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NITRATES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nitrates arise from a number of environmental and industrial sources which include fertilizers (see POISINDEX management "Fertilizers"), nitrogen concentrating plants, contaminated well water, and various organic nitrate drugs. As medications, nitrates are used to produce vasodilation and induce methemoglobinemia.
    B) HUMANS - Nitrates may be converted to nitrites in the oral cavity, and under certain conditions, in the stomach. When a high nitrate load is given, nitrates are recycled through the oral cavity and some are converted to nitrites. Refer to the NITRITES management for further information.
    C) RUMINANTS - Ruminants will convert nitrates to nitrites via ruminal microorganisms.

Specific Substances

    A) Plant Sources
    1) Amaranthus species (Pigweed)
    2) Avena sativa (Oat foliage)
    3) Brassica species (Rape)
    4) Bromus species (Brome or Fescue grass)
    5) Chenopodium (Lamb's quarters)
    6) Datura species
    7) Helianthus species (Sunflowers)
    8) Hordeum vulgare (Barley, foliage only)
    9) Kochia species (Fireweed)
    10) Melilotus species (Sweet Clover)
    11) Panicum species (Witchgrass)
    12) Rumex species (Dock)
    13) Solanum species (Nightshades)
    14) Solidago species (Goldenrod)
    15) Sorghum species (Johnson grass)
    16) Sudan grasses
    17) Thistles
    18) Triticum aestivum (Wheat)
    19) Zea mays (Corn, foliage)
    20) References: Howard, 1986; Kingsbury, 1964
    Organic Nitrates
    1) Sodium nitrate (CAS 7631-99-4)
    2) Ammonium nitrate (6484-52-2)
    3) PENTYL NITRATE
    4) NITRATE, INORGANIC, N.O.S
    5) AMMONIUM(I) NITRATE (1:1)
    6) AMMONIUM SALTPETER
    7) NORWAY SALTPETER
    8) AN (AMMONIUM NITRATE)
    9) NITRATE D'AMMONIUM
    10) NITRIC ACID, AMMONIUM SALT
    11) NITRATES, INORGANIC, AQUEOUS SOLUTION, N.O.S
    12) NITRATE OF AMMONIA
    13) NITRATE
    14) AMMONIUMNITRAT
    15) GERMAN SALTPETER

Available Forms Sources

    A) FORMS
    1) AMMONIUM NITRATE - Ammonium nitrate is available in cold packs, which contain 50 to 234 grams per pack (Challoner & McCarron, 1988).
    B) SOURCES
    1) NITRATES - Building, printing, and chemical industries are sources of nitrates in China. Seventy-two of 80 nitrate-poisoned patients in one series were building workers (Gao & Guo, 1990).
    2) FOOD - Stored food grown in areas containing high nitrate levels may contain nitrates.
    a) Foods that are high in nitrates include beets, spinach, carrots, and cured meats such as sausage (Benowitz, 1982).
    3) CROPS - Crops may include any of the following:
    1) Amaranthus (Pigweed)
    2) Chenopodium (Lamb's quarters)
    3) Barley (Foliage only)
    4) Corn (Foliage only)
    5) Oats (Foliage only)
    6) Sudan grasses
    7) Thistles
    4) WATER - Water may become contaminated with nitrates from fertilizers or natural causes (Buenger & Mauro, 1989).
    5) Organic Nitrate Drugs:
    1) Isosorbide Dinitrate
    2) Nitroglycerin
    3) Sodium nitroprusside
    6) HUMANS - Nitrates may be converted to nitrites in the oral cavity, and under certain conditions, in the stomach (Mirvish, 1983). When a high nitrate load is given, nitrates are recycled through the oral cavity and some are converted to nitrites (Hart & Walter, 1983; Spiegelhalder et al, 1976).
    7) RUMINANTS - Ruminants will convert nitrates to nitrites via ruminal microorganisms (Burrows, 1990).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Nitrates occur naturally in many plants and are used as fertilizer. Ammonium nitrate is used in instant cooling packets. Well water may become contaminated with nitrates from fertilizers or natural causes. Nitrate-based medications are used as vasodilators (including isosorbide, nitroprusside and nitroglycerin) and are covered in separate managements.
    B) PHARMACOLOGY: Nitrates cause vasodilation by being converted to nitrites and eventually to nitric oxide.
    C) TOXICOLOGY: The toxicity of nitrates is due to in vivo conversion to nitrites. Excessive vasodilation may cause hypotension and hypoperfusion. Nitrates are potent oxidizers and can produce methemoglobinemia and hemolysis.
    D) EPIDEMIOLOGY: Nitrate exposures are uncommon. Severe effects are rare except in cases where large exposures to fertilizers produces high methemoglobin concentrations.
    E) MILD TO MODERATE TOXICITY: Overdose generally causes orthostatic hypotension and reflex tachycardia. Headache, nausea, and vomiting are also fairly common. Syncope, dizziness or lightheadedness, diaphoresis, and flushed skin may develop. Mild methemoglobinemia generally does not cause symptoms. Cyanosis and dyspnea develop with moderate methemoglobinemia. Nitrates can be irritating to the gastrointestinal tract, eyes, and mucous membranes.
    F) SEVERE TOXICITY: In severe poisonings, unconsciousness, dizziness, fatigue, shortness of breath, and hypotension may develop. Hypotension, dysrhythmias, myocardial ischemia, seizures, confusion, coma, metabolic acidosis, and death may occur with methemoglobin concentrations of greater than 50%.
    0.2.3) VITAL SIGNS
    A) Orthostatic hypotension and tachycardia are common. Frank hypotension and bradycardia are possible.
    0.2.4) HEENT
    A) Nitrate salts may be irritating to the eyes and mucous membranes.
    0.2.5) CARDIOVASCULAR
    A) Nitrite-induced peripheral vasodilatation may occur after nitrates have been converted to nitrites in vivo. Orthostatic hypotension and tachycardia are common. Hypotension, decreased peripheral vascular resistance, cardiovascular collapse, or bradycardia occur less often.
    B) Dysrhythmias including atrial fibrillation, frequent ventricular premature beats, and bigeminy may occur with severe poisoning. Ischemia may also occur with severe poisoning.
    C) Coronary vasospasm and ischemia have been reported after abrupt withdrawal from chronic occupational nitrate exposure.
    0.2.6) RESPIRATORY
    A) Once nitrates have been converted to nitrites, cyanosis and dyspnea may develop due to methemoglobin formation.
    0.2.7) NEUROLOGIC
    A) Headache is a common symptom once nitrates have been converted to nitrites. Nitrates themselves produce few neurologic symptoms. Coma has been reported with severe poisoning.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting are the first signs to be noted following ingestion.
    B) Diarrhea and abdominal pain are also noted. Gastrointestinal inflammation has been seen at autopsy.
    0.2.11) ACID-BASE
    A) Falsely elevated CO2 levels with a negative anion gap were associated with elevated potassium levels secondary to ingestion of potassium nitrate.
    B) Elevated anion gap acidosis may occur.
    0.2.13) HEMATOLOGIC
    A) Methemoglobinemia may be noted, and is associated with cyanosis that does not respond to oxygen therapy.
    0.2.20) REPRODUCTIVE
    A) ISOSORBIDE DINITRATE, ISOSORBIDE DINITRATE AND HYDRALAZINE COMBINATION, and NITROGLYCERIN are classified as US FDA Pregnancy Category C. ISOSORBIDE MONONITRATE is classified as Pregnancy Category B. Nitrate-based medications (eg, isosorbide mononitrate and dinitrate, nitroglycerin, and sodium nitroprusside) are typically used as vasodilators. Please refer to the NITROGLYCERIN and SODIUM NITROPRUSSIDE documents for more information on these agents.
    0.2.21) CARCINOGENICITY
    A) An increased incidence of stomach cancer was seen in one group of workers with occupational exposure to nitrate fertilizer.

