ANION GAP METABOLIC ACIDOSIS (AGMA)

AG = Na − (Cl + HCO3) >12 mEq/L (corrected for albumin) — always calculate delta ratio; identify the cause; treat the underlying disorder

SYMPTOMS / ASSOCIATED SX

  • Kussmaul respirations (deep, rapid — compensatory hyperventilation); air hunger

  • Nausea, vomiting, abdominal pain (especially DKA, lactic acidosis, salicylate toxicity)

  • Fatigue, confusion, AMS (severe acidosis)

  • Cardiac: decreased contractility, vasodilation, arrhythmias → hypotension at pH <7.2

  • Hyperkalemia (H+ enters cells, K+ exits — each 0.1 pH decrease → K rises ~0.6 mEq/L)

  • Toxidrome signs: visual disturbance (methanol), oxalate crystals in urine (ethylene glycol), tinnitus/hyperventilation (salicylates)

DENIES

  • Drug or toxin ingestion (methanol, ethylene glycol, salicylates, isoniazid, acetaminophen)

  • Polyuria, polydipsia, abdominal pain, missed insulin (DKA)

  • Alcohol use (AKA, lactic acidosis)

  • Symptoms of sepsis or tissue hypoperfusion (lactic acidosis)

SOCIAL HISTORY

  • Alcohol use (AKA, type B lactic acidosis); metformin use (metformin-associated lactic acidosis in AKI)

  • DM history (DKA); dialysis/CKD (uremic acidosis); intentional ingestion history

MAIN ETIOLOGY — MUDPILES or GOLDMARK

  • Methanol (formic acid accumulation → visual loss, high osmolar gap)

  • Uremia (CKD/AKI — organic acid accumulation)

  • DKA / Diabetic ketoacidosis (BHB, acetoacetate) — glucose usually >250; also euglycemic DKA (SGLT-2 inhibitors)

  • Propylene glycol (IV medications: lorazepam, diazepam drips — osmolar gap elevated)

  • Isoniazid (seizures; blocks pyridoxine → lactic acidosis) / Iron overdose

  • Lactic acidosis — Type A (hypoperfusion: sepsis, shock, ischemia) vs. Type B (no hypoperfusion: metformin, liver failure, thiamine deficiency, malignancy, nucleoside analogues)

  • Ethylene glycol (calcium oxalate crystals in urine; renal failure; high osmolar gap)

  • Salicylates (mixed AGMA + primary respiratory alkalosis; tinnitus; serum level diagnostic)

  • AKA (alcoholic ketoacidosis: low/normal glucose, ketosis, ETOH history)

MOST COMMON DDX

  • DKA (glucose >250, BHB elevated, urine ketones, insulin-deficient history)

  • Lactic acidosis (lactate >2 mmol/L; identify type A vs. B cause)

  • Uremic acidosis (BUN/Cr elevated; typically mild AG initially, higher AG later)

  • AKA (low/normal glucose, heavy ETOH use, ketosis — treat with D5W + thiamine, NOT insulin)

  • Methanol ingestion (high osmolar gap + visual symptoms + formate on levels)

  • Ethylene glycol ingestion (high osmolar gap + renal failure + oxalate crystals in urine)

  • Salicylate toxicity (serum salicylate level; mixed AGMA + respiratory alkalosis)

  • Propylene glycol toxicity (high osmolar gap + ICU patient on lorazepam/diazepam drip)

DATA

  • ABG or VBG (pH, pCO2, HCO3, lactate)

  • BMP → calculate AG = Na − (Cl + HCO3); normal 8–12

  • Correct AG for albumin: corrected AG = measured AG + 2.5 × (4 − albumin); critical in hypoalbuminemia

  • Delta ratio = (AG − 12) / (24 − HCO3):

    • <0.4 = pure non-AG metabolic acidosis

    • 0.4–1.0 = mixed AGMA + NAGMA

    • 1.0–2.0 = pure AGMA

    • 2.0 = AGMA + concurrent metabolic alkalosis

  • Serum lactate (lactic acidosis type A vs. B)

  • Serum beta-hydroxybutyrate (BHB) — most sensitive for ketoacidosis

  • Urine ketones (less sensitive than serum BHB)

  • Serum osmolality → osmolar gap = measured − [2×Na + glucose/18 + BUN/2.8]; >10 = osmolar gap acidosis (methanol, EG, propylene glycol)

  • Serum salicylate level, methanol level, ethylene glycol level (if ingestion suspected)

  • Urine microscopy (calcium oxalate crystals → EG ingestion)

  • Winter's formula: expected pCO2 = 1.5 × HCO3 + 8 ± 2; if actual pCO2 higher than expected = concurrent respiratory acidosis; if lower = concurrent respiratory alkalosis

  • LFTs; ammonia (hepatic lactic acidosis); CBC; troponin (ischemia); procalcitonin (sepsis)

  • Blood cultures ×2 if sepsis suspected

HOME MEDS

  • Metformin — HOLD immediately if lactic acidosis or AKI; do not restart until renal function normal

  • NSAIDs — hold (worsen AKI, type IV RTA)

  • Aspirin — check salicylate level if any concern; document dose

  • SGLT-2 inhibitors — hold; cause euglycemic DKA; do not restart for ≥3 days after resolution

  • Topiramate, acetazolamide — cause proximal RTA (non-AG); hold if contributing

PLAN

  • Treat the underlying cause — this is the most critical step; bicarb is NOT a treatment for the cause

  • DKA: insulin + IVF + K replacement (see Uncontrolled Diabetes card)

  • Lactic acidosis:

    • Type A: aggressive source control (sepsis — antibiotics, IVF, vasopressors; ischemia — revascularization; shock — pressors and IVF)

