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Nitrate/Nitrite Toxicity
Initial Check

Course: WB 2342
CE Original Date: December 5, 2013
CE Expiration Date: December 5, 2015
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Instructions

This Initial Check will help you assess your current knowledge about nitrate/nitrite toxicity. To take the initial check, read the case below, and then answer the questions that follow.

Case Study

A 2 month old infant has vomiting, diarrhea, tachypnea, and cyanosis.

A two-month-old female infant is brought to your clinic in a rural area for a routine well-baby checkup. According to the child's chart, she was delivered 2 weeks early because of maternal pre-eclampsia. There was no neonatal distress; her birth weight was 7 pounds and 2 ounces.

Today, the mother states that she has noticed an intermittent bluish discoloration of the baby's:

  • Lips,
  • Tip of the nose, and
  • Ears.

Physical examination of the infant is negative for cardiac murmurs and abnormalities on lung auscultation. You note a below average weight gain. Feedings consist of 4 ounces of diluted formula every 2 hours. The infant has occasional loose stools. You instruct the parents to increase caloric feedings, which should include vitamin and mineral supplements. You tell the parents to call you immediately if any further episodes of the bluish discoloration occur.

Approximately 3 weeks later, the baby's frantic parents call your office; the infant is crying incessantly and has vomiting and profuse diarrhea.

Vital Signs

When the baby is brought to your clinic a few minutes later, she is afebrile but has tachypnea, central cyanosis, and drowsiness. You note her vital signs as

  • Blood pressure (BP) = 78/30 millimeter (mm) mercury (Hg) (normal 50th percentile for her age is 80/46 mm Hg)
  • Heart rate = 160 beats/minute (normal range for 0-3 months = 100-150 beats/minute)
  • Respiration = 60 breaths/minute (normal range for 0-3 months = 35-55 breaths/minute)

Additional Information

An ambulance is summoned and 100% oxygen is administered by face mask. No improvement in the cyanosis is noted on her arrival at the hospital emergency department.

Emergency Treatment

The examining emergency physician now notes a grade II/VI systolic murmur and central cyanosis, which has not improved despite administration of 100% oxygen for nearly 1 hour. The infant shows no evidence of

  • Cardiac failure,
  • Atelectasis,
  • Pneumonitis, or
  • Pneumothorax.

Therapy with methylene blue is started, which results in a dramatic resolution of the cyanosis. The infant is discharged on the second hospital day with no evidence of central nervous system hypoxic damage.

Initial Check

  1. Considering the differential diagnosis for cyanosis, what is the most likely cause of this infant's cyanosis?
  2. What laboratory tests, either obtained during the hospitalization or ordered subsequently, would help confirm the diagnosis?
  3. What steps, if any, can be taken to prevent a recurrence of cyanosis and distress in this infant?
  4. What questions will you ask the parents of the infant to help determine the cause of the cyanosis?
  5. If well water used to dilute formula is implicated in the cyanosis, what are some possible causes of its nitrate contamination?
  6. What recommendations can you make to the infant's family to prevent further cyanotic episodes?
  7. What factors make infants younger than 4 months of age more susceptible to developing methemoglobinemia when exposed to nitrates?
  8. Why might some patients with methemoglobinemia not respond to treatment with methylene blue?
  9. What options are available to treat significant methemoglobinemia in a patient who has glucose 6-phosphate dehydrogenase (G6PD) deficiency?

Initial Check Answers

  1. The differential diagnosis for cyanosis in an infant includes (by mechanism)
    • Alveolar Hypoventilation
      • CNS depression (i.e., asphyxia, seizure, meningitis, encephalitis, intraventricular hemorrhage, drug induced)
      • Airway obstruction (i.e., choanal atresia, laryngomalacia)
      • Neuromuscular disease (i.e., phrenic nerve injury, myasthenia gravis)
    • Decreased oxygen carrying capacity of blood (less oxygen available at tissue level)
      • Methemoglobinemia (acquired or congenital
    • Decreased peripheral circulation (peripheral cyanosis)
      • Sepsis
      • Shock (any cause)
      • Polycythemia
      • Hypothermia
      • Hypoglycemia
      • Low cardiac output (i.e. hypocalcemia, cardiomyopathies)
    • Impaired Oxygen Diffusion
      • Pulmonary edema (i.e. left sided obstructive cardiac disease as seen with aortic stenosis, cardiomyopathy)
      • Pulmonary fibrosis
    • Right-to-left shunt
      • Cardiac anomalies (i.e. tetralogy of fallot, transposition of the great arteries, truncus arteriosus, total anomalous pulmonary venous return, tricuspid atresia, pulmonary atresia, hypoplastic left heart)
      • Persistent pulmonary hypertension of the newborn
      • Pulmonary anomalies (i.e., pulmonary arteriovenous malformation)
    • Ventilation/perfusion mismatch
      • Airway disease (i.e. transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), pneumonia, aspiration, atelectasis, diaphragmatic hernia, pulmonary hypoplasia, pulmonary hemorrhage)
      • Extrinsic compression of the lungs (i.e., pneumothorax, pleural effusion, hemothorax)

