Epidemiology

Etiology

Dapsone
Local/topical anesthetics (eg, benzocaine, teething medications)
Nitrates/nitrites (eg, drinking ground water)

Pathophysiology

Methemoglobin is created when reduced ferrous iron (Fe2+) bound to oxyhemoglobin is oxidized to ferric iron (Fe3+).
Ferric iron in methemoglobin cannot bind oxygen→ ↓ total blood oxygen content and ↓ blood oxygen saturation → tissue hypoxia

Tip

The ferric iron in methemoglobin has a high affinity for cyanide, thus, amyl nitrite-induced methemoglobin is used as a competitive inhibitor in the treatment of cyanide poisoning.

Clinical features

Cyanosis (brownish-blue or gray skin and membranes) t

Diagnostics

Due to the wavelength of light absorbed by Fe3+ heme, pulse oximetry converges on 85% as the proportion of methemoglobin increases, regardless of the true oxygen saturation status.
Bedside testing: Blood appears dark brown (“chocolate-colored”) and does not turn red with exposure to oxygen.

Cyanide poisoning vs CO poisoning

Feature Carbon Monoxide (CO) Methemoglobinemia Cyanide (CN)
Mechanism Binds Hb (200x affinity); Left Shift Fe³⁺ (ferric) state; Left Shift Inhibits Complex IV (ETC); Normal Curve
Causes Car exhaust, gas heaters, house fires Nitrites, Benzocaine, Dapsone, Sulfonamides Burning rubber/plastic, Nitroprusside
Key Sign ”Cherry Red” skin ”Chocolate Brown” blood, Cyanosis ”Bitter Almond” breath
Pulse Ox Falsely Normal ~85% (Fixed) Normal
PaO₂ Normal Normal Normal
Treatment 100% O2, Hyperbaric O2 Methylene Blue (Vit C if G6PD def.) Hydroxocobalamin, Nitrites, Thiosulfate

Feature Carbon Monoxide (CO) Poisoning Cyanide (CN) Poisoning Methemoglobinemia (MetHb)
Mechanism Binds Hemoglobin (forms COHb) → ↓ O2 carrying & delivery. Inhibits Cytochrome C Oxidase (Complex IV) → blocks ATP prod. Iron in heme oxidized (Fe2+ → Fe3+) → cannot bind O2.
Source Incomplete combustion (fires, car exhaust, faulty heaters). Fires (plastics, wool), industrial, nitroprusside. Oxidizing drugs (dapsone, nitrites, benzocaine), G6PD deficiency.
Presentation Gradual onset: headache, dizziness, N/V. Cherry-red skin (late, unreliable). Normal SaO2 on pulse ox. Rapid onset: confusion, seizures, coma. Cherry-red skin. Almond breath (unreliable). Cyanosis (dusky/brown skin/blood) unresponsive to O2. Dyspnea.
Dx ↑ COHb level (CO-oximetry). Pulse ox misleadingly normal. ↑ Lactate. Clinical suspicion + history. High venous O2. ↑ MetHb level (co-oximetry). “Saturation gap” (pulse ox ~85%). Chocolate-brown blood.
Tx 100% O2. Hyperbaric O2 (HBO) if severe. Hydroxycobalamin or Nitrites + Sodium Thiosulfate. Methylene blue. O2. (Avoid MB in G6PD def.).
CT/MRI Brain Bilateral globus pallidus lesions (hypodense CT, T2 hyper MRI). Less specific; diffuse edema or basal ganglia lesions possible. Non-specific hypoxic changes if severe.
O2-Myoglobin Curve Shifts Left (impairs O2 release to muscle). No direct significant effect. No direct significant effect; O2-HGB curve shifts left for normal Hb.
Buzzwords ”Faulty heater,” “car exhaust,” “globus pallidus lesions." "Almond breath,” “plastic fire,” “nitroprusside." "Dapsone,” “benzocaine,” “chocolate-brown blood,” “saturation gap.”
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Feature	Carbon Monoxide (CO)	Methemoglobinemia	Cyanide (CN)
Mechanism	Binds Hb (200x affinity); Left Shift	Fe³⁺ (ferric) state; Left Shift	Inhibits Complex IV (ETC); Normal Curve
Causes	Car exhaust, gas heaters, house fires	Nitrites, Benzocaine, Dapsone, Sulfonamides	Burning rubber/plastic, Nitroprusside
Key Sign	”Cherry Red” skin	”Chocolate Brown” blood, Cyanosis	”Bitter Almond” breath
Pulse Ox	Falsely Normal	~85% (Fixed)	Normal
PaO₂	Normal	Normal	Normal
Treatment	100% O2, Hyperbaric O2	Methylene Blue (Vit C if G6PD def.)	Hydroxocobalamin, Nitrites, Thiosulfate

Feature	Carbon Monoxide (CO) Poisoning	Cyanide (CN) Poisoning	Methemoglobinemia (MetHb)
Mechanism	Binds Hemoglobin (forms COHb) → ↓ O2 carrying & delivery.	Inhibits Cytochrome C Oxidase (Complex IV) → blocks ATP prod.	Iron in heme oxidized (Fe2+ → Fe3+) → cannot bind O2.
Source	Incomplete combustion (fires, car exhaust, faulty heaters).	Fires (plastics, wool), industrial, nitroprusside.	Oxidizing drugs (dapsone, nitrites, benzocaine), G6PD deficiency.
Presentation	Gradual onset: headache, dizziness, N/V. Cherry-red skin (late, unreliable). Normal SaO2 on pulse ox.	Rapid onset: confusion, seizures, coma. Cherry-red skin. Almond breath (unreliable).	Cyanosis (dusky/brown skin/blood) unresponsive to O2. Dyspnea.
Dx	↑ COHb level (CO-oximetry). Pulse ox misleadingly normal.	↑ Lactate. Clinical suspicion + history. High venous O2.	↑ MetHb level (co-oximetry). “Saturation gap” (pulse ox ~85%). Chocolate-brown blood.
Tx	100% O2. Hyperbaric O2 (HBO) if severe.	Hydroxycobalamin or Nitrites + Sodium Thiosulfate.	Methylene blue. O2. (Avoid MB in G6PD def.).
CT/MRI Brain	Bilateral globus pallidus lesions (hypodense CT, T2 hyper MRI).	Less specific; diffuse edema or basal ganglia lesions possible.	Non-specific hypoxic changes if severe.
O2-Myoglobin Curve	Shifts Left (impairs O2 release to muscle).	No direct significant effect.	No direct significant effect; O2-HGB curve shifts left for normal Hb.
Buzzwords	”Faulty heater,” “car exhaust,” “globus pallidus lesions."	"Almond breath,” “plastic fire,” “nitroprusside."	"Dapsone,” “benzocaine,” “chocolate-brown blood,” “saturation gap.”

Treatment

Methylene blue is the first-line treatment for acquired methemoglobinemia.
- Acts as a cofactor to reduce methemoglobin to hemoglobin

Tip

100% supplemental oxygen is not useful in methemoglobinemia, in contrast to monoxide poisoning and cyanide poisoning.

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Methemoglobinemia

Epidemiology

Etiology

Pathophysiology

Clinical features

Diagnostics

Cyanide poisoning vs CO poisoning

Treatment

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