Do you need to repeat acetaminophen (Tylenol) and aspirin levels after a diphenhydramine (Benadryl) overdose?

Acetaminophen and Aspirin Levels After Diphenhydramine Overdose

Yes, you should obtain acetaminophen and aspirin levels in patients presenting with diphenhydramine (Benadryl) overdose, particularly when intentional overdose is suspected or the history is unreliable.

Rationale for Screening

• Acetaminophen is commonly co-ingested in intentional overdoses because it is widely available and frequently combined with other medications including antihistamines 1
• Delayed diagnosis of acetaminophen toxicity is associated with reduced response to antidote, liver failure, and mortality, making early detection critical 1
• Acetaminophen overdose often causes no symptoms or only nonspecific symptoms in the first 12-24 hours after ingestion, meaning patients may not report or recognize co-ingestion 1
• A recent study found that 0.9% of patients with intentional overdose who denied acetaminophen ingestion had detectable levels, and 0.2% required N-acetylcysteine (NAC) treatment 1

When to Obtain Levels

Obtain acetaminophen and aspirin levels in the following scenarios:

• Any patient with stated or suspected self-harm or intentional overdose, regardless of reported substances ingested 2
• Patients with altered mental status suspected to be secondary to overdose 1
• When the history is unreliable or incomplete, as patients may be unaware of all ingredients in combination products 2, 1
• All patients meeting diphenhydramine overdose criteria (≥7.5 mg/kg or 300 mg in patients ≥6 years old) who require emergency department evaluation 3

Timing of Laboratory Assessment

• Obtain acetaminophen level at 4 hours post-ingestion or as soon as possible thereafter if the patient presents to the emergency department 2
• If time of ingestion is unknown, obtain levels immediately and treat based on detectable levels and clinical presentation 4, 1
• The Rumack-Matthew nomogram should be used to guide treatment decisions when acetaminophen level is drawn 4-24 hours post-ingestion with known timing 4, 2

Critical Pitfalls to Avoid

• Do not rely solely on patient history to exclude acetaminophen or aspirin co-ingestion in intentional overdoses, as patients may not accurately report all substances taken 1
• Do not delay obtaining levels based on absence of symptoms, as acetaminophen toxicity presents with a delayed clinical course 1, 5
• Given the serious consequences of acetaminophen toxicity and the low cost of screening, the threshold for testing should be low in high-risk suicidal patients 1
• Remember that combination products containing diphenhydramine may also contain acetaminophen or aspirin, making co-ingestion more likely than suspected 2, 6

Management Algorithm

1. Obtain acetaminophen and aspirin levels on arrival for any intentional diphenhydramine overdose or altered mental status case 1
2. If acetaminophen level plots above the treatment line on the Rumack-Matthew nomogram (drawn 4-24 hours post-ingestion), initiate NAC immediately 4, 2
3. If timing is unknown and acetaminophen is detectable (≥10 μg/mL), initiate NAC 4, 1
4. For aspirin co-ingestion, manage according to salicylate toxicity protocols including repeat levels to assess for continued absorption 7

The evidence strongly supports routine screening for acetaminophen in all intentional overdoses, and by extension aspirin, given the potentially fatal consequences of missed diagnosis and the effectiveness of early antidote administration 4, 1, 5.