Toxicity Associated with Salicylate/Reye Syndrome

At a Glance

Aspirin (acetylsalicylic acid) is a pro-drug metabolized to salicylic acid, which exerts its pharmacologic action through a blockade of prostaglandin synthesis. The active form of the drug is highly protein-bound, so, following overdose, the free fraction is typically elevated. Clinical symptoms of salicylate overdose include tinnitus, nausea and vomiting, increased rate of respiration, hyperthermia, lethargy, and, in some cases, seizures. In addition, acid-base abnormalities are observed in salicylate overdose.

In pediatric patients with a fever, administration of aspirin can result in Reye syndrome. The exact cause of this syndrome remains unknown, but there is significant evidence linking Reye syndrome to salicylate-containing medications and previous viral infections. Reye syndrome develops in two stages: Stage I includes persistent vomiting, changes in mental status, listlessness, and drowsiness; Stage II includes personality changes, irritability, aggressive behavior, confusion and disorientation, seizures, and coma.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

To confirm exposure to salicylate, a blood salicylate test should be ordered with concentrations greater than 300 mg/L indicative of toxicity. Historically, the Done Nomogram has been used to evaluate blood salicylate results. However, this nomogram was developed based on an immediate release, single-drug formulation; it does not apply to chronic ingestion, extended release formulations, or combinations with opiates or other drugs (e.g., Percodan). In addition, the nomogram was developed in a pediatric population, so its utility is limited in adult populations. An alternative approach is to take serial measurements of blood salicylate and calculate the half-life of the drug in the patient; since the pharmacokinetic elimination pathways for salicylate are saturable, an extended half-life is suggestive of salicylate overdose.

In addition, blood gas testing is useful to assess acid-base changes that may accompany salicylate toxicity. An unexplained increase in Anion Gap ([Na+] – [Cl-] – [HCO3-]) may be a clue that a metabolic acidosis is present in the patient, caused by excessive salicylate ingestion.(Table 1)

Table 1
Blood Salicylate Blood pH Anion Gap
> 300 mg/L < 7.4 > 12

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Salicylate testing is colorimetric in nature, so anything that will interfere with absorbance measurements may also impact the measurement of salicylate, including excessive hemolysis or lipemia. Icteric specimens may also present a challenge.

Other substances that may impact the colorimetric salicylate measurement include ketones, catecholamines, and oxalate, which is sometimes used as a preservative in some blood collections tubes. Enzymatic methods do not share these interferences.

What Lab Results Are Absolutely Confirmatory?

Blood salicylate testing is the only laboratory method that will absolutely confirm salicylate exposure or intoxication.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Occasionally, a clinical laboratory may perform a screening method called a “spot test.” These tests are colorimetric, qualitative methods based on a reaction with ferric chloride, or something called Trinder’s reagent. When these tests are used, phenothiazines, acetoacetate (present in ketosis), and sodium azide may interfere with the screening tests.