MetHb is an uncommon and potentially reversible cause of hypoxia in the perioperative setting (Cefalu et al. 2020). It is a condition where the bound ferrous iron of oxyhaemoglobin is oxidized to the bound ferric iron of methaemoglobin (Cefalu et al. 2020). This reaction continuously occurs in vivo where ferric form gets normally reduced predominantly by cytochrome-b5 reductase (CYB5R) to keep its concentration always less than 2% in healthy humans (Lin et al. n.d.). Haemoglobin in the ferric state is incapable of binding oxygen which can lead to life-threatening hypoxemia (Hurford and Kratz 2004). Clinically significant MetHb may occur because of one of the following 3 reasons; greatly increased production of methaemoglobin; an abnormal haemoglobin which, once oxidized, is resistant to reduction and decreased activity of erythrocyte NADH-CYB5R (Chisholm and Stuart 1994).

MetHb can be of two types — congenital and acquired. Congenital MetHb is extremely rare and is of three types. Two are inherited as autosomal recessive traits: due to CYB5R and cytochrome-b5 deficiency. The third type is an autosomal dominant disorder, haemoglobin M disease, in which there is a mutation in the globin molecule. The carrier or heterozygous state of patients is characterized by an intermediate level of enzyme activity, and thus, they are more susceptible to the effects of oxidizing agents. Genetic risk factors for MetHb include haemoglobin M disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and congenital MetHb genotypes (Chisholm and Stuart 1994). The severity of symptoms may be exacerbated by complicating medical conditions and other factors, such as heart disease, lung disease, anaemia, G6PD deficiency, infancy and old age (Trapp and Will 2010). In the case report published by Lin et al. (n.d.), congenital MetHb was first suspected intraoperatively because of a mismatch of SpO2 of finger pulse oximetry and SaO2 of arterial blood and was later confirmed by multiple-wavelength co-oximetry.

MetHb commonly results from exposure to oxidizing agents which results in the oxidation of haemoglobin by drugs or chemicals, usually exogenous oxidants such as nitrites, LA and sulfonamides (Hurford and Kratz 2004). When the production of methaemoglobin exceeds its reduction, MetHb occurs and potentially compromises tissue oxygenation (Hurford and Kratz 2004). The rate of such oxidation is accelerated by many drugs and toxic chemicals, the former including lidocaine, benzocaine, prilocaine and nitrites, which are often used in the perioperative period (Maurtua et al. 2004; Kreeftenberg et al. 2007). The most common drugs implicated in methaemoglobinemia include cocaine-derived anaesthetics like benzocaine and lidocaine, antibiotics such as dapsone (Prasad et al. 2008), and gases such as nitric oxide (Cefalu et al. 2020). Prasad et al. (2008) published a case report on acquired MetHb with dapsone in a patient who underwent an elective coronary artery bypass graft. Contamination of food during manufacture or degradation of nitrates in vegetables will also cause MetHb (Chan 1996). A high index of suspicion for MetHb should follow any presentation of hypoxic and cyanotic patients who are not improving with 100% oxygen therapy. Taking a thorough history and detailed medication with importance to the discrepancy between the SpO2 and SaO2 which is refractory to oxygen therapy is recommended.

Monitoring arterial oxygenation by pulse oximetry is the standard method of assessing tissue oxygen delivery in anaesthetic practice (Hurford and Kratz 2004). A discrepancy between SpO2 and the calculated SaO2 may be the earliest indicator of MetHb (Cefalu et al. 2020). The pulse oximetry readings may be inaccurate or not informative if patients have higher levels of MetHb, carboxyhaemoglobin or other abnormal haemoglobin species (Lin et al. n.d.). Co-oximetry using multiple wavelengths can measure the levels of haemoglobin, oxyhaemoglobin, carboxyhaemoglobin, and MetHb and can demonstrate values in fractional saturation (Lin et al. n.d.). Furthermore, a decreased SpO2 often with a nadir of 85%, chocolate-coloured or black/brown blood, physiologically appropriate PaO2 on ABG, metabolic acidosis, and tachycardia are all associated with MetHb (Cefalu et al. 2020). Also, the oxyhaemoglobin dissociation curve is shifted to the left and hypoxia results (Prasad et al. 2008).

The classic appearance of “chocolate brown blood” of blood is present with MetHb as low as 15%; at 20%, the patient may experience anxiety, light-headedness, and headaches; and with 30–50%, there may be tachypnea, confusion, and loss of consciousness. The patient is at risk for seizures, dysrhythmias, metabolic acidosis, and coma at 50% and levels above 70% are fatal (Chan 1996). It should be noted that in patients with lifelong congenital MetHb or with a history of chronic MetHb secondary to chronic exposure to drugs or toxins, the levels can be as high as 40% and still be well tolerated with cyanosis (bluish cast to the mucous membranes of the skin) being the only presenting manifestation (Wilkerson 2010).

Treatment is based on the degree of MetHb levels, the severity of symptoms, the etiological process (acute or chronic) and the presence of complicating medical conditions. Symptomatic treatment includes promoting the reduction of MetHb back to oxyhaemoglobin using methylene blue, ascorbic acid, riboflavin, and hyperbaric oxygen therapy. As a last resort in emergency situations, red blood cell transfusion therapy can be attempted in cases of critically elevated methaemoglobin levels exceeding 70% (Somervaille 2001). When the methaemoglobin level is less than 20% and oxygenation is adequate, conservative treatment could suffice. However, the administration of 100% oxygen, correction of metabolic acidosis and use of methylene blue if the patient is symptomatic is recommended. In a patient with acute toxic MetHb, the first step in treatment consists of correcting metabolic abnormalities, discontinuing potential offending pharmaceuticals, and maintaining dextrose-containing fluids, which can adequately supply substrates for the production of NADH and NADPH.

Methylene blue activates NADPH diaphorase, an enzyme capable of reducing methylene blue to leukomethylene blue, and the latter, via a non-enzymatic pathway, reduces MetHb to haemoglobin. The IV administration of 1–2 mg/kg over a period of 5 min significantly reduces its level within 1 h. It can be repeated if necessary in 30–60 min provided the total does not exceed a maximum dosage of 7 mg/kg. It should be noted that excessive administration may produce haemolysis because methylene blue can also act as an oxidant (do Nascimento et al. 2008). Ascorbic acid is cheap and easily available and a good alternative (Sahu et al. 2016).