Case 1: A blue infant with chocolate-coloured blood

A six-week-old male infant presented with a two-day history of abdominal distension and diarrhea. He was born at term without complications. His birth weight was 2.72 kg. At four weeks, he weighed 3.4 kg and his weight remained unchanged at six weeks (less than the fifth percentile). No cyanosis was noted at birth. He had been on soy formula one week before presentation for a presumed milk protein allergy presenting as specks of blood in the stool.

A review of systems was positive for increased fussiness, fever and vomiting. There was no history of exposure to drugs or toxins.

His physical examination on admission showed a weight of 3.4 kg and a head circumference of 36.5 cm (greater than the 25th percentile). The infant was cyanotic with normal vital signs and no acute distress. The oxygen saturation was 94% on room air. The infant’s abdomen was soft and distended, and his bowel sounds were of normal pitch. Capillary refill was 3 s and there was decreased skin turgor. The rest of the examination was unremarkable.

The infant was admitted with a diagnosis of failure to thrive and dehydration. He was given a fluid bolus and was put on a hydration protocol. Laboratory investigations revealed a white blood cell count of 14.2×10⁹/L (normal 4×10⁹/L to 19.5×10⁹/L), a hemoglobin level of 83 g/L (normal 107 g/L to 161 g/L) and a platelet count of 730×10⁹/L (normal 180×10⁹/L to 327×10⁹/L). There were 46% neutrophils (normal 35% to 45%), 7% bands (normal 5% to 9%) and 33% lymphocytes (normal 40% to 70%). Electrolytes were normal, with a bicarbonate level of 12 mmol/L (normal 16 mmol/L to 24 mmol/L). Blood urea nitrogen and creatinine levels were normal. Blood drawn was chocolate brown in colour. Results of additional blood tests confirmed the diagnosis.

CASE 1 DIAGNOSIS: METHEMOGLOBINEMIA

A capillary blood gas analysis revealed a pH of 7.09 (normal 7.35 to 7.45) and methemoglobin of 30.9% (normal 0% to 1%). The infant was given a dose of methylene blue (1 mg/kg), which resulted in a decrease in the level of methemoglobin to 2.5% and an increase in the pH to 7.32. Clinically, his perfusion also improved. He was tested for hemoglobin M by electrophoresis and NADH-cytochrome b5 reductase deficiency, both of which were negative.

The infant was initially started on a protein hydrolysate formula, which resulted in another increase in the methemoglobin level to 12% as well as a recurrence of diarrhea. The formula was then changed to an amino acid-based formula; the result was an improvement of the methemoglobinemia and diarrhea. When the patient was discharged home, he was asymptomatic, gaining weight and had a normal methemoglobin level.

Methemoglobin is formed when the iron in hemoglobin is oxidized from the ferrous (Fe²⁺) to the ferric (Fe³⁺) state. Methemoglobin is ineffective as an oxygen carrier and, thus, causes varying degrees of cyanosis (1).

Methemoglobinemia is caused by toxin-induced exposures, acidosis, well water nitrates, dietary factors and genetic enzyme deficiencies. Methemoglobin in children six months of age or older usually results from ingestion or skin exposure to oxidizing agents, including aniline dyes, ink and smoke inhalation. Methemoglobinemia in young infants (younger than six months of age) is usually caused by severe metabolic acidosis from diarrhea and dehydration. Such infants are predisposed to methemoglobinemia because they have quantitatively lower red blood cell levels of cytochrome b5 reductase (50% of adult levels); have a higher intestinal pH, which promotes growth of Gram-negative organisms that convert nitrates to nitrites; and have fetal hemoglobin, which is more easily oxidized. Transient methemoglobinemia with acidosis has also been reported in infants with or without diarrhea as a complication of milk protein and soy intolerance (2).

Small infants with methemoglobinemia may present with dyspnea, diarrhea and cyanosis that fails to respond to supplemental oxygen. In small infants, cyanosis may be associated with congenital or acquired pulmonary abnormalities, congenital heart defects and hemoglobinopathies. When cyanosis is associated with diarrhea, methemoglobinemia should be considered in the differential diagnosis (3). Blood has a characteristic chocolate brown colour. Dyspnea, nausea and tachycardia may be seen at methemoglobin levels of 30% or higher. Lethargy and decreasing levels of consciousness occur as levels approach 55%. Circulatory failure and death occur at levels of approximately 70% (1).

Although it has been suggested that methemoglobinemia associated with milk or soy protein allergy may be successfully treated with either a hydrolysate formula or amino acid-based formula, in a subset of patients, a hydrolysate formula may result in recurrence of methemoglobinemia and should be avoided (4). The protective effect of human milk against diarrhea is well known. In view of the absence of methemoglobinemia in breastfed infants, the list of protective properties of milk may also include protection against methemoglobinemia.

Once the diagnosis is confirmed, severe cases can be treated with 1 mg/kg to 2 mg/kg of methylene blue administered intravenously (1). Others may be managed with hydration alone. Patients may develop recurrences even in the absence of any congenital abnormality. In these cases, the administration of methylene blue can be repeated.

CLINICAL PEARLS

• Methemoglobinemia should be considered when an infant presents with diarrhea and cyanosis. The characteristic colour of the blood suggests the diagnosis.

• A detailed history should be obtained so that if a cause is identified, it can be removed.

• Severe methemoglobinemia is a medical emergency that requires prompt recognition and appropriate treatment.