Clinical review

Methaemoglobinaemia associated with sodium nitrite in three siblings

Alan Finan, paediatric registrar,  Peter Keenan, consultant in accident and emergency,  Frances O' Donovan, consultant paediatric anaesthetist,  Philip Mayne, consultant paediatric chemical pathologist,  John Murphy, consultant paediatrician. 

Children's Hospital, Dublin 1

Correspondence to: Dr A Finan, Market Harborough, Leicestershire LE16 8EP af22{at}le.ac.uk

Oxidation of the iron in haemoglobin from the ferrous to the ferric state yields methaemoglobin, which does not carry oxygen and imparts a chocolate hue to the blood. The diagnosis should be suspected when a blood sample is brown coloured and does not redden on exposure to air. Blood concentrations of methaemoglobin do not normally exceed 2%. The aetiology of methaemoglobinaemia may be congenital due to deficiency in cytochrome b₅ reductase and to structural abnormalities in the haemoglobin molecule (haemoglobin M disorders) or be acquired as the result of drug treatment or the presence of toxinsmost commonly nitrites or nitrates. For example, methaemoglobinaemia is not uncommon in patients receiving inhaled nitric oxide.¹ Concentrations of methaemoglobin up to 20% are generally well tolerated, while values above 40% are associated with cardiorespiratory symptoms. Life threatening methaemoglobinaemia is rare and is usually the result of acute poisoning by drugs or toxins.²

We report life threatening methaemoglobinaemia associated with sodium nitrite in three previously healthy siblings, 4 year old twin boys (cases 1 and 2) and their sister aged 2 years (case 3).

	Case report

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The children had been well going to bed at 7.30 pm. At 8 pm the parents were alerted by a thud on the ceiling caused by a partly consumed bottle of milky tea belonging to one of the twins (case 1) falling off the bed on to the floor. The other twin (case 2) was a deep blue colour and was difficult to rouse, but the other two children (cases 1 and 3) appeared normal. An ambulance was summoned immediately, and all three children were brought to hospital with their parents.

On arrival in this accident and emergency department, the twin in case 2 was deeply cyanosed and was brought immediately to the resuscitation area; his twin brother and his sister (cases 1 and 3) seemed well and remained in the waiting area with their parents. Within 10 minutes, however, both required admission to the resuscitation area as they too developed the same deep cyanosis as their brother.

In the resuscitation area all three children were initially responsive to verbal commands, but they soon showed deteriorating levels of consciousness. All were profoundly cyanosed despite good respiratory effort, a clear airway, and good bilateral breath sounds on auscultation. Pulse oximetry showed oxygen saturations of 60% (case 2), 80% (case 1), and 50% (case 3) while all were breathing air with a fractional inspirational oxygen concentration of 1.0. Cases 2 and 3 were significantly worse than case 1, and both children required intubation for a deteriorating Glasgow coma scale, apnoea, and hypotension. Intubation and ventilation did not result in any improvement in their degree of cyanosis. Case 3 had one episode of pulseless electrical activity, which responded quickly to cardiopulmonary resuscitation and a single dose of intravenous adrenaline.

Toxin induced methaemoglobinaemia was diagnosed on the basis of three siblings presenting simultaneously with rapid onset profound cyanosis in the absence of any apparent airway or lung disease. Each child was treated with an intravenous bolus of methylene blue (2 mg/kg), and all three became pink within 15 minutes. They were well the following day with no evidence of neurological impairment.

The source of the toxin was identified after much probing: the children's father was a butcher by trade who used sodium nitrite as a meat curing agent. The pure white crystals of sodium nitrite are diluted in large volumes of water for the purposes of curing meat, but used undiluted these crystals are also an effective insecticide. It was for this purpose that the children's father had been using the sodium nitrite in the house. On the day of admission a small bag of the crystals had been left on the kitchen counter and one of the children had mistaken it for sugar and emptied it into the sugar bowl. That evening the children were put to bed with a bottle of milky tea, each sweetened with a spoonful of the sugar.

