A two-month-old female infant presents to your rural clinic for her well child check. She was a normal vaginal delivery; birth weight was 7 pounds, 9 ounces. The childís mother states she has noticed an intermittent bluish discoloration of her daughterís lips, tip of the nose, and ears. Physical exam today is negative for both cardiac murmurs and breathing abnormalities upon auscultation. Weight has been around the 25th percentile, however today the infantís weight is in the 15th percentile. Feedings have consisted of four ounces of diluted formula every two hours. The infant has occasional loose stools. Mother reports that the infant tolerates the formula well and denies any formula changes. Parents do not smoke. Mother does not work outside the home and father works as a farmer. There are no siblings and parents are not experiencing any illnesses or similar symptoms at the present time.
You instruct the parents to increase caloric feedings with vitamin and mineral supplements and to call immediately if any further episodes of the bluish discoloration are observed.
Three weeks later, the infantís parents call your office. They state the infant is crying incessantly and has vomiting and profuse diarrhea. When the infant presents to your clinic a few minutes later, she is afebrile, but has tachypnea, cyanosis, and drowsiness. Her blood pressure is 78/30 mm Hg (normal 50th percentile for her age is 80/46 mm Hg), pulse is 140/min at awake/rest (normal for her age is 80-150 awake/rest), and respiration rate is 40/min (normal for her age is 30/min). An ambulance is summoned and 100% oxygen by face mask is administered; however, no improvement in the cyanosis is noted on her arrival at the hospitalís emergency room.
The examining emergency physician notes a grade II/VI systolic murmur and central cyanosis. There is no evidence of cardiac failure, atelectasis, pneumonitis, or pneumothorax. Oxygen is administered at 100%, however, after one hour of oxygen therapy the cyanosis continues. The emergency physician consults a medical toxicologist through the poison control center, who suspects nitrate/nitrite poisoning. The infantís methemoglobin level is 35% (normal, physiologic methemoglobin is 1-2% as a result of exposure to oxidizing substances and diet). The emergency physician confirms with you that this infant does not have a history of glucose-6-phosphate dehydrogenase deficiency and thus IV methylene blue therapy is started at 2mg/kg over 5 to 10 minutes in a 1% saline solution. IV therapy results in a dramatic resolution of the cyanosis. On follow up consultation with the infantís parents it is determined that the likely source of nitrates is their private well on their farm. The parents agree to immediate well water testing for nitrates and coliform bacteria and to using bottled water for drinking water/reconstituting formula. The infant is discharged on the 2nd hospital day with no evidence of central nervous system hypoxic damage.
What is the most likely cause of this infantís cyanosis?
In an infant, cyanosis that is unresponsive to oxygen therapy is most likely due to methemoglobinemia. Methemoglobin cannot reversibly bind or transport circulating oxygen. Clinical laboratory tests that will help confirm the diagnosis of methemoglobinemia are blood color and arterial blood gases. When a drop of methemoglobin-containing blood is placed on filter paper, it dries a deep chocolate brown or slate-gray color. Analysis of arterial blood gases will reveal normal PO2 levels despite the presence of methemoglobin. The definitive test for methemoglobinemia is the measured proportion of methemoglobin to hemoglobin.
The most common cause of methemoglobinemia in children is ingestion of water contaminated with nitrates from agricultural fertilizers, barnyard runoff, or septic system wastewater and sludge. Nitrate is the second most frequently cited ground water contaminant (Environmental Protection Agency (EPA), Office of Water, Report to Congress 1996/1998). Drinking water is the main source of nitrate in infants, although vegetables (spinach, carrots, celery, and cabbage) are the main dietary source of nitrate in adults and older children. Children younger than 4 months should not be fed vegetables high in nitrates. There is little or no evidence relating to the exposure of infants to nitrates via breastfeeding. Transplacental transfer of nitrates is also unclear.
Are infants more susceptible to methemoglobinemia than older children and adults?
