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Q1: Mechanism and recognition (3 min)
Examiner: A previously well young man becomes centrally cyanosed within 30 minutes of a benzocaine throat spray for endoscopy. SpO2 is 85 percent and does not rise with 100 percent oxygen; PaO2 is 95 mmHg. Walk me through the mechanism and why this is methaemoglobinaemia.
Expected answer:
- Methaemoglobin (MetHb) = haemoglobin with its iron in the ferric (Fe3+) state (normal is ferrous Fe2+). Ferric iron cannot bind oxygen AND shifts the dissociation curve left, so oxygen bound to remaining normal Hb is released less readily to tissues — a double hit (functional anaemia + impaired unloading).
- The defining paradoxes: SpO2 plateaus at ~85 percent because MetHb absorbs at both pulse-oximeter wavelengths (660 nm, 940 nm); the standard ABG calculates a normal SaO2 because it assumes all Hb is normal; the PaO2 is normal because lung gas exchange is intact and PaO2 reflects dissolved oxygen. Only CO-OXIMETRY measures MetHb directly.
- The trigger — benzocaine (an oxidant) — is the classic iatrogenic cause. The bedside blood-colour test: chocolate-brown blood that does not turn red on oxygen exposure.
Follow-up: What is the normal MetHb and why is it held there? Under 1 percent of total Hb; ~0.5-3 percent forms daily by spontaneous auto-oxidation and is held in check by the major NADH-cytochrome b5 reductase pathway (~95 percent of reduction).
Q2: The reducing pathways and the basis of therapy (3 min)
Examiner: Tell me about the red-cell reducing systems and how methylene blue works.
Expected answer:
- MAJOR pathway (~95 percent): NADH-cytochrome b5 reductase (diaphorase I) — uses NADH from glycolysis to reduce cytochrome b5, which reduces MetHb-Fe3+ to Hb-Fe2+. This is the pathway genetically deficient in cytochrome b5 reductase deficiency (congenital methaemoglobinaemia).
- MINOR pathway (~5 percent): NADPH-dependent methaemoglobin reductase (diaphorase II) — uses NADPH from the hexose-monophosphate shunt, but is normally dormant because it lacks an endogenous electron carrier.
- Methylene blue supplies that missing carrier: it is reduced to leukomethylene blue by NADPH-methaemoglobin reductase, and leukomethylene blue non-enzymatically reduces MetHb-Fe3+ back to Hb-Fe2+. This is the molecular basis of therapy.
- This is also the molecular basis of the G6PD contraindication: no G6PD → no NADPH → the pathway cannot run, AND methylene blue (an oxidant dye) then causes haemolysis.
- Minor non-enzymatic reduction by ascorbic acid and glutathione — the rationale for ascorbic acid as an alternative antidote.
Follow-up — reproduce the methylene-blue dose: 1-2 mg/kg IV over 5 min (= 0.1-0.2 mL/kg of 1 percent); repeat after 30-60 min; maximum 7 mg/kg in 24 h. Response within 30-60 min (patient visibly turns pink).
Q3: Management ladder and the G6PD caveat (3 min)
Examiner: How do you manage this patient, with doses? And what if he is G6PD-deficient?
Expected answer — stepwise:
- ABCDE; STOP the oxidant (withhold benzocaine); high-flow 100 percent oxygen; IV access; continuous ECG.
- Methylene blue 1-2 mg/kg IV over 5 min for symptomatic disease (here confused, dyspnoeic) OR MetHb over 30 percent (here confirmed by co-oximetry). Repeat after 30-60 min if needed.
- Check G6PD as soon as possible (do not delay methylene blue in a severely symptomatic patient).
- Supportive/ICU for severe disease; treat arrhythmia/ischaemia; observe with serial MetHb.
If G6PD-deficient — methylene blue is absolutely contraindicated (fails AND causes haemolysis). Use:
- Ascorbic acid 300-1000 mg/day (slow non-enzymatic reduction).
- N-acetylcysteine (glutathione precursor).
