What is the approach to diagnosing and managing an elevated anion gap?

Approach to Elevated Anion Gap

Begin immediate hemodialysis for anion gaps >27 mmol/L when ethylene glycol poisoning is suspected, while simultaneously calculating the anion gap using Na+ + K+ - Cl- - HCO3- and obtaining arterial blood gases to confirm metabolic acidosis. 1

Initial Diagnostic Assessment

Calculate and Confirm the Elevation

• Use the formula: Na+ + K+ - Cl- - HCO3- to calculate the anion gap 1
• Obtain arterial blood gases to determine if metabolic acidosis is present 1
• The modern reference range is 3-11 mmol/L (not the outdated 8-16 mmol/L), so values >12 mmol/L are elevated 2

Essential Laboratory Workup

• Obtain plasma glucose, blood urea nitrogen/creatinine, serum ketones, electrolytes, serum osmolality, urinalysis with urine ketones, complete blood count, and electrocardiogram 1
• Consider bacterial cultures (urine, blood, throat) if infection is suspected as a precipitating factor 1
• HbA1c helps distinguish previously undiagnosed/poorly controlled diabetes from acute events in well-controlled patients 1

Calculate Delta Gap to Identify Mixed Disorders

The delta ratio (Δ anion gap/Δ HCO3-) reveals coexisting acid-base disturbances that would otherwise be missed. 3, 4

• Calculate: Δ gap = (observed AG - normal AG) and Δ HCO3- = (normal HCO3- - observed HCO3-) 3, 4
• Ratio of 1:1 indicates simple high anion gap acidosis 3
• Ratio <1:1 suggests combined high and normal anion gap acidosis 1, 3
• Ratio >2:1 indicates combined metabolic alkalosis with high anion gap acidosis 1, 3

Immediate Life-Threatening Interventions

Toxic Alcohol Ingestion (Ethylene Glycol/Methanol)

• Anion gap >27 mmol/L with suspected ethylene glycol: immediately initiate hemodialysis (strong recommendation) 1
• Anion gap 23-27 mmol/L with suspected ethylene glycol: consider hemodialysis (weak recommendation) 1
• Administer fomepizole immediately upon suspicion based on anion gap metabolic acidosis, increased osmolar gap, visual disturbances, or oxalate crystals in urine 5
• Loading dose: 15 mg/kg fomepizole, followed by 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours 5
• Hemodialysis should be added for ethylene glycol or methanol concentrations ≥50 mg/dL, significant metabolic acidosis, or renal failure 5
• Comparing anion gap with osmolar gap narrows diagnosis to toxic alcohols like ethylene glycol and methanol 4

Diabetic Ketoacidosis (DKA)

• Begin fluid resuscitation with isotonic saline (0.9% NaCl) at 15-20 mL/kg/hour for the first hour 1
• Initiate insulin therapy to suppress ketogenesis 1
• Monitor and replace potassium as needed throughout treatment 1
• Insulin requirements typically decrease around 18 hours after treatment initiation 1

Lactic Acidosis

• Address the underlying cause: shock, sepsis, or tissue hypoxia 1
• Focus on improving tissue perfusion and oxygen delivery 1
• Bicarbonate use is controversial and rarely successful; it generates PCO2 which may worsen outcomes 6

Uremic Acidosis

• Manage underlying renal failure 1
• Consider renal replacement therapy when indicated 1

Differential Diagnosis by Anion Gap Magnitude

• Anion gap >24 mmol/L strongly suggests metabolic acidosis and warrants immediate investigation 2
• Anion gap 13-20 mmol/L (mean 16 mmol/L) represents the typical range for elevated gaps in hospitalized patients 2
• Anion gap <20 mEq/L rarely has a defined etiology 6

Critical Pitfalls to Avoid

• Do not rely solely on anion gap without clinical context; it has poor predictive value when used indiscriminately 1
• Hypoalbuminemia significantly lowers the anion gap, potentially masking concurrent high anion gap acidosis 1, 7
• Lithium or barium intoxication increases unmeasured cations, falsely lowering the calculated anion gap 1, 7
• Glycolate can falsely elevate plasma lactate on some analyzers 1
• The anion gap may overestimate severity with concomitant AKI or ketoacidosis, or underestimate with hypoalbuminemia 1
• Patients with ketoacidosis can be normothermic or hypothermic despite infection due to peripheral vasodilation 1

Special Populations

• In pregnancy, use lower thresholds for extracorporeal treatment in toxic alcohol ingestions 1
• Distinguish DKA from starvation ketosis and alcoholic ketoacidosis by clinical history and plasma glucose (mildly elevated or hypoglycemic in non-DKA causes) 1

Discontinuation Criteria

• Discontinue fomepizole when ethylene glycol or methanol concentrations are undetectable or reduced below 20 mg/dL, and the patient is asymptomatic with normal pH 5
• Continue monitoring electrolytes until resolution of the underlying condition 1