Agency for Toxic Substances and Disease Registry 
Case Studies in Environmental Medicine (CSEM) 

Nitrate/Nitrite Toxicity
How Should Patients Exposed to Nitrates/Nitrites Be Treated and Managed?

Learning Objectives

Upon completion of this section, you will be able to

• describe two treatments for methemoglobinemia caused by nitrate/nitrite toxicity.

Introduction

General principles of supportive care, with attention to removal of the cause, will suffice for most identified cases of methemoglobinemia resulting from nitrates and nitrites. Not all patients require specific antidotal therapy.

For infants, well water used in preparing formula is a primary etiologic suspect. Patients with chronic congenital methemoglobinemia may have adapted to the chronic cyanosis, such that very high levels of methemoglobin are tolerated without any overt symptoms (40). Proper fluid, electrolyte, and pH balance is vital, especially in infant methemoglobinemia complicated or caused by serious illness (74).

Comatose patients may require intravenous naloxone and glucose. Activated charcoal may be used, especially for ingested substances known to cause methemoglobinemia (see Table 1) (75). Monitor clinical and laboratory parameters for evidence of escalating or rebound methemoglobinemia, worsening oxygen delivery, or possible concomitant hemolysis (48, 49).

Once methemoglobinemia is recognized and confirmed, a decision to treat must be made immediately. Patients who are symptomatic or have significant concurrent problems that compromise oxygen delivery (heart disease, lung disease, carbon monoxide poisoning, or anemia) may need antidotal treatment at methemoglobin levels as low 10%. Because methemoglobin levels are typically reported as a percentage of hemoglobin, symptoms may vary depending on the total hemoglobin level. As an easy to remember guideline, the treatment action level is often considered to be 20% methemoglobin in symptomatic patients and 30% in asymptomatic patients (49, 76).

Methylene Blue

Methylene blue is an effective antidote for most patients with methemoglobinemia. Methylene blue is provided as a 1% solution (10 mg/mL). The dose is 1 to 2 mg/kg (0.2 mL/kg of a 1% solution) infused intravenously over 3 to 5 minutes. The dose may be repeated at 1 mg/kg if methemoglobin does not resolve within 30 minutes. Methylene blue should reduce methemoglobin levels significantly in less than an hour. It does this by acting as a cofactor to increase the activity of NADPH-methemoglobin reductase. Infants with methemoglobinemia resulting from diarrhea and acidosis may improve with aggressive hydration and bicarbonate to correct the acidosis. However, methemoglobin levels greater than 20% should be treated with methylene blue (40).

A second dose of methylene blue will be required in only very severe cases or if there is evidence of ongoing methemoglobin formation (48). The total dose should not exceed 7 mg/kg because the drug by itself is an oxidating agent. Certain drugs, such as dapsone, create methemoglobin over a long biologic half-life. In these situations, some clinicians prefer continuous infusions of methylene blue titrated from a starting rate of 0.1 mg/kg/hour, rather than intermittent bolus therapy (77).

Methylene blue may discolor skin and mucous membranes, making visual interpretation of cyanosis inaccurate. It may also interfere further with pulse oximetry readings. After administration of methylene blue, it is prudent to reassess the patient’s clinical status and current methemoglobin levels before proceeding with repeat doses (49). Methylene blue is excreted primarily by the kidneys. Although side effects are uncommon, large rapidly administered doses have been associated with nausea, retrosternal chest pain, tachycardia, hypertension, and anxiety. Urine will subsequently develop a blue-green discoloration (78).

Because glucose is necessary for the effectiveness of methylene blue, normoglycemic patients should receive maintenance amounts of dextrose and hypoglycemic patients should receive standard dextrose therapy (40).

G6PD Deficiency

Known or suspected G6PD deficiency is a relative contraindication to the use of methylene blue (18, 40). G6PD is a key enzyme in the formation of NADPH. G6PD-deficient individuals generate insufficient NADPH to efficiently reduce methylene blue to leukomethylene blue, which is necessary for the activation of the NADPH-dependent methemoglobin reductase system. G6PD-deficient individuals are also prone to methylene blue-induced hemolysis. Methylene blue may also add to oxidative hemolysis. Young infants without G6PD deficiency have developed Heinz body hemolytic anemia at doses as low as 4 mg/kg (79, 80). Moreover, in the presence of hemolysis, high dose methylene blue can itself initiate methemoglobin formation (48, 81). Perinatal administration of higher doses of methylene blue (4 mg/kg), given amniotically, has been reported to induce hemolysis and methemoglobinemia in infants without G6PD deficiency (40).

Treatment Alternatives

For severe, life-threatening methemoglobinemia, when the patient responds poorly to methylene blue therapy or when the patient has G6PD deficiency, clinicians have tried various treatment alternatives. These treatment options include exchange transfusion and hyperbaric oxygen therapy (82, 83). During treatment in the hyperbaric chamber, sufficient oxygen can be dissolved directly in the blood to support life; reversible binding to hemoglobin is not required (84). Ascorbic acid and vitamin E (alpha-tocopherol) have been investigated, but do not seem promising as treatments for acute poisoning (48). Wright has demonstrated in vitro efficacy of N-actetylcysteine in reducing methemoglobinemia (84); however, this approach requires more study.

Be aware that many G6PD-deficient patients have only a partial enzyme deficiency. Methylene blue may still lower methemoglobin levels, and the resultant hemolysis may be mild. Therefore, methylene blue is still the first-line treatment in G6PD-deficient patients with life-threatening methemoglobin. Exchange transfusion is reserved only for patients in whom methylene blue treatment is ineffective. A lower starting dose of methylene blue (0.3 to 0.5 mg/kg) is recommended. The dose may be titrated upward to further reduce methemoglobin, if necessary. If the patient's condition worsens, methylene blue treatment should be stopped and exchange transfusion considered (40).

Key Points

• Many patients with methemoglobinemia require only supportive care.
• Methylene blue is an effective antidote for most patients with methemoglobinemia
• For severe methemoglobinemia, or when the patient responds poorly to methylene blue therapy, treatment options include exchange transfusion and hyperbaric oxygen therapy.

Progress Check