Laboratory Monitoring

    A) Testing in patients with severe symptoms should be directed toward evaluation of end organ ischemia (eg, arterial blood gases). No testing is required for patients with transient hypotension.
    B) Blood methemoglobin concentrations should be measured in patients with clinical evidence of methemoglobinemia (eg, symptoms of hypoxia or skin discoloration). Asymptomatic exposures do not require methemoglobin determination.
    C) Patients with clinically significant methemoglobinemia should be evaluated for hemolysis.
    D) Patients with hemolysis should have testing for G6PD deficiency.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Mild to moderate hypotension is treated by placing the patient in a supine position. Infusion of IV crystalloid is usually sufficient to reverse nitrate induced hypotension.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat hypotension with IV fluids. Vasopressors are rarely required. Treat symptomatic methemoglobinemia with methylene blue.
    C) DECONTAMINATION
    1) PREHOSPITAL: Remove patients from the exposure and to fresh air. Administer oxygen to symptomatic patients.
    2) HOSPITAL: Decontamination is unlikely to be of assistance as these agents are rapidly absorbed.
    D) AIRWAY MANAGEMENT
    1) Nitrates may cause airway irritation but it is rare for patients to require intubation.
    E) ANTIDOTE
    1) None
    F) HYPOTENSIVE EPISODE
    1) Hypotension after nitrate overdose is secondary to venodilation. Keep the patient supine; primary therapy is restoring intravascular volume with fluid. Administer 10 to 20 mL/kg 0.9% saline. Central venous pressure monitoring may be useful to guide further fluid therapy. Vasopressors should be used only in patients who do not respond to adequate fluid resuscitation.
    G) METHEMOGLOBINEMIA
    1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    H) ENHANCED ELIMINATION
    1) Nitrates are removed by dialysis but it is unlikely to be used clinically as most cases reverse relatively quickly.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with inadvertent exposure may be observed at home.
    2) OBSERVATION CRITERIA: Observe patients with symptomatic hypotension until symptoms resolve. Observe patients treated with methylene blue for 6 hours.
    3) ADMISSION CRITERIA: Admit patients with persistent hypotension or end organ ischemia. Admit patients with methemoglobinemia and evidence of hemolysis or patients requiring a second treatment with methylene blue.
    4) CONSULT CRITERIA: Consult a medical toxicologist for patients who have persistent symptoms, require treatment with methylene blue or who have G6PD deficiency.
    J) PITFALLS
    1) It is important to be aware that methemoglobinemia may recur.
    K) TOXICOKINETICS
    1) Nitrates are highly and rapidly absorbed. Approximately 60% are excreted in urine and approximately 10% of a dose is converted to nitrites in the gastrointestinal tract, which enhances toxic effects.
    L) PREDISPOSING CONDITIONS
    1) Patients with G6PD deficiency may develop hemolysis secondary to methemoglobinemia and may not respond to methylene blue therapy. Infants younger than 4 months of age are at increased risk for methemoglobinemia from nitrate contaminated ground water.
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes nitrite exposure or exposure to other vasodilators or oxidizing agents.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

Range Of Toxicity

    A) TOXICITY: The exact toxic dose is not well known. Nitrates in well water used to prepare infant feeding formula have been implicated as causing significant illness in children at 90 parts per million and death at 150 parts per million. Methemoglobinemia was not observed if water nitrate concentrations were below 10 mg/L nitrate-N.

Clinical Effects

Summary Of Exposure

    A) USES: Nitrates occur naturally in many plants and are used as fertilizer. Ammonium nitrate is used in instant cooling packets. Well water may become contaminated with nitrates from fertilizers or natural causes. Nitrate-based medications are used as vasodilators (including isosorbide, nitroprusside and nitroglycerin) and are covered in separate managements.
    B) PHARMACOLOGY: Nitrates cause vasodilation by being converted to nitrites and eventually to nitric oxide.
    C) TOXICOLOGY: The toxicity of nitrates is due to in vivo conversion to nitrites. Excessive vasodilation may cause hypotension and hypoperfusion. Nitrates are potent oxidizers and can produce methemoglobinemia and hemolysis.
    D) EPIDEMIOLOGY: Nitrate exposures are uncommon. Severe effects are rare except in cases where large exposures to fertilizers produces high methemoglobin concentrations.
    E) MILD TO MODERATE TOXICITY: Overdose generally causes orthostatic hypotension and reflex tachycardia. Headache, nausea, and vomiting are also fairly common. Syncope, dizziness or lightheadedness, diaphoresis, and flushed skin may develop. Mild methemoglobinemia generally does not cause symptoms. Cyanosis and dyspnea develop with moderate methemoglobinemia. Nitrates can be irritating to the gastrointestinal tract, eyes, and mucous membranes.
    F) SEVERE TOXICITY: In severe poisonings, unconsciousness, dizziness, fatigue, shortness of breath, and hypotension may develop. Hypotension, dysrhythmias, myocardial ischemia, seizures, confusion, coma, metabolic acidosis, and death may occur with methemoglobin concentrations of greater than 50%.