Yes! Infants less than 4 months of age are more susceptible to developing methemoglobinemia because the pH of the gut is normally higher than in older children and adults, which enhances the conversion of ingested nitrate to the more potent nitrite. The bacterial flora in the gut of an infant 4 months old or younger is also different from that found in older children and adults and may be more likely to convert ingested nitrate to nitrite. Gastroenteritis can increase both the in vivo transformation of nitrate to nitrite and the systemic absorption of nitrite from the large intestine. Thus, testing water sources for coliform bacteria is also beneficial when nitrate/nitrite poisoning is suspected.
What steps, if any, can be taken to prevent a recurrence of cyanosis and distress in this infant?
The initial step in preventing a recurrence of the infantís cyanosis and distress is to identify the cause of the infantís cyanosis; the next step is to correct or eliminate the cause. If the infant is suffering from methemoglobinemia, the agent must be identified and removed from the infantís environment.
If it is determined that the well water was contaminated with nitrates, can the parents boil the water before mixing it with the formula?
Boiling the water tends to increase nitrate concentrations. However, boiling water for 1 minute is sufficient to kill microorganisms such as Cryptosporidium without over-concentrating nitrates. Alternative sources of water include bottled water that is free of nitrates and monitored water supplies, or drilling new and deeper wells protected from agricultural runoff and animal waste runoff.
The Lincoln Water System supplies water to the city of Lincoln and monitors and regulates the amount of nitrates/nitrites and coliform bacteria in Lincolnís water supply. All public water supplies must meet maximum contaminant levels (MCL) determined by the EPA or they cannot supply water to consumers. The Lincoln Water System provides reports to the public regarding the safety and quality of the drinking water it monitors and regulates. The reports are available on the Internet at: http://www.lincoln.ne.gov/city/pworks/water/faq.htm. The levels of nitrate/nitrite in the Lincoln Water System have always been below the EPA's MCL for nitrate/nitrite. Nitrate/nitrite levels below the EPAís MCL have not been known to cause methemoglobinemia.
What are other causes of methemoglobinemia in children and what questions can I ask to help determine the cause?
Causes of methemoglobinemia, other than nitrate contamination of well water, discussed in this case study, include exposure to; other organic/inorganic nitrate/nitrites, copper sulfate, chlorates, and nitrogen oxides. Possible sources of these substances include silver nitrate burn cream (nitrate), inhalants (amyl/sodium nitrite), room deodorizers (butyl/isobutyl nitrite), pharmaceuticals (nitroglycerin), laundry ink (aniline), industrial solvents (nitrobenzene), local anesthetics (benzocaine, lidocaine), antibiotics (sulfonamides), mothballs (naphthalene), and antimalarials (chloroquine, primaquine).
Questions that may help define the cause of the methemoglobinemia include dwelling location; surrounding activities; type of sewer system; occupations, and hobbies of family members; drinking water source and supply; construction of the well, in infants, feeding regimen, and source of dilution water; family history, including recent use of all medications by both infant and mother; and in infants, a history of gastroenteritis.
What recommendations can you make to prevent further cyanotic episodes?
Well water should be tested for nitrate concentration and presence of coliform bacteria. It is important to identify the source of the methemoglobin-inducing agent and to prevent any further exposures. If nitrate-contaminated well water is the source, consumption from the source should cease immediately, and bottled water or other uncontaminated water should be used to dilute formula. Transdermal absorption of toxins (including nitrates) is higher in infants and young children as compared to adults, so bathing or washing in contaminated water should be avoided as well. Frequent testing of the well for nitrate concentration and bacterial contamination, or drilling a new and deeper well, taking into consideration the proximity of septic sewer systems, location of animal wastes, and proximity to agricultural land that may be regularly treated with nitrogen-based fertilizers.
Agency for Toxic Substances and Disease Registry. (1992). Case studies in environmental medicine: Nitrate/Nitrite Toxicity. As seen in Environmental Medicine. Pope, A. & Rall, D. (Eds.). Washington, DC: National Academy Press.
American Academy of Pediatrics. (1999). Handbook of Pediatric Environmental Health, (Etzel, Balk, Eds.).
Children's Environmental Health