Blood samples were taken from all three children to measure methaemoglobin concentration during their resuscitation. These were 77% in case 2 and 38% in case 1; the sample for case 3 was mislaid. The three bottles of milky tea were retrieved and were analysed for concentrations of nitrite. The concentrations were 5100 mg/l (case 2), 4953 mg/l (case 1), and 4940 mg/l (case 3). The maximum admissible concentration of nitrite in drinking water is 0.1 mg/l in the European Union.³

	Discussion

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Sodium nitrite is ubiquitous and is used commercially as a colouring agent, as a food preservative, and to inhibit corrosion. Previous cases of methaemoglobinaemia associated with ingestion of sodium nitrite have been reported both in isolated and in multiple cases. Accidental poisoning usually results from ingestion of contaminated food and water. The most common source in the literature is water in pipes and tanks that has been contaminated with sodium nitrite in corrosion inhibitor solutions, and this has also caused localised outbreaks of methaemoglobinaemia. Most published cases have not been life threatening. ^{4 5} Cases as severe as the three presented are unusual. In one fatal case in a young boy the blood methaemoglobin concentration was 76%, less than that measured in case 2.⁶

Methylene blue (tetramethylthionine chloride) is primarily used to treat drug or toxin induced methaemoglobinaemia and methaemoglobinaemia due to deficiency in cytochrome b₅ reductase. It is not effective in methaemoglobinaemia due to structural abnormalities of haemoglobin. Cytochrome b₅ reductase is responsible for over 90% of methaemoglobin reduction under physiological conditions, with methaemoglobin reductase in red cells accounting for about 5%. Methylene blue acts as a coenzyme with methaemoglobin reductase to accelerate the reduction of methaemoglobin.² It may be administered orally or by intravenous injection. The intravenous route has a more rapid onset of action. The usual intravenous dose of methylene blue for adults and children is a 1% solution at doses of 1-2 mg/kg body weight over several minutes. A repeat dose may be given after one hour if required. Methylene blue is generally considered to be safe, but it may cause oxidation of haemoglobin to methaemoglobin in high doses, as well as haemolytic anaemia in patients with glucose 6-phosphate dehydrogenase deficiency. It is contraindicated in severe renal impairment. Methylene blue should be readily available in all anaesthetic departments as methaemoglobinaemia is a well described complication of some of the commonly used anaesthetic agents.⁷

The survival of these three children was the fortunate result of their early presentation to hospital. The least severely affected child (case 1) finished only half of his bottle before falling asleep and letting the bottle fall to the floor. Had this not happened the outcome could certainly have been tragic. The quick recovery of these three children depended on the immediate availability of methylene blue, as well as the prompt recognition of the condition and institution of treatment without waiting for blood results to establish the diagnosis.

	References

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1. Nakajima W, Ishida A, Arai H, Takada G. Methaemoglobinaemia after inhalation of nitric oxide in infant with pulmonary hypertension. Lancet 1997; 350: 1002-1003[Medline].
2. Mansouri A. Review: methaemoglobinemia. Am J Med Sci 1985; 289: 200-209[Medline].
3. European Economic Community. Drinking water regulations. Brussels: EEC, 1988:S.I.81.
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5. Askew GL, Finelli L, Genese CA. Boilerbaisse: an outbreak of methaemoglobinemia in New Jersey in 1992. Pediatrics 1994; 94: 381-384[Abstract/Free Full Text].
6. Saito T, Takeichi S, Yukawa N. Fatal methaemoglobinemia caused by liniment solutions containing sodium nitrite. J Forensic Sci 1996; 41: 169-171[Medline].
7. Kreutz RW, Kinni ME. Life threatening toxic methaemoglobinaemia induced by prilocaine. Oral Surg 1983; 56: 480-483.