Vital Signs

    3.3.1) SUMMARY
    A) Orthostatic hypotension and tachycardia are common. Frank hypotension and bradycardia are possible.
    3.3.4) BLOOD PRESSURE
    A) Hypotension may occur (Prod Info isosorbide mononitrate extended-release oral tablets, 2005).
    3.3.5) PULSE
    A) Both tachycardia and bradycardia have been reported (Paris et al, 1986).

Heent

    3.4.1) SUMMARY
    A) Nitrate salts may be irritating to the eyes and mucous membranes.
    3.4.3) EYES
    A) IRRITATION: Nitrates are irritating; eye irritation ranging from mild to severe may occur, depending on the nitrate salt involved and the physical form (solution, crystal, etc).
    B) INTRAOCULAR PRESSURE: Oral, intravenous, and topical ophthalmic nitrates have been reported to lower intraocular pressure in normal volunteers and in patients with open-angle glaucoma (Grant & Schuman, 1993).
    C) MIOSIS: Unilateral ptosis and miosis with ipsilateral headache has been reported in a patient following vasodilation induced by isosorbide dinitrate (Grant & Schuman, 1993).
    D) MYOPIA: Myopia without miosis was reported in a patient each time isosorbide dinitrate was taken. Cycloplegic eyedrops counteracted this effect (Grant & Schuman, 1993).
    3.4.5) NOSE
    A) Nitrates may irritate the mucous membranes of the nose.

Cardiovascular

    3.5.1) SUMMARY
    A) Nitrite-induced peripheral vasodilatation may occur after nitrates have been converted to nitrites in vivo. Orthostatic hypotension and tachycardia are common. Hypotension, decreased peripheral vascular resistance, cardiovascular collapse, or bradycardia occur less often.
    B) Dysrhythmias including atrial fibrillation, frequent ventricular premature beats, and bigeminy may occur with severe poisoning. Ischemia may also occur with severe poisoning.
    C) Coronary vasospasm and ischemia have been reported after abrupt withdrawal from chronic occupational nitrate exposure.
    3.5.2) CLINICAL EFFECTS
    A) VASODILATATION
    1) WITH POISONING/EXPOSURE
    a) Peripheral vasodilatation may occur after nitrates have been converted to nitrites in vivo.
    1) Presenting symptoms may include headache, nausea, vomiting, postural lightheadedness, warm flushed diaphoretic skin that later becomes cold and cyanotic, syncope, and tachycardia (Prod Info isosorbide mononitrate extended-release oral tablets, 2005; Gosselin et al, 1984; Prod Info isosorbide mononitrate extended-release oral tablets, 2005; HSDB , 2000).
    b) Vasodilatation may produce hypotension, decreased peripheral vascular resistance, cardiovascular collapse, seizures, and coma in severe toxicity (Prod Info isosorbide mononitrate extended-release oral tablets, 2005; Gosselin et al, 1984; Ellenhorn & Barceloux, 1988; HSDB , 2000). Hypotension, decreased peripheral vascular resistance, cardiovascular collapse, or bradycardia occur less often.
    B) VASOSPASM
    1) Acute coronary vasospasm secondary to industrial nitroglycerin withdrawal has been reported (Przybojewski & Heyns, 1983).
    C) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Bradycardia was reported in 1 patient who ingested 96 grams of ammonium nitrate (Challoner & McCarron, 1988).
    D) VENTRICULAR ARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Dysrhythmias including atrial fibrillation, frequent ventricular premature beats, and bigeminy may occur with severe poisoning. Ischemia may also occur with severe poisoning. Atrial fibrillation, cardiac ischemia, frequent ventricular premature beats, bigeminy, and occasional VPB were noted in a series of 80 patients with nitrate poisoning. ECG abnormalities were normal within 2 days (Gao & Guo, 1990).
    E) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Mild hypotension was reported after ingestion of 96 g of ammonium nitrate in an adult (Challoner & McCarron, 1988).

Respiratory

    3.6.1) SUMMARY
    A) Once nitrates have been converted to nitrites, cyanosis and dyspnea may develop due to methemoglobin formation.
    3.6.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) Once nitrates have been converted to nitrites, cyanosis may result due to methemoglobin formation. Suspect methemoglobinemia in all cyanotic patients who do not improve with supplemental oxygen.

Neurologic

    3.7.1) SUMMARY
    A) Headache is a common symptom once nitrates have been converted to nitrites. Nitrates themselves produce few neurologic symptoms. Coma has been reported with severe poisoning.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) A throbbing headache may occur after nitrate conversion to nitrite (Grant & Schuman, 1993).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Two patients in a series of 80 nitrate-poisoned patients presented 3 hours postingestion with coma, cyanosis, dyspnea, and pallor (Gao & Guo, 1990).
    C) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Nitrite toxicity results in the oxidation of the ferrous iron in deoxyhemoglobin to the ferric valence state, which produces methemoglobin. Depending on the degree of methemoglobin, the clinical features may include progressive central nervous system effects. These effects can range from mild dizziness to coma and seizure activity (ATSDR, 2001). Seizures may occur in severe cases with methemoglobin levels of 50% or greater (Rodriguez et al, 1994; Eldadah & Fitzgerald, 1993).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Seizures have been seen in animals after nitrate has been converted to nitrite.

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting are the first signs to be noted following ingestion.
    B) Diarrhea and abdominal pain are also noted. Gastrointestinal inflammation has been seen at autopsy.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting are the first signs to be noted following ingestion. Spontaneous emesis and gastritis were reported in 3 patients who ingested 127 to 234 g of ammonium nitrate; 2 had signs of gastrointestinal hemorrhage (Challoner & McCarron, 1988).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea is also one of the first signs noted.
    C) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain may be reported.
    D) GASTRITIS
    1) WITH POISONING/EXPOSURE
    a) Gastrointestinal inflammation has been seen at autopsy (McQuiston, 1936; Barton, 1954).

Acid-Base

    3.11.1) SUMMARY
    A) Falsely elevated CO2 levels with a negative anion gap were associated with elevated potassium levels secondary to ingestion of potassium nitrate.
    B) Elevated anion gap acidosis may occur.
    3.11.2) CLINICAL EFFECTS
    A) HYPERKALEMIA
    1) WITH POISONING/EXPOSURE
    a) Falsely elevated CO2 levels (Ekachrom 700 system) with a negative anion gap were associated with potassium levels of 7.6 mEq/L secondary to ingestion of 1 tablespoon of potassium nitrate every 2 hours for 5 doses (Sporer & Mayer, 1991).
    1) Methemoglobin level was 2.6% in this patient.
    B) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis occurs when methemoglobin levels are high enough to result in tissue hypoxia (generally greater than 50%).

