingestion): indicated for ingestion of >150 mg/kg
• Charcoal: may repeat
• Antacids: to decrease local GI toxicity
• Alkalinization of Blood/Urine: using bicarbonate (titrated to achieve normal blood pH)
  • Moves salicylic acid out of tissues (and CNS) and enhances renal excretion
  • Acetazolamide enhances urinary bicarbonate excretion but should not be used in these cases
• Hydration with Forced Diuresis (with mannitol, etc.): renal excretion is also enhanced in presence of increased GFR with high urine flow
• Use cautiously in setting in pulmonary edema
• Glucose Administration: crucial since brain glucose may be depleted even in presence of normal serum glucose levels
• Hemodialysis/Charcoal Hemoperfusion (for severe or refractory cases): removes salicylic acid and corrects metabolic acidosis

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References

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