    In an infant with no known cardiopulmonary disease, cyanosis that is unresponsive to oxygen therapy is most likely due to methemoglobinemia.

    Methemoglobinemia is a condition of excess oxidized "ferric" hemoglobin where the reducing systems to return hemoglobin to a ferrous state are overwhelmed, impaired, or lacking. Causes of methemoglobinemia can be generally grouped into three categories: endogenous (i.e., related to diarrhea, systemic acidosis, infection); exogenous (i.e. medication or toxin-induced); and genetic (i.e., related to methemoglobin reductase enzyme system deficiency or structural variant of hemoglobin (HbM)).

    A high index of suspicion is the key to proper and timely diagnosis. Note that methemoglobinemia can also occur with subtle or no symptoms depending on the methemoglobin level.

    Other forms of abnormal hemoglobin (dyshemoglobin) that also have an impaired ability to transport oxygen and carbon dioxide include carboxyhemoglobin and sulfhemoglobin. Therefore, carboxyhemoglobinemia and sulfhemoglobinemia should also be considered in the differential diagnosis.

    More detailed information regarding this answer including further discussion of differential diagnosis and clinical work up can be found in the "What Are Health Effects from Exposure to Nitrate and Nitrites?" and "How Should Patients Potentially Overexposed to Nitrates and Nitrites Be Evaluated (Clinical Assessment)?" sections.

  2. Laboratory tests useful for screening a patient with suspected methemoglobinemia include
    • Examination of blood color with bedside "filter paper" (chocolate brown color of blood remains unchanged with exposure to oxygen)
    • Arterial blood gases (ABGs) with co-oximetry (to determine MetHb level, oxygen saturation, presence of other dyshemoglobins, etc.)
    • Complete blood counts (CBC) with peripheral blood smear (can be used to identify and characterize anemias, differentiate hemoglobinopathies from thalassemias, etc.)
    • Serum-free hemoglobin (can be used to detect hemolytic anemias)
    • Serum haptoglobin (can be used to detect hemolytic anemias; i.e. decreased haptoglobin, RBC count, hemoglobin and hematocrit with increased reticulocyte count are supportive of a hemolytic anemia diagnosis)

    More detailed information regarding this answer including further discussion of differential diagnoses and clinical work up can be found in the "How Should Patients Potentially Overexposed to Nitrates and Nitrites Be Evaluated (Clinical Assessment)?" section.

  3. The initial step in preventing a recurrence of the infant's cyanosis and distress is to identify the cause of the cyanosis. The next step is to correct or eliminate the cause.

    If the infant's cyanosis is due to an acquired methemoglobinemia, the agent must be identified and removed from the infant's environment. For example, there have been cases of infantile acquired methemoglobinemia through ingestion of baby formula prepared using nitrate contaminated well water. Ingestion of nitrate containing water is a common cause of methemoglobinemia in infants, especially those living in rural areas. EPA suggests maintenance testing of private well water annually (to include nitrates, coliform bacteria, total dissolved solids and pH). Resources and information regarding private well testing including any additional testing applicable to local/area conditions are typically available from local and state health departments. If contaminated well water is suspected, an alternate water source should be used until testing results are available.

    If the cyanosis is due to a congenital methemoglobinemia, it could be from inheritance of HbM (can be detected by hemoglobin electrophoresis) or from inherited methemoglobin reduction system defects (such as NADH- dependent methemoglobin reductase deficiency which can be detected by enzyme analysis).

    More detailed information regarding this answer can be found in the "Who Is at Risk of Adverse Health Effects from Overexposure to Nitrates and Nitrites?", "What Are the Health Effects from Exposure to Nitrates and Nitrites" and "How Should Patients Potentially Overexposed to Nitrates and Nitrites Be Evaluated (Clinical Assessment)?" sections.