Hematologic

    3.13.1) SUMMARY
    A) Methemoglobinemia may be noted, and is associated with cyanosis that does not respond to oxygen therapy.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) TOPICAL EXPOSURE
    1) CERIUM NITRATE: A retrospective review of medical and pharmacy records, from January 2005 to October 2009, was conducted to determine the incidence of methemoglobinemia in patients prescribed cerium nitrate/silver sulfadiazine cream for the treatment of burns. During this time period, 170 patients were identified as having been prescribed the cerium nitrate/silver sulfadiazine cream. Eighteen patients (approximately 10%) developed methemoglobinemia, with methemoglobin levels ranging from 3.4% to 10% in 15 patients and methemoglobin levels greater than 10% in 3 patients (Kath et al, 2011).
    2) WITH POISONING/EXPOSURE
    a) Methemoglobinemia may be noted when nitrates are converted to nitrites (Christian, 1928). It is associated with cyanosis that does not respond to oxygen therapy. Infants younger than 6 months are particularly susceptible to methemoglobinemia since their methemoglobin reductase system is not yet mature. This results in a greater susceptibility of fetal hemoglobin to oxidation by nitrites contributing to a decrease in available oxygen for infant tissues (Dusdieker & Dungy, 1996).
    1) If nitrite-induced, methemoglobinemia can be delayed in onset and has sustained circulating levels (Smith et al, 1967).
    2) Methemoglobinemia generally does not develop after even large doses of nitroglycerin (Paris et al, 1986).
    b) ORGANIC NITRATE DRUGS: Clinical trials have not shown that these agents will produce methemoglobinemia, but several case reports have demonstrated methemoglobin levels of 9.6%, 12%, 12.5%, 16.5%, and 28.2% Zurick et al, 1984; (Bojar et al, 1987; Robicsek, 1985; Gibson et al, 1982; Kaplan et al, 1985).
    c) NITRATE-POLLUTED DRINKING WATER: Nitrate-polluted drinking water is the most common cause of nitrate-induced methemoglobinemia in infants, particularly those under 6 months old. Runoff of nitrates from various sources into rivers are reported to be the major nitrate contaminants of drinking water in areas supplied by wells. Other sources of nitrates causing methemoglobinemia in infants include topical absorption of nitrates from inks, paints, dyes, and shoe polish. Some commercial baby foods are reported to have low levels of nitrates and are not meant for consumption by infants younger than 6 months (Dusdieker & Dungy, 1996).
    d) AMMONIUM NITRATE
    1) CASE REPORT: Ingestion of 96 and 127 g resulted in mild methemoglobinemia (13% and 12%, respectively) (Challoner & McCarron, 1988).
    2) CASE REPORTS: Cyanosis and methemoglobinemia were reported after ingestion of 54 g of ammonium nitrate by a 32-year-old patient, and after ingestions of 24 and 89 grams in a 47-year-old patient (Eusterman & Keith, 1929).
    3) CASE REPORT: Ingestion of 15 g/day for 10 days produced cyanosis in an adult patient (Barker & O'Hare, 1928).
    4) CASE REPORT: A patient with chronic nephrosis and constipation developed methemoglobinemia after ingestion of 120 g distributed over 12 days (Keith et al, 1930).
    5) CASE REPORT: One report described a 45-year-old patient who was able to tolerate 696 g of ammonium nitrate (6 g/day) without methemoglobinemia, but developed this condition after 2 weeks of 9 g/day (Tarr, 1933).
    e) CASE REPORT: A patient with a burn covering 90.5% of body surface area due to hot sodium nitrate developed methemoglobinemia and died (Mozingo et al, 1988).

Reproductive

    3.20.1) SUMMARY
    A) ISOSORBIDE DINITRATE, ISOSORBIDE DINITRATE AND HYDRALAZINE COMBINATION, and NITROGLYCERIN are classified as US FDA Pregnancy Category C. ISOSORBIDE MONONITRATE is classified as Pregnancy Category B. Nitrate-based medications (eg, isosorbide mononitrate and dinitrate, nitroglycerin, and sodium nitroprusside) are typically used as vasodilators. Please refer to the NITROGLYCERIN and SODIUM NITROPRUSSIDE documents for more information on these agents.
    3.20.2) TERATOGENICITY
    A) HUMANS
    1) An association between drinking nitrate-contaminated groundwater and congenital anomalies (especially neural tube defects) has been suggested (Dorsch et al, 1984; Scragg et al, 1982).
    a) Nitrate levels of 26 parts per million in drinking water, derived from private wells, were associated with a moderate, but not statistically significant, increase in the risk of CNS effects in human infants (Arbuckle et al, 1988).
    B) ANIMAL STUDIES
    1) There is no evidence of teratogenicity from animal data using acceptable nitrate ingestions. High levels of nitrates may cause teratogenicity or embryotoxicity in animals.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Isosorbide dinitrate, isosorbide dinitrate and hydralazine combination, and nitroglycerin are classified as US FDA Pregnancy Category C (Prod Info BIDIL(R) oral tablets, 2013; Prod Info ISORDIL(R) TITRADOSE(R) oral tablets, 2007; Prod Info Nitrostat(R) sublingual tablets, 2011; Prod Info RECTIV(TM) intra-anal ointment, 2011; Prod Info NITROMIST(R) lingual aerosol, 2011). ISOSORBIDE MONONITRATE is classified as Pregnancy Category B (Prod Info Isosorbide Mononitrate extended-release oral tablets, 2008)
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Nitrates are excreted in breast milk and may cause methemoglobinemia in infants. Clinical methemoglobinemia reported in a breastfed infant was resolved when the mother discontinued drinking well water (Donahue, 1949).
    a) Extra caution and anticipatory care should be exercised because neonatal gastric pH allows bacterial proliferation and conversion of nitrates to nitrites (Gosselin et al, 1984).
    2) Other evidence would indicate that nitrate is not concentrated in breast milk (Fan et al, 1987).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) An increased incidence of stomach cancer was seen in one group of workers with occupational exposure to nitrate fertilizer.
    3.21.3) HUMAN STUDIES
    A) GASTRIC CARCINOMA
    1) A slight increase in stomach cancer incidence was seen in a group of 1756 male workers at a nitrate fertilizer plant; no increased risk for total cancers was seen (Zandjani et al, 1994).
    B) COLON CANCER
    1) A case control study found no association between nitrate in public water supplies and the incidence of colon and rectum cancer. For subjects with more than 10 years exposure to a water supply with an average nitrate concentration greater than 5 mg/L, the OR for colon cancer was 1.2 (95% CI: 0.9 to 1.6) and for rectal cancer OR was 1.1 (90% CI: 0.7 to 1.5). On subgroup analysis, subjects with more than 10 years exposure to a water supply with an average nitrate concentration of greater than 5 mg/L had an increased risk of colon cancer if they also had low vitamin C intake (OR 2.0; 95%; CI: 1.2 to 3.3) or high meat intake (OR 2.2; 95% CI: 1.4 to 3.6) (De Roos et al, 2003).