- Exchange transfusion for severe disease (physically removes MetHb and supplies functional Hb).
- Hyperbaric oxygen as salvage (provides dissolved O2 independent of Hb carriage).
Follow-up — what if methylene blue fails despite normal G6PD? Re-examine for ongoing exposure (dapsone — add cimetidine, which inhibits CYP450 hydroxylamine formation), haemoglobin M disease / cytochrome b5 reductase deficiency (response poor), sulphhaemoglobinaemia (irreducible), or too-low initial dose — re-dose.
Q4: Causes and the dapsone scenario (2 min)
Examiner: List the causes you would consider, and tell me specifically about dapsone.
Expected answer — by category:
- Nitrates/nitrites — contaminated well water (infants — 'blue baby'; gut flora reduces nitrate to nitrite), sodium nitrite food preservative, amyl/sodium/butyl nitrite 'poppers'.
- Local anaesthetics — benzocaine (classic iatrogenic), prilocaine (EMLA, dental), lidocaine (rarer).
- Antimicrobials — dapsone, sulphonamides, primaquine (also G6PD haemolysis), chloroquine.
- Other drugs — phenazopyridine (orange urine clue), nitroprusside (cyanide + nitrite), nitroglycerin, metoclopramide, rasburicase (contraindicated in G6PD).
- Industrial/chemical — aniline dyes, chlorates, naphthalene, nitrobenzene.
- Smoke inhalation — combined CO + cyanide + MetHb.
- Congenital — cytochrome b5 reductase deficiency (AR), haemoglobin M disease (AD).
Dapsone specifically: its N-hydroxylamine metabolite is the oxidant, and dapsone has a long half-life (20-40 h), so MetHb recurs after each methylene-blue dose. Management: repeat/continuous methylene blue + ADD CIMETIDINE 300 mg every 6 h (inhibits the CYP450 hydroxylamine formation) + consider N-acetylcysteine + monitor MetHb every 4-6 h for 24-48 h. In chronic dapsone therapy (leprosy, dermatitis herpetiformis, Pneumocystis prophylaxis), co-prescribe cimetidine from the outset and use the lowest effective dose.
Q5: Differential diagnosis and pitfalls (2 min)
Examiner: How do you distinguish methaemoglobinaemia from the other dyshaemoglobins, and what are the classic pitfalls?
Expected answer — the dyshaemoglobins:
- MetHb — slate-grey cyanosis, chocolate-brown blood, SpO2 ~85 percent plateau, normal PaO2; methylene blue reduces it (unless G6PD).
- Carboxyhaemoglobinaemia (CO) — cherry-red blood, SpO2 falsely HIGH (CO-Hb misread as oxy-Hb, near 100 percent), normal PaO2; treat with high-flow / hyperbaric O2, NOT methylene blue.
- Sulphaemoglobinaemia — greenish blood, IRREDUCIBLE (lasts RBC lifespan ~120 days), methylene blue does NOT work, cyanosis at lower threshold (~0.5 g/dL); same oxidant drugs (sulphonamides, phenazopyridine); withdraw and wait.
- Pseudocyanosis (argyria, drugs) — slate-grey skin, normal blood/gases.
Classic pitfalls:
- Trusting the pulse oximeter or the calculated SaO2 — both misleading in MetHb.
- Missing the diagnosis in an anaemic patient — cyanosis absent (total Hb too low to reach 1.5 g/dL absolute MetHb), yet severe hypoxia; use absolute MetHb, transfuse.
- Giving methylene blue to a G6PD-deficient patient — haemolysis + failure.
- Excessive methylene blue (over 7 mg/kg/24 h) — causes MetHb and haemolysis.
- Confusing sulph-Hb (irreducible) with MetHb.
- Boiling nitrate-contaminated water to 'make it safe' — boiling CONCENTRATES nitrate.
- Forgetting the serotonin-syndrome interaction with SSRIs/SNRIs/MAOIs (methylene blue is a weak MAO inhibitor).