Discussion
Methaemoglobin (MetHb) is formed when the iron atom in haemoglobin is oxidised from a ferrous (Fe2+) to a ferric (Fe3+) state that cannot bind oxygen. At the same time, the normal oxyhaemoglobin dissociation curve shifts to the left, which increases its affinity for oxygen, with the result that less oxygen is released to tissues (3–5). This causes blood to be darker in colour, as an indication of the levels of methaemoglobin. Conventional pulse oximetry does not detect methaemoglobin, and at high levels SpO2 is interpreted as approximately 85 % irrespective of the actual oxygen saturation of haemoglobin (6).
The clinical presentation of methaemoglobinaemia is due to hypoxaemia, and clinical features range from weakness, dizziness, headache, 'chocolate cyanosis' (brownish-blue colour/chocolate-coloured blood) and dyspnoea to arrhythmias, seizures, respiratory and circulatory failure, coma and death (3–5). The severity of the condition depends on the level of methaemoglobinaemia, as well as the accumulation rate, the individual's ability to reduce methaemoglobin and any underlying comorbidities (3).
Methaemoglobinaemia should be suspected in patients with discoloured blood (dark red, blueish, chocolate-coloured), particularly when they also present with dyspnoea, chocolate cyanosis and hypoxaemia that is refractory to oxygen therapy, and their arterial partial pressure of oxygen (PaO2) is normal (3–5). The diagnosis is confirmed by biochemistry and blood gas analysis with CO-oximetry, which measures the four haemoglobin derivatives specifically, rather than indirectly using blood PaO2 (4, 6, 7).
The causes of methaemoglobinaemia can be congenital (enzyme defects or abnormal haemoglobin) or acquired (3, 4). Acquired causes of methaemoglobinaemia are most common and include medicinal products or toxic agents, most frequently local anaesthetics, such as benzocaine, lidocaine and prilocaine. Other substances that can induce methaemoglobinaemia are dapsone, chloroquine and nitrites/nitrates (3–5).
Treatment depends on the severity of methaemoglobinaemia and clinical presentation.
Most cases are mild and do not require treatment other than removal of the causative agent (3, 4). High-flow oxygen therapy increases oxygen delivery to tissues and enhances the natural degradation of methaemoglobin (5). Methylene blue is recommended for patients with very high levels of methaemoglobin (above 30–40 %) and patients with lower levels and significant symptoms, particularly those with known cardiopulmonary disease (3, 4). Methylene blue is converted in red blood cells to leucomethylene blue, which reduces oxidised iron (Fe3+) in the haemoglobin back to the ferrous state (Fe2+) that is able to bind oxygen (4, 5). Methylene blue is administered as an intravenous infusion at a dosage of 1–2 mg/kg over 5–10 minutes. Treatment response should be checked 30 minutes after administration, and then every 3–4 hours until stabilisation (8). Due to methylene blue's short half-life, the dose often needs to be repeated, guided by clinical findings and arterial blood gas analyses.
Methylene blue can cause serotonergic syndrome in patients receiving serotonergic antidepressants. Methylene blue should be avoided in patients with known glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of severe haemolysis. In these patients, methaemoglobinaemia is treated with ascorbic acid and, if necessary, exchange transfusion (3–5).
Most patients only require a limited period of observation, but patients with persistent symptoms despite initiation of treatment and/or with severe comorbidities must be admitted to hospital (5). Genetic testing may be appropriate where a hereditary cause is suspected (3). Before discharge, the patient should be given detailed information and advised against future use of causative medicinal products. Adverse drug reactions should also be notified to the Norwegian Medical Products Agency.
A key differential diagnosis is a toxic reaction to local anaesthesia, which is known as LAST (Local Anaesthetic Systemic Toxicity) syndrome. However, apart from syncope, the patient had none of the central nervous system symptoms/signs (seizures, paraesthesia, confusion, agitation) or cardiovascular findings (bradycardia, hypotension, arrhythmia) that are typical of LAST syndrome (9). LAST syndrome was considered unlikely since elevated methaemoglobin was detected and symptoms improved following treatment.