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Testing in patients with severe symptoms should be directed toward evaluation of end organ ischemia (eg, arterial blood gases). No testing is required for patients with transient hypotension.
    B) Blood methemoglobin concentrations should be measured in patients with clinical evidence of methemoglobinemia (eg, symptoms of hypoxia or skin discoloration). Asymptomatic exposures do not require methemoglobin determination.
    C) Patients with clinically significant methemoglobinemia should be evaluated for hemolysis.
    D) Patients with hemolysis should have testing for G6PD deficiency.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Monitor CBC and methemoglobin levels in symptomatic patients. Normal methemoglobin level is less than 3%. A G6PD assay is indicated in patients who develop methemoglobinemia and/or hemolysis. Blood with methemoglobinemia that has been exposed to oxygen has a characteristic chocolate brown color.
    B) ACID/BASE
    1) Arterial blood gases (with a cooximeter to measure methemoglobin) should be monitored in symptomatic or cyanotic patients. Most pulse oximeters are inaccurate in the presence of methemoglobin.
    2) MEASURED oxygen saturation will be low (Forsyth & Moulden, 1991).
    3) The oxygen saturation value provided by many blood gas analyzers will be high, because it is CALCULATED from the measured arterial oxygen tension (pO2) assuming a normal oxyhemoglobin dissociation curve (Forsyth & Moulden, 1991).
    4) Arterial blood will be blue or "chocolate brown" even after exposure to oxygen (Forsyth & Moulden, 1991).
    C) LABORATORY INTERFERENCE
    1) Falsely elevated CO2 levels (Ekachrom 700 system) with a negative anion gap were associated with hyperkalemia (7.6 mEq/L) secondary to ingestion of one tablespoon of potassium nitrate every 2 hours for five doses (Sporer & Mayer, 1991).
    2) The Ekachrom system, which measures CO2, uses a method which cross-reacts positively with nitrate. This can cause spurious total CO2 results (and resultant artificially decreased anion gap in the face of a non-alkalotic blood gas) (Senecal et al, 1991).
    D) BLOOD/SERUM CHEMISTRY
    1) Serum electrolytes, glucose, BUN, and creatinine levels should be measured to assess elevated anion gap acidosis.
    4.1.3) URINE
    A) URINARY LEVELS
    1) The test for determining nitrate in the urine depends on the conversion of nitrate to nitrite by bacterial action. The test requires a minimum of 4 hours between ingestion of the nitrate and testing (overnight is better).
    a) The Multistix test is used. In an acid pH, nitrites will react with para-arsanilic acid to give a diazonium salt. This combines with benzoquinoline to form a pink dye. It will detect 0.075 mg of nitrite/dL.
    b) False positives occur when medications which turn the urine red are present. False negatives occur when there is ascorbic acid or urobilinogen present, or if there is a pH under 6.
    2) Testing for urinary nitrate is of some importance because bacteria (like those seen in urinary tract infections) may convert nitrates to nitrites, then to nitrosamines which are potentially carcinogenic (Radomski et al, 1978).
    a) Some texts (Sollmann, 1957) and early studies (Mitchell et al, 1916) have shown levels from 0.4% to 100 to 400 mg/L.
    b) In a 1978 study done in Dade County, Florida, the means of nitrate in the urine were 41 to 55.6 ppm (mg/mL) (Radomski et al, 1978).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) ECG and creatine kinase should be monitored in symptomatic patients to assess cardiac effects of methemoglobinemia.

Methods

    A) OTHER
    1) BLOOD METHEMOGLOBIN LEVELS should be determined for diagnostic and therapeutic monitoring.
    2) Results may be expressed as grams of methemoglobin per deciliter (dL), or as a percentage (percent of hemoglobin that has been converted to methemoglobin).
    3) To calculate percent methemoglobin, determine the ratio of methemoglobin/hemoglobin in grams. For example, if MetHb = 3 g/100 mL blood and Hb = 12 g/100 mL blood, then 3/12 x 100 = 25% methemoglobinemia. Greater than 30% is usually symptomatic.
    4) CAUTION: Methemoglobin levels will be reduced if blood is not analyzed rapidly (a few hours) by endogenous methemoglobin reductase.
    5) BEDSIDE METHOD: Initial bedside determination can be made by placing a drop of blood on filter paper with a control drop of blood nearby.
    a) If there is greater than 15% methemoglobinemia, the affected blood will have a chocolate brown color in comparison with the control blood.
    B) MULTIPLE ANALYTICAL METHODS
    1) Nitrite may be determined in biological fluids:
    a) By a sulfanilic acid-alpha-naphthylamine colorimetric diazotization technique (Baselt, 1980)
    2) With the use of an ion-selective electrode (Choi & Fung, 1980)
    3) With high-pressure liquid chromatography (Thayer & Huffaker, 1980)
    4) By a kinetic cadmium reduction method (Cortas & Wakid, 1990)
    5) A method using silver sulfate, 2,4-dimethylphenol, and a colorimetric method has been described (Radomski et al, 1978).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit patients with persistent hypotension or end organ ischemia. Admit patients with methemoglobinemia and evidence of hemolysis or patients requiring a second treatment with methylene blue.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with inadvertent exposure may be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist for patients who have persistent symptoms, require treatment with methylene blue or who have G6PD deficiency.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Observe patients with symptomatic hypotension until symptoms resolve. Observe patients treated with methylene blue for 6 hours.

