Classical presentation of methemoglobinemia treated by a non-classical method – a case report

Hemoglobin is the oxygen-carrying protein contained in red blood cells that ensures delivery of inspired oxygen from lungs to all tissue cells. This process depends on oxygen forming a reversible ionic link with ferrous iron (Fe⁺⁺) contained within the hemoglobin molecule. Methemoglobin (MetHb) is a dysfunctional form of hemoglobin (Hb) that cannot bind and transport oxygen because the iron it contains is in the oxidized, ferric (Fe⁺⁺⁺) rather than the reduced, ferrous (Fe⁺⁺) state.

In health, methemoglobin comprises no more than around 1 % of total hemoglobin. Methemoglobinemia is a potentially fatal condition characterized by increased methemoglobin concentration and consequent reduced blood oxygen transport and, thereby, reduced tissue oxygenation (hypoxia). 

Methemoglobinemia can result from an inherited (congenital) defect in the enzyme system responsible for endogenous conversion (reduction) of methemoglobin to hemoglobin. More often, however, the condition is acquired by ingestion or absorption of any one of many potential oxidizing drugs and toxic chemicals that convert (”oxidize”) hemoglobin to methemoglobin. 

A case of acquired severe methemoglobinemia – in which MetHb comprised 49 % of the patient’s total Hb – is recently reported that nicely demonstrates several classical features of the condition, including discrepancy between the two routine methods of determining blood oxygenation: pulse oximetry (which generates SpO₂) and arterial blood gas analysis (which generates pO₂(a) and sO₂(a)).

The case concerns a 25-year-old man who came to his hospital emergency department following accidental ingestion of around 20-30 mL of paint thinner that had caused local burning sensation and episodes of vomiting; relatives had noticed bluish discoloration of his face, lips and hands. 

Clinical examination on arrival at hospital confirmed central and peripheral cyanosis reported by relatives, as well as increased respiration (26 breaths/min) and heart rate (124 beats/min). Digital pulse oximetry revealed marked reduction in oxygen saturation (SpO₂ 82 % on room air – FO₂(I) 21 %) that did not respond as expected to oxygen therapy (SpO₂ 85 % on oxygen – FO₂(I) 50 %). Arterial blood was sampled for blood gas analysis and noted to be dark brown in color, rather than the normal bright red of well-oxygenated blood. Analysis revealed pO₂(a) 129 mmHg (17.2 kPa) and oxygen saturation (sO₂(a)) 96 % whilst on oxygen.

The combination of three classical features suggested that methemoglobinemia was the likely cause of the patient’s cyanosis: 

• Discrepancy between S_pO₂ (reduced, typically around 85 %) and sO₂(a) (normal)
• Failure of oxygen therapy to materially affect SpO₂
• Dark brown ”chocolate”-colored arterial blood

The proposed diagnosis was supported by knowledge of the temporal relationship between ingestion of a potentially toxic chemical and onset of symptoms, and by lack of evidence of a cardio-pulmonary illness that could explain the patient’s cyanosis.

Diagnosis was confirmed with subsequent measurement of MetHb by CO-oximetry; the level was found to be very high (46.4 %).

The standard recommended treatment for acute methemoglobinemia is iv infusion of methylene blue (1.5-2.0 mg/kg). Methylene blue is converted in vivo by the endogenous enzyme, NADPH-dependent methemoglobin reductase ,to leucomethylene blue, which in turn reduces methemoglobin to hemoglobin. Unfortunately, methylene blue was not available at the hospital so an alternative, occasionally used, high-dose vitamin C therapy was trialed in this patient.

MetHb rapidly decreased from 49 % to 25.4 % 4 hours after intravenous administration of 2 g vitamin C. Continued injections (1 g every 6 hours) and a total dose of 12 g delivered over 60 hours resulted in resolution of cyanosis by day 2 and further reduction of MetHb to 3.2 % by day 7, when the patient was discharged in good condition. SpO₂ on room air at discharge was a healthy 95 %. Subsequent forensic analysis of the offending paint thinner revealed that constituent nitrobenzene was the likely cause of methemoglobinemia in this case.