  4. Questions that may help determine the cause of the infant's cyanosis include
    • Where is the home located?
    • What activities have been occurring around the home?
    • What type of sewer system connects to the home?
    • What are family members' occupations, avocations, and hobbies?
    • What is the source of the family's drinking water and how is it supplied?
    • What is used for home heating and cooking? (i.e., central heating [gas/electric], fireplace [wood burning/gas], portable heater [gas/ electric], stove [wood burning/gas/electric and if properly vented], use of emergency generators).

    Information to gather from families with infants includes

    • The type of formula, feeding regimen, and source of dilution water;
    • The infant's history of recent gastroenteritis; and
    • Family history, including recent use of all medications by both infant and mother.

    For information on taking a complete exposure history including questions to ask adults and children, see ATSDR Case Studies in Environmental Medicine: Taking an Exposure History http://www.atsdr.cdc.gov/csem/csem.asp?csem=17&po=0

    and

    ATSDR Case Studies in Environmental Medicine: Taking a Pediatric Exposure History http://www.atsdr.cdc.gov/csem/csem.asp?csem=26&po=0

    More detailed information regarding this answer can be found in the "How Should Patients Potentially Overexposed to Nitrates or Nitrites Be Evaluated (Clinical Assessment)?" section.

  5. Causes of high nitrate concentrations in well water include runoff from the use of nitrogen containing agricultural fertilizers (including anhydrous ammonia) and seepage of organic nitrogen-containing material from animal wastes or septic sewer systems.

    More detailed information regarding this answer can be found in the "Where Are Nitrates and Nitrites Found?" section.

  6. The well water should be tested for nitrate concentration, the presence of coliform bacteria, total dissolved solids and pH (this is what EPA recommends for annual private well water testing). The family can contact the local or state health department to perform or suggest contractors that can run these and any other tests applicable to local/area conditions. It is most important to identify the source of the methemoglobin-inducing agent and to preclude any further exposure. If nitrate-contaminated well water is the source, you should recommend using an alternative water source other than the contaminated well to dilute infant formula.

    More detailed information regarding this answer and private well water testing/maintenance can be found in the "Who Is at Risk of Adverse Health Effects from Overexposure to Nitrates and Nitrites?" and "What Instructions Should Be Given to Patients to Prevent Overexposure to Nitrates and Nitrites?" sections.

  7. Infants younger than 4 months of age are more susceptible to developing methemoglobinemia for a number of reasons including:

    • HbF
      • A large proportion of hemoglobin in young infants is in the form of fetal hemoglobin. Fetal hemoglobin (HbF) is more readily oxidized to MetHb by nitrites than is adult hemoglobin.
    • Impaired reduction of MetHb:
      • At birth, NADH-dependent methemoglobin reductase (also called cytochrome-b5 reductase), the enzyme responsible for reduction of induced methemoglobin back to normal hemoglobin, has only about half the activity it has in adults.
    • Infant gut pH
      • Infant gut pH is normally higher than in older children and adults. The higher gastric pH enhances bacterial growth in the infant intestinal tract involved in conversion of ingested nitrate to the more potent nitrite (which acts as a potent oxidizing agent).
    • Other factors
      • Gastroenteritis can increase in vivo transformation of nitrate to nitrite and systemic absorption of nitrite from the large intestine.
      • Young infants can develop methemoglobinemia with systemic metabolic acidosis. The systemic metabolic acidosis is often caused by dehydration associated with diarrhea or sepsis, but it can occur with renal disorders as well.

    More detailed information regarding this answer can be found in the "Who Is at Risk of Adverse Side Effects from Overexposure to Nitrates and Nitrites?", "What Is the Biologic Fate of Nitrates and Nitrites in the Body?" and "What Are the Health Effects from Exposure to Nitrates and Nitrites?" sections.

  8. The most common cause of a poor response to methylene blue treatment is unrecognized G6PD deficiency.

    More detailed information regarding this answer can be found in the "How Should Patients Potentially Overexposed to Nitrates and Nitrites Be Treated and Managed?" section.

  9. Treatment options for patients with G6PD deficiency might include exchange transfusion and/or hyperbaric oxygen therapy.

    More detailed information regarding this answer can be found in the "How Should Patients Potentially Overexposed to Nitrates and Nitrites Be Treated and Managed?" section.

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