Monitoring

    A) Testing in patients with severe symptoms should be directed toward evaluation of end organ ischemia (eg, arterial blood gases). No testing is required for patients with transient hypotension.
    B) Blood methemoglobin concentrations should be measured in patients with clinical evidence of methemoglobinemia (eg, symptoms of hypoxia or skin discoloration). Asymptomatic exposures do not require methemoglobin determination.
    C) Patients with clinically significant methemoglobinemia should be evaluated for hemolysis.
    D) Patients with hemolysis should have testing for G6PD deficiency.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Remove patients from the exposure and to fresh air. Administer oxygen to symptomatic patients.
    6.5.2) PREVENTION OF ABSORPTION
    A) Administer oxygen to symptomatic patients. Decontamination is unlikely to be of assistance as these agents are rapidly absorbed.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. Mild to moderate hypotension is treated by placing the patient in a supine position. Infusion of IV crystalloid is usually sufficient to reverse nitrate induced hypotension.
    2) MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Treat hypotension with IV fluids. Vasopressors are rarely required. Treat symptomatic methemoglobinemia with methylene blue.
    B) MONITORING OF PATIENT
    1) Testing in patients with severe symptoms should be directed toward evaluation of end organ ischemia (eg, arterial blood gases). No testing is required for patients with transient hypotension.
    2) Blood methemoglobin concentrations should be measured in patients with clinical evidence of methemoglobinemia (eg, symptoms of hypoxia or skin discoloration). Asymptomatic exposures do not require methemoglobin determination.
    3) Patients with clinically significant methemoglobinemia should be evaluated for hemolysis.
    4) Patients with hemolysis should have testing for G6PD deficiency.
    C) HYPOTENSIVE EPISODE
    1) Hypotension after nitrate overdose is secondary to venodilation. Keep the patient supine; primary therapy is restoring intravascular volume with fluid. Administer 10 to 20 mL/kg 0.9% saline. Central venous pressure monitoring may be useful to guide further fluid therapy. Vasopressors should be used only in patients who do not respond to adequate fluid resuscitation.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    4) EXCHANGE TRANSFUSION
    a) Exchange transfusion should be performed in severely symptomatic patients, especially neonates and children, if the methemoglobinemia is not responsive to methylene blue therapy or if the level is not brought below 70% in a symptomatic patient (Kirby, 1955; Harrison, 1977).
    b) This may be useful for patients with known G6PD or NADPH-dependent methemoglobin reductase deficiencies (Harrison, 1977).
    c) Exchange transfusion is limited in applicability because of the inherent risks of large blood volumes required in adults.
    d) It has been used successfully, at least once, in nitrite-induced methemoglobinemia (Kirby, 1955).
    5) HYPERBARIC OXYGEN THERAPY
    a) Hyperbaric oxygen (HBO) may be used as a supportive measure while preparations for exchange transfusion are being made. HBO therapy can provide sufficient oxygen to maintain life as dissolved oxygen in blood, and obviates temporarily the need for functional hemoglobin (Hall, 1991).
    b) Further studies on the role of hyperbaric oxygen in human nitrite poisoning are indicated (Smith & Gosselin, 1976).
    c) Hyperbaric oxygen has an additive effect with methylene blue in protecting mice against death by nitrite (Sheehy & Way, 1974).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Nitrates are removed by dialysis but it is unlikely to be used clinically as most cases reverse relatively quickly.

Abstracts

Case Reports

    A) SPECIFIC AGENT
    1) AMMONIUM NITRATE
    a) ADULT: A 22-year-old man ingested 96 g of ammonium nitrate and presented with mild hypotension, bradycardia, and methemoglobinemia (Challoner & McCarron, 1988).
    1) He was given syrup of ipecac and sodium sulfate 1.5 hours postingestion. Admission blood gases included a pH of 7.36 and a bicarbonate of 16.
    2) The 6-hour postingestion methemoglobin level of 13% spontaneously dropped to 2.6% by the 12th hour.
    b) ADULT: A 32-year-old man ingested 127 g of ammonium nitrate and was given syrup of ipecac. Hematemesis developed 6 days later, and mild hypotension was present. The methemoglobin level was 12% (Challoner & McCarron, 1988).
    c) ADULT: A 32-year-old man ingested 127 g of ammonium nitrate and received gastric lavage, activated charcoal, and magnesium citrate. Gastritis was the only effect noted. The methemoglobin level was 5% (Challoner & McCarron, 1988).
    d) ADULT: A 24-year-old man ingested 234 g of ammonium nitrate and vomited spontaneously. No other signs or symptoms developed (Challoner & McCarron, 1988).

Range Of Toxicity

Summary

    A) TOXICITY: The exact toxic dose is not well known. Nitrates in well water used to prepare infant feeding formula have been implicated as causing significant illness in children at 90 parts per million and death at 150 parts per million. Methemoglobinemia was not observed if water nitrate concentrations were below 10 mg/L nitrate-N.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) Estimated adult oral lethal dose of nitroglycerin is 200 to 1200 mg (Prod Info nitroglycerin transdermal system, 2005). Toxic dose is variable and influenced by underlying disease state.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) ACCEPTABLE DAILY INTAKE OF NITRATES (excluding infants under 6 months old) is 5 mg/kg (WHO, 1965)
    B) ROUTE OF EXPOSURE
    1) DRINKING WATER
    a) Nitrates in well water used to prepare infant feeding formula have been implicated as causing significant illness in children at 90 parts per million (Comly, 1987) and death at 150 parts per million (Johnson et al, 1987). Infant studies observed no cases of methemoglobinemia when nitrates in drinking water were below 10 mg/L nitrate-N. Some regulatory agencies use these infant studies to set the maximum contaminant levels for nitrates in drinking water at below 10 mg/L nitrate-N level (Ward et al, 2005; Walton, 1951).
    b) Of 2000 cases of infant methemoglobinemia reported during a 25 year period, more than 80% involved known nitrate contamination levels greater than 100 parts per million (Fan et al, 1987).
    c) Ingestion of nitrates ranging from 1 to 15.54 mg/kg/day in 111 infants aged less than 6 months was associated with a mean methemoglobin level of 1.6%, with the highest level 5.3%. No infants had clinical signs or symptoms (Winton et al, 1971).
    C) SPECIFIC SUBSTANCE
    1) AMMONIUM NITRATE
    a) SUMMARY: At one time ammonium nitrate was used as a cathartic. Occasionally, methemoglobinemia would develop. No specific toxic dose was determined. Symptoms were seen with as little as 24 g and as much as 276 g in adults.
    1) Factors which seemed to influence the development of symptoms included the daily dose, total dose, and condition of the patient. Patients with bowel diseases, constipation, or other illnesses seemed to be more likely to develop toxicity (Tarr, 1933).
    b) CASE REPORTS
    1) Ingestion of 64 to 234 g of ammonium nitrate produced mild toxicity in a series of 5 patients. Ingestion of 96 and 127 g resulted in mild methemoglobinemia (13% and 12%, respectively) (Challoner & McCarron, 1988).
    2) Cyanosis and methemoglobinemia developed after ingestion of 54 g of ammonium nitrate in a 32-year-old patient and after ingestions of 24 and 89 g in a 47-year-old patient (Eusterman & Keith, 1929).
    3) Ingestion of 15 g/day for 10 days produced cyanosis in an adult patient (Barker & O'Hare, 1928).
    4) A patient with chronic nephrosis and constipation developed methemoglobinemia after ingestion of 120 g distributed over 12 days (Keith et al, 1930).
    5) A 45-year-old patient was able to tolerate 696 g of ammonium nitrate (6 g/day) without methemoglobinemia but developed this condition after two weeks of 9 g/day (Tarr, 1933).
    6) A total of 50 g of ammonium nitrate over 8 days produced methemoglobinemia and cyanosis in a 48-year-old (Tarr, 1933).
    7) Two hundred and fifty-two g (6 g/day) over 42 days produced methemoglobin in a 73-year-old patient (Tarr, 1933).
    8) Headache, nausea, and dizziness preceded the development of methemoglobinemia in a 65-year-old patient who ingested 276 grams over 46 days (Tarr, 1933).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) OTHER
    a) SALIVA
    1) The normal level of nitrite in the saliva is about 5 to 10 mg/L. However, after a nitrate load, it may be 350 mg/L (Tannenbaum et al, 1976).
    2) In one study, a salivary nitrate level of 23 mcmol/L was observed (Cortas & Wakid, 1991).
    b) PLASMA
    1) The plasma level before loading with nitrates in one study was approximately 37 mcmol/L (Cortas & Wakid, 1991).
    c) URINE
    1) Urinary nitrate levels will increase after a dose of vegetables containing nitrates (Radomski et al, 1978).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nitrates cause vasodilation by being converted to nitrites and eventually to nitric oxide (Ward et al, 2005).

