Methaemoglobinaemia: a potential confounder in COVID-19 respiratory failure

INTRODUCTION

Methaemoglobinaemia is a state of excessive methaemoglobin (metHb) in the blood, which reduces the oxygen-carrying capacity, and hence tissue oxygen delivery. Most cases of methaemoglobinaemia are acquired from exposure to oxidising agents. A metHb level >30% can result in fatal hypoxia. We describe a case of methaemoglobinaemia in a patient with coronavirus disease 2019 (COVID-19) who presented with low peripheral oxygen saturation (SpO₂). The patient is a migrant worker (MW) in the construction industry, with a history of exposure to industrial solvents. As >90% of the cases of COVID-19 in Singapore were diagnosed in MWs, most of whom worked in the construction sector, physicians need to be aware of other potential causes of low SpO₂ in these patients.

CASE DESCRIPTION

Our patient is a 45-year-old Indian man who was admitted to the intensive care unit (ICU) in May 2020 with fever and SpO₂ of 91% (normal range [NR] 95%–100%) on room air. He lived in a dormitory and had been recently diagnosed with COVID-19. He had no past medical history and was not on chronic medications. Despite escalating oxygen therapy, SpO₂ remained at <92%. Arterial blood gas (ABG) on a fraction of inspired oxygen (FiO₂) of 60% and flow rate of 60 L/min on high-flow nasal cannula revealed chocolate-coloured blood [Figure 1], an arterial partial pressure of oxygen (PaO₂) of 264 mmHg (NR 75–100) and arterial oxygen saturation (SaO₂) of 100% (NR 95%–100%). Due to his dark complexion, cyanosis was not immediately apparent to clinicians in the emergency department. The chocolate-coloured blood and stark discrepancy between SaO₂ and SpO₂ (‘saturation gap’) prompted us to perform co-oximetry, which revealed methaemoglobinaemia.

Figure 1.

Photograph shows chocolate-coloured blood on arterial blood gas.

Despite a metHb level of 41.6% (NR 0.4%–1.5%), the patient’s serum lactate was 1.1 mmol/L (NR 0.5–2.2). Biochemically, there was no evidence of haemolysis — haemoglobin (Hb) 17.5 g/dL (NR 13.6–16.6), haptoglobin 91 mg/dL (NR 36–200) and lactate dehydrogenase 432 U/L (NR 270–550). As he was clinically stable and his glucose-6-phosphate dehydrogenase (G6PD) status was unknown, we treated him with 1.5 g of intravenous ascorbic acid (AA) six-hourly rather than methylene blue (MB). The patient was monitored with twice-daily co-oximetry and the oxygen therapy titrated according to his PaO₂. His MetHb levels dropped to 13.3% over 48 h, and AA was continued orally at 1 g every 8 h.

While the patient’s metHb levels decreased, his PaO₂ also decreased on account of progression of COVID-19 pneumonia over the next 3 days. He did not receive any specific therapies for COVID-19. Furthermore, we ensured that hydroxychloroquine was not used in the treatment of COVID-19 in this patient because it could potentially worsen his methaemoglobinaemia.[1,2] Awake prone positioning strategies were applied, and he did not require intubation. He was discharged from ICU with a metHb level of 10.6%. Since the patient was asymptomatic despite significant methaemoglobinaemia and polycythaemia (Hb 17.5 g/dL [NR 13.6–16.6]), this pointed to longstanding hypoxia resulting in an increase in haematopoiesis to improve the oxygen-carrying capacity of blood. He was investigated for congenital methaemoglobinaemia. He had normal Hb electrophoresis results and no family history of blood disorders. However, we were unable to completely exclude a congenital cause, as the patient declined genetic testing. His occupational history of 15 years of exposure to industrial solvents for waterproofing and polishing surfaces constitutes a risk factor for acquired methaemoglobinaemia.

DISCUSSION

Oxidative stress results in the conversion of Hb to metHb, as haem iron is oxidised from the normal ferrous (Fe²⁺) state to the ferric (Fe³⁺) state. Ferric haem is unable to bind to oxygen and also increases the oxygen affinity of the remaining ferrous haem molecules within the same Hb molecule. Reduction in the oxygen-carrying capacity of blood results in a left shift of the Hb–oxygen dissociation curve, leading to hypoxia. In healthy individuals, several pathways (predominantly, cytochrome b5 reductase) convert metHb back to Hb, thus ensuring that metHb comprises only about 1% of total Hb.

