A Child with Diarrhea and Cyanosis

6-week-old old full term, NSVD female brought to the ED by her mother for worsening diarrhea and lethargy.  Mom denies use of new medications or OTC meds but reports that she recently had several days of worsening diarrhea.  Denies fevers, cough, and other systemic symptoms.  The baby’s initial vital signs were as follows: BP 86/42, HR 110, RR 38, O2 sat 85% on RA.  Patient was placed on non rebreather with no improvement in her oxygen saturation.  A diagnostic test was performed to confirm the diagnosis of...

  • What do you think is going on?
  • What is the diagnostic test to order?
  • What is the treatment?
  • What is the likely cause of this toxicologic condition?

The child had a blood gas performed and her co-oximetry revealed a methemoglobin (MetHgb) level of 52%.  MetHgb occurs when the iron atom in hemoglobin loses one electron to an oxidant, and the ferrous (Fe2+) state of iron is transformed into the ferric (Fe3+) state.  Under normal circumstances, MetHgb is reduced to functional hemoglobin by NADH cytochrome-b5 reductase (major pathway) and NADPH methemoglobin reductase (minor pathway) to maintain MetHgb at levels less than 1% in healthy individuals.  This is important since hemoglobin only transports oxygen in the reduced ferrous state and when oxidized, this abnormal hemoglobin is unable to carry oxygen causing a functional anemia.  Further hypoxia occurs since ferric heme groups impair the release of oxygen from nearby ferrous heme groups on the same hemoglobin tetramer and causing a shift of the oxygen-dissociation curve to the left.  There are two kinds of MetHgb - congenital and acquired.  Congenital methemoglobinemia is characterized by diminished enzymatic reduction of MetHgb back to functional hemoglobin.  Affected patients appear cyanotic but are generally asymptomatic.  Acquired methemoglobinemia typically results from an exposure to a specific drug or agents that cause an increase in the production of MetHgb.  The most commonly reported toxicologic causes of methemoglobinemia are topical local anesthestics.  Dapsone is most reported drug to cause MetHgb.  In rural areas, well water may contain high levels of nitrates from fertilizer runoff and can cause methemoglobinemia especially in young infants.

Infants less than 3 months of age are particularly susceptible to methemoglobinemia for several reasons: they have lower amounts and activity of NADH-cytochrome b5 reductase, their lower gastric pH results in the proliferation of intestinal flora that reduces ingested nitrates to nitrites, and fetal hemoglobin is more easily oxidized to methemoglobin than adult hemoglobin.

Although typically not life-threatening, methemoglobinemia may produce symptoms of cellular hypoxia and lead to death if not treated properly.  The diagnosis should be considered in the differential diagnosis in any cyanotic patient.  Cyanosis can occur when just 10% of methemoglobin is present (1.5 g/dL with baseline hemoglobin of 15 g/dL).  Concurrent diseases such as anemia, congestive heart failure, chronic lung disease, and pneumonia may greatly increase the clinical effects of methemoglobinemia with clinical signs of hypoxia occurring at even lower methemoglobin blood levels.

A clue that a patient has methemoglobinemia is an abnormal pulse oximetry reading within a very narrow range, with oxygen saturation values typically in the mid 80’s.  The reason for the low saturation is that traditional pulse oximeters function by transilluminating tissue at two wavelengths of light with oxyhemoglobin absorbing strongly at the spectrophotometer at 940 nm, whereas deoxyhemoglobin absorbs at 660 nm.  Methemoglobin absorbs strongly at both 660 and 940 nm and therefore the ratio of light absorbance at the two wavelengths become unified, and as the methemoglobin level reaches and exceeds approximately 30-35%, the derived value on traditional pulse oximetery reads at approximately 85%.  Other clues include a normal measured PaO2 and a characteristic chocolate brown appearance to their blood because MetHgb does not brighten in color after exposure to air. 

Methylene blue is a highly effective antidote for treating acquired methemoglobinemia.  Methylene blue therapy is indicated if levels exceed 25% or if the patient has clinical signs of hypoxia.  In neonates, the dose is 0.3-1 mg/kg as a 1% solution slow IV over 3-5 minutes and beneficial effects usually occur within 30 minutes; typically the dose does not need to be repeated.  Methylene blue is an oxidizing agent, which, in the presence of NADPH methemoglobin reductase, is reduced to leukomethylene blue.  Leukomethylene blue then becomes available to reduce methemoglobin to hemoglobin.  In the presence of methylene blue, the role of the NADPH pathway is dramatically increased and becomes the most efficient means of methemoglobin reduction.  Because of its oxidizing properties, methylene blue is contraindicated in diseases such as G6PD deficiency where oxidizing agents can be lethal.  Methylene blue is a dye and will also alter pulse oximetry readings secondary to the interference with light absorption, further decreasing the pulse oximetry readings.  To avoid frightening parents and patients, it is important to inform treatment may impart a bluish-green discoloration to the urine.

In this patient the likely cause of the methemoglobinemia was likely oxidative stress from gastroenteritis leading to increased nitrite production in the gut.  Campylobacter and rotavirus have been reported agents.  The child is undergoing testing to determine if she has NADH methemoglobin reductase deficiency.  She improved with methylene blue and her MetHgb went down to 3.5%.