Toxicologic Mechanism

    A) The toxicity of nitrates is due to in vivo conversion to nitrites (Ward et al, 2005). Excessive vasodilation may cause hypotension and hypoperfusion. Nitrates are potent oxidizers and can produce methemoglobinemia and hemolysis (Ward et al, 2005).
    B) METHEMOGLOBINEMIA
    1) Methemoglobinemia may lead to cyanosis. Cyanosis may be detected at above 15% conversion of normal hemoglobin to methemoglobin. Nitrites convert HbFe++ to MeHbFe+++. Add methylene blue, and MetHb+++ is reduced to HbFe++.
    2) In treatment, methylene blue is converted to leucomethylene blue in the patient by accepting a hydrogen ion and 2 electrons. The leucomethylene blue then reacts with the MetHb+++ to produce normal hemoglobin.
    a) Methylene blue, in its blue oxidized state, is then apparently regenerated by releasing the hydrogen ion and the one remaining electron. MetHb+++ is unable to transport oxygen.

Animal Toxicology

Clinical Effects

    11.1.1) AVIAN/BIRD
    A) Signs of nitrate ingestion include polydipsia, vomiting, diarrhea, and hypothermia. Weakness and death follow rapidly. Cyanosis is easily noted on comb and wattles (Personal Communication, 1988).
    11.1.5) EQUINE/HORSE
    A) ACUTE - Signs include depression, tachycardia, tachypnea, and weakness. Mucous membranes may be icteric, cyanotic, or chocolate brown, depending on the severity (Robinson, 1987).
    B) CHRONIC INGESTION - Chronic ingestion may cause infertility and abortion, stunted growth, immunosuppression, and interference with iodine metabolism (Robinson, 1987).
    11.1.10) PORCINE/SWINE
    A) Signs include tachypnea, salivation, miosis, weakness, and ataxia progressing to terminal seizures and death. Mucous membranes are cyanotic or chocolate brown (Leman, 1986).
    11.1.13) OTHER
    A) OTHER
    1) ACUTE - Signs include vomiting, salivation, diarrhea, tachycardia, tachypnea, and cyanosis. Weakness, tremors, or ataxia progress to terminal seizures and death in 6 to 24 hours (Beasley et al, 1989).
    2) CHRONIC INGESTION - Chronic ingestion may cause infertility and abortion, stunted growth, immunosuppression, and interference with iodine metabolism (Beasley et al, 1989).
    3) Animals may ingest materials high in nitrates, then convert them to nitrites. Possible symptoms are listed above. Less important, but also seen is a direct irritation due to nitrate ingestion. This is seen more in monogastric animals such as swine (Burrows, 1990).