Methaemoglobinaemia can be congenital or acquired. Congenital methaemoglobinaemia is rare and can be caused by cytochrome b5 reductase deficiency (most common), Hb M disease or cytochrome b5 deficiency. In most cases, methaemoglobinaemia is acquired from exposure to oxidising substances. The most commonly implicated substances are local anaesthetics (e.g., benzocaine) and antibiotics (in particular, dapsone).[3,4] However, nitrates and nitrites, as well as solvents and dyes like nitrobenzene and aniline (used in the paint and dye industries) have also been implicated.[5,6] Chronic dapsone use can also cause chronic haemolysis; therefore, patients with methaemoglobinaemia should be assessed for chronic haemolysis.

Symptoms of methaemoglobinaemia arise from tissue hypoxia. At metHb levels of 20%, patients may experience light-headedness and headache. At 30%–50%, there may be confusion and loss of consciousness. MetHb levels ≥50% can cause seizures, dysrhythmias, coma and death.[7] However, patients with chronic methaemoglobinaemia usually have compensatory polycythaemia and may be relatively asymptomatic (as seen in our patient). A diagnosis of methaemoglobinaemia may be suspected in patients with low SpO₂ refractory to oxygen supplementation, chocolate-coloured blood or a saturation gap. Standard pulse oximetry uses light-emitting diodes that absorb light at two wavelengths of 660 nm and 940 nm, and hence only provides an accurate measure of oxyhaemoglobin (oxyHb) as a percentage of total Hb in the absence of dyshaemoglobins (e.g., carboxyhaemoglobin [COHb] and metHb). The diagnosis of methaemoglobinaemia requires co-oximetry, which uses multiple wavelengths to distinguish percentages of oxyHb, deoxyHb, COHb and metHb.

Treatment for methaemoglobinaemia includes removal of the precipitating agent (if acquired), supplemental oxygen and other supportive measures. Administration of intravenous MB or AA may be required in patients with severe symptoms and/or metHb levels >30%. Methylene blue works by acting as an electron carrier intermediate for the nicotinamide adenine dinucleotide phosphate hydrogen–metHb reductase pathway, an alternative pathway capable of converting metHb back to Hb. It is preferred because it acts rapidly. However, its use in patients with G6PD deficiency may precipitate haemolysis, and in patients taking serotonergic agents, MB can precipitate serotonin syndrome. Ascorbic acid also has reducing potential and is an alternative when MB is contraindicated. Patients should also be counselled on avoiding substances that induce metHb formation.

The dominant respiratory feature of severe COVID-19 is arterial hypoxaemia and a low SpO₂ or SaO₂.[8] COVID-19 pneumonia causes hypoxaemia through ventilation/perfusion mismatch, shunt and diffusion limitation. Methaemoglobinaemia decreases the oxygen-carrying capacity of blood. In combination, these two conditions can compromise oxygen delivery and cause fatal tissue hypoxia. This case highlights the possible discrepancy between SpO₂ and PaO₂/SaO₂. A low SpO₂ in the setting of normal/supranormal indices of oxygenation on ABG should prompt the consideration of a diagnosis of methaemoglobinaemia, especially in patients with a history of exposure to industrial chemicals. This is especially important in Singapore, where MWs, many of whom are exposed to industrial chemicals, accounted for the vast majority (94%) of COVID-19 cases.[9] Thus, it should not be assumed that a low SpO₂ in such a patient is due to COVID-19 pneumonia alone.

In conclusion, methaemoglobinaemia is a rare but potentially life-threatening disease that typically presents with symptoms of tissue hypoxia. We report a case of methaemoglobinaemia in a patient with COVID-19 infection, possibly secondary to industrial solvent exposure. There are similar reports of methaemoglobinaemia in COVID-19 patients, although these patients had received COVID-19 treatment agents. Singapore experienced an outbreak of COVID-19 among MWs living in dormitories. As such, with a large population at risk of COVID-19 infection, who are also exposed to industrial agents that potentially cause methaemoglobinaemia, both pathologies may arise in a single patient. Clinicians should thus be wary of premature diagnostic closure in patients with COVID-19 and be cognisant of other causes of a low SpO₂.

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Conflicts of interest

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