    • Type B: stop metformin; treat underlying condition; thiamine 100 mg IV if deficiency suspected

    • NaHCO3 NOT routinely indicated (BICAR-ICU trial: bicarb in severe lactic acidosis + AKI at pH <7.2 may reduce need for RRT and 28-day mortality — selective use only)

  • AKA: D5W 1–2 L IV + thiamine 100 mg IV before glucose; do NOT give insulin (not DKA; glucose low/normal)

  • Uremic acidosis: NaHCO3 supplementation for moderate CKD (target HCO3 >22); emergent dialysis if severe, symptomatic, or refractory

  • Methanol and ethylene glycol:

    • Fomepizole (4-MP) 15 mg/kg IV loading dose → 10 mg/kg IV q12h × 4 doses → 15 mg/kg q12h (blocks alcohol dehydrogenase — prevents formation of toxic metabolites)

    • Emergent hemodialysis (removes parent compound and toxic metabolites): indicated if pH <7.3, renal failure, visual symptoms (methanol), or serum level >20 mg/dL

    • If fomepizole unavailable: ethanol (competitive inhibitor) — less preferred, requires careful monitoring

    • Acyclovir NOT needed; folinic acid (leucovorin) 1 mg/kg IV q4h for methanol (enhances formate metabolism)

    • Thiamine 100 mg IV q6h + pyridoxine 50 mg IV q6h for ethylene glycol (enhances oxalate metabolism to nontoxic metabolites)

  • Salicylate toxicity:

    • Urinary alkalinization: NaHCO3 1–2 mEq/kg IV bolus then 100–150 mEq/L D5W infusion; target urine pH 7.5–8.0 (traps ionized salicylate in urine → enhanced elimination)

    • Aggressive IVF; potassium repletion (alkalinization impossible if hypokalemic)

    • Emergent hemodialysis if: serum salicylate >100 mg/dL, severe CNS toxicity, renal failure, or refractory acidosis

    • Do NOT give acetazolamide (systemic acidosis worsens CNS salicylate entry)

  • Propylene glycol: stop offending infusion (lorazepam or diazepam drip); switch to alternative sedation; hemodialysis if severe

  • NaHCO3 indications (very selective):

    • pH <7.1 with hemodynamic instability (temporizing only; does NOT treat cause)

    • TCA toxicity: 1–2 mEq/kg IV bolus (target pH 7.45–7.55; Na-channel blockade reversal)

    • Salicylate toxicity: urinary alkalinization (see above)

    • RTA: chronic oral supplementation

  • Continuous cardiac telemetry for pH <7.2 or hemodynamic instability

  • ICU if pH <7.1, hemodynamic instability, AMS, or requires close monitoring

  • Nephrology consult: renal failure, uremic acidosis, methanol/EG (emergent dialysis), refractory acidosis

  • Toxicology consult: suspected ingestion or overdose

  • Trend: BMP q2–4h during active treatment; lactate trends; ABG/VBG; urine output

DISCHARGE:

  • DKA: endocrine follow-up; insulin regimen adjustment; sick-day rules for SGLT-2 patients

  • Lactic acidosis: eliminate metformin if contributing; address underlying condition

  • Methanol/EG: ophthalmology follow-up (methanol — visual damage); psychiatry if intentional ingestion; nephrology if renal sequelae

  • Salicylate: psychiatry if intentional; PCP follow-up with medication review

RED FLAGS

  • pH <7.1 → ICU; emergent nephrology; cardiac monitoring; high mortality

  • AG >20 with unknown cause → osmolar gap and toxic ingestion screen urgently; do NOT wait for levels before treating

  • Methanol: visual symptoms (blurred vision, scotomata, blindness) → ophthalmology + emergent dialysis; visual loss can be permanent

  • Ethylene glycol: AKI + urine oxalate crystals + AG acidosis → emergent fomepizole + dialysis

  • Lactic acidosis + metformin → STOP metformin immediately; dialysis clears metformin

  • Salicylate + AMS or seizures → emergent dialysis; CNS salicylate entry worsens with acidosis → do NOT allow pH to fall

  • SGLT-2 inhibitor + normal glucose + ketosis = euglycemic DKA — check BHB in all SGLT-2 patients with unexplained AGMA

SENIOR IM RESIDENT PEARLS

  • Always correct AG for albumin: every 1 g/dL drop in albumin below 4 → AG falsely decreases by ~2.5; hypoalbuminemic patients can have significant AGMA with a "normal" uncorrected AG

  • Delta ratio is your most important additional calculation after confirming AGMA — it tells you what else is going on:

    • <1 = also a NAGMA; >2 = also a metabolic alkalosis; use to avoid missing mixed disorders

  • Winter's formula: if pCO2 is higher than predicted → concurrent respiratory acidosis (inadequate compensation); if lower → concurrent respiratory alkalosis (salicylates classically cause this)

  • Osmolar gap >10 = osmolar gap acidosis until proven otherwise; calculate it in every AGMA without a clear cause before levels return; fomepizole empirically if methanol/EG suspected

  • AKA vs. DKA: in AKA, glucose is low or normal, ETOH history present, NO insulin deficit — treat with D5W + thiamine, never insulin; urine ketones may be falsely negative (BHB not detected by nitroprusside test)

  • Common mistake: treating lactic acidosis with bicarb without fixing the cause — bicarb temporizes but increases CO2 production, may worsen intracellular acidosis, and does not improve mortality in isolation

  • Serum BHB is far more sensitive than urine ketones for DKA — urine nitroprusside test detects acetoacetate only; BHB is the dominant ketone; can have DKA with negative urine ketones

  • Common mistake: not recognizing euglycemic DKA in SGLT-2 inhibitor patients — glucose may be <200; always check serum BHB in any unexplained AGMA in a patient on an SGLT-2 inhibitor