Can aspirin (acetylsalicylic acid) cause high anion gap metabolic acidosis in a post-hip replacement surgery patient taking it for venous thromboembolism prophylaxis or cardiovascular indications?

Can Aspirin Cause High Anion Gap Metabolic Acidosis?

Yes, aspirin (salicylate) toxicity is a well-established cause of high anion gap metabolic acidosis, but therapeutic doses used for VTE prophylaxis or cardiovascular indications after hip replacement surgery do not typically cause this complication.

Aspirin and Metabolic Acidosis: The Clinical Context

Salicylate toxicity is classically included in the MUDPILES mnemonic (Methanol, Uraemia, Diabetes, Paraldehyde, Iron/Isoniazid, Lactate, Ethylene glycol, Salicylate) and the more recent GOLD MARK mnemonic (Glycols, Oxoproline, L-lactate, D-lactate, Methanol, Aspirin, Renal failure, Ketoacidosis) as recognized causes of high anion gap metabolic acidosis 1.

Dose-Dependent Toxicity

• Therapeutic dosing (75-325 mg daily) for cardiovascular prophylaxis or VTE prevention does not cause high anion gap metabolic acidosis in patients with normal renal function 2.
• Toxic doses of salicylates cause metabolic acidosis through direct uncoupling of oxidative phosphorylation and accumulation of organic acids 1.
• The perioperative guidelines recommend aspirin doses of 75-100 mg daily for cardiovascular protection, which are far below toxic thresholds 2, 3, 4.

Critical Drug Interaction: Aspirin + Acetazolamide

A particularly dangerous combination exists when aspirin is used concomitantly with acetazolamide in patients with any degree of renal impairment 5. This combination can precipitate:

• Severe metabolic acidosis (even with therapeutic aspirin doses)
• Hyperammonemia
• Life-threatening complications 5

This interaction is clinically relevant because acetazolamide may be used perioperatively for various indications, and the combination should be strictly avoided in post-surgical patients with even mild chronic kidney disease 5.

Differential Diagnosis Considerations

When evaluating unexplained high anion gap metabolic acidosis in a post-hip replacement patient on aspirin, consider:

More Likely Causes Than Aspirin Toxicity:

• Lactic acidosis from hypoperfusion, sepsis, or tissue ischemia (most common perioperatively) 1, 6
• Ketoacidosis from prolonged fasting or stress response 1
• 5-oxoproline (pyroglutamic acid) acidosis from acetaminophen use, which is commonly administered perioperatively for pain control 6, 7, 8

5-Oxoproline Acidosis: An Important Mimic

This is particularly relevant in the perioperative setting because:

• Acetaminophen is routinely used for multimodal analgesia after orthopedic surgery 6, 7, 8
• Risk factors include sepsis, malnutrition, renal dysfunction, female gender, and liver disease—all potentially present perioperatively 6, 8
• It can cause severe high anion gap metabolic acidosis that resolves with acetaminophen discontinuation 7, 8
• Salicylate assays may show false-positive results in the presence of benzoic acid (a common preservative), potentially confusing the clinical picture 1

Clinical Algorithm for Post-Hip Replacement Patients

When to Suspect Aspirin-Related Acidosis:

1. Check salicylate level if high anion gap metabolic acidosis develops 1

   • Therapeutic aspirin (75-100 mg daily): salicylate levels typically <10 mg/dL 1
   • Toxic levels: >30 mg/dL (acute), >20 mg/dL (chronic) 1

2. Review medication list for:

   • Acetazolamide (contraindicated with aspirin in renal impairment) 5
   • Acetaminophen (consider 5-oxoproline acidosis) 6, 7, 8
   • NSAIDs or other salicylate-containing products 4

3. Assess renal function closely:

   • Even mild CKD increases risk of drug-induced acidosis 5, 8
   • Acetazolamide + aspirin combination is particularly dangerous 5

Management Priorities:

• Continue aspirin at therapeutic doses (75-100 mg) for cardiovascular/VTE prophylaxis unless salicylate toxicity is confirmed 2, 3, 4
• Discontinue acetazolamide immediately if being used concomitantly 5
• Stop acetaminophen if 5-oxoproline acidosis is suspected (resolves within 24-48 hours) 7, 8
• Do not empirically discontinue aspirin for unexplained acidosis, as this increases thrombotic risk without addressing the underlying cause 3, 4

Common Pitfalls to Avoid

• Do not assume therapeutic-dose aspirin is causing high anion gap acidosis without measuring salicylate levels and excluding more common causes 1, 6
• Do not overlook acetaminophen as a cause of high anion gap acidosis in perioperative patients receiving multimodal analgesia 6, 7, 8
• Do not combine aspirin with acetazolamide in any patient with renal impairment, regardless of severity 5
• Do not discontinue aspirin empirically in high-risk cardiovascular patients, as this increases mortality and morbidity from thrombotic events 3, 4