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Minimize stress. Exertion, including handling for treatment purposes, will exacerbate hypoxia and may precipitate terminal seizures and death.
    2) Determine and remove all possible sources of exposure.
    3) Treatment is aimed at reversing the methemoglobinemia and preventing further absorption of ingested nitrates/nitrites.
    4) Methylene blue will induce methemoglobinemia, so exceeding the recommended dose may exacerbate the animal's condition.
    5) Treatment should be under the care and supervision of a veterinarian. For more information, contact the nearest college of veterinary medicine to consult with an ABVT board certified toxicologist. Assistance may also be obtained by calling the National Animal Poison Control Center.
    a) ANIMAL POISON CONTROL CENTERS
    1) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    2) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    3) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) SMALL ANIMALS
    a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac orally.
    1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or given orally.
    2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram.
    3) Do not use an emetic if the animal is hypoxic.
    4) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate.
    b) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram per kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) orally.
    2) LARGE ANIMALS
    a) DO NOT ATTEMPT EMESIS IN RUMINANTS or EQUIDS.
    b) CATHARTIC -
    1) Give mineral oil orally via stomach tube. Small ruminants and swine, 60 to 200 milliliters; equids and cattle, 2 to 4 liters per 450 kilograms body weight.
    2) Give 0.5 kilogram sodium sulfate or magnesium sulfate per 400 kilograms of body weight. Dissolve in 0.5 to 1 liter of water and give orally via a stomach tube.
    3) The saline cathartics are especially effective when given 30 to 45 minutes after mineral oil.
    11.2.5) TREATMENT
    A) BIRD
    1) Removal of all sources is the only treatment. The stress of attempting to treat individuals will precipitate death.
    B) CAT
    1) Methylene Blue: Cats may develop severe, often fatal Heinz body anemia when given methylene blue.
    2) Although some experimental evidence supports the use of methylene blue to treat methemoglobinemia due to acetaminophen toxicity in cats (Personal Communication, 1991), its use cannot be recommended in the treatment of nitrate toxicosis at this time.
    C) CATTLE
    1) Inject 1 to 8 milligrams methylene blue (1 to 4 percent solution) per kilogram body weight, slowly intravenously (Beasley et al, 1989; Ruhr & Osweiler, 1986; Humphreys, 1988).
    D) DOG
    1) Inject 4 milligrams methylene blue (1 percent solution) per kilogram body weight, slowly intravenously (Beasley et al, 1989).
    E) HORSE
    1) Methylene blue is relatively ineffective in equids.
    2) Provide supplemental oxygen.
    3) If severely anemic or hypoxic, a whole blood transfusion may be necessary.
    a) WHOLE BLOOD TRANSFUSION - In adult horses, 4 to 8 liters of blood are normally transfused at one time. This amount of fresh blood may be collected from a single healthy adult donor that has not been bled in the last 30 days.
    b) Epinephrine should be available in case of transfusion reaction. Dose: 3 to 5 milliliters of a 1:1000 dilution, given intravenously.
    F) SWINE
    1) Inject 10 milligrams methylene blue (4 percent solution) per kilogram body weight, slowly intravenously (Leman, 1986).
    G) SHEEP
    1) Inject 20 milligrams methylene blue (4 percent solution) per kilogram body weight, slowly intravenously, or inject 6.6 milligrams toluidine blue per kilogram body weight, slowly intravenously (Humphreys, 1988).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) BIRD
    1) A 1.5 to 2 percent solution of sodium nitrite caused severe toxicity and occasional death in 1 kilogram chickens (Beasley et al, 1989). The oral LD50 for calcium nitrite in turkeys is 588 milligrams nitrate per kilogram of body weight (Ley, 1986).
    B) CATTLE
    1) 330 to 616 milligrams nitrate or 150 to 170 milligrams nitrite per kilogram body weight are a lethal dose for cattle (Humphreys, 1988).
    2) Acute poisoning may be expected in cattle when levels exceed 500 milligrams of nitrate per liter in the water or 1 percent (dry matter basis) nitrate in the feed (Ruhr & Osweiler, 1986).
    3) Ruminants can tolerate higher levels of nitrate and nitrite if they are exposed to slowly increasing amounts due to an adaptive increase in ruminal nitrate and importantly nitrite reductase activity (Burrows et al, 1987).
    4) The presence of readily fermentable carbohydrates, such as corn, in the diet will help protect ruminants against nitrate toxicosis (Beasley et al, 1989).
    C) HORSE
    1) Water for horses should not exceed 10 milligrams of nitrite per liter (Robinson, 1987).
    D) SWINE
    1) 90 milligrams nitrite per kilogram body weight is a lethal dose for swine (Beasley et al, 1989).
    E) RABBIT
    1) 80 to 90 milligrams of nitrite per kilogram body weight is a lethal dose for rabbits (Beasley et al, 1989).
    F) SHEEP
    1) 170 milligrams nitrite per kilogram body weight or 308 milligrams nitrate per kilogram body weight are lethal doses for sheep (Beasley et al, 1989).
    G) GENERAL
    1) WATER CONCENTRATIONS - Acute poisoning may be expected in livestock when nitrate levels exceed 500 milligrams per liter in water or 1% (dry matter) in the feed (Ruhr & Osweiler, 1986).
    2) CARNIVORES AND OMNIVORES are only susceptible to preformed nitrites, because they do not reduce significant amounts of nitrate in their gastrointestinal tracts (Beasley et al, 1989).
    3) NEONATES - Fetuses and neonates are believed to be more sensitive to nitrites than older animals (Beasley et al, 1989).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Minimize stress. Exertion, including handling for treatment purposes, will exacerbate hypoxia and may precipitate terminal seizures and death.
    2) Determine and remove all possible sources of exposure.
    3) Treatment is aimed at reversing the methemoglobinemia and preventing further absorption of ingested nitrates/nitrites.
    4) Methylene blue will induce methemoglobinemia, so exceeding the recommended dose may exacerbate the animal's condition.
    5) Treatment should be under the care and supervision of a veterinarian. For more information, contact the nearest college of veterinary medicine to consult with an ABVT board certified toxicologist. Assistance may also be obtained by calling the National Animal Poison Control Center.
    a) ANIMAL POISON CONTROL CENTERS
    1) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    2) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    3) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) SMALL ANIMALS
    a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac orally.
    1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or given orally.
    2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram.
    3) Do not use an emetic if the animal is hypoxic.
    4) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate.
    b) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram per kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) orally.
    2) LARGE ANIMALS
    a) DO NOT ATTEMPT EMESIS IN RUMINANTS or EQUIDS.
    b) CATHARTIC -
    1) Give mineral oil orally via stomach tube. Small ruminants and swine, 60 to 200 milliliters; equids and cattle, 2 to 4 liters per 450 kilograms body weight.
    2) Give 0.5 kilogram sodium sulfate or magnesium sulfate per 400 kilograms of body weight. Dissolve in 0.5 to 1 liter of water and give orally via a stomach tube.
    3) The saline cathartics are especially effective when given 30 to 45 minutes after mineral oil.
    11.4.3) TREATMENT
    11.4.3.5) SUPPORTIVE CARE
    A) GENERAL
    1) Ongoing treatment is symptomatic and supportive.
    11.4.3.6) OTHER
    A) OTHER
    1) GENERAL
    a) LABORATORY -
    1) PREMORTEM -
    a) Serum, urine, gastric lavage fluid, samples of all feed sources, and samples of all water sources should be frozen and transported on ice for nitrate and nitrite analysis.
    b) When interpreting results, the effects of all sources of nitrates and nitrites are cumulative (Beasley et al, 1989).
    2) METHEMOGLOBIN -
    a) Methemoglobin levels can be quantitated spectrophotometrically on whole blood (Robinson, 1987).
    b) Clinical signs appear at 20% and death occurs at 80% methemoglobinemia (Humphreys, 1988).
    c) Whole blood must be mixed 1:20 with phosphate buffer (pH 6.6) and frozen to preserve the methemoglobin if the sample cannot be tested within 3 hours (Ruhr & Osweiler, 1986).

Kinetics

    11.5.1) ABSORPTION
    A) RUMINANT
    1) Oral exposure in ruminants results in passive absorption of nitrates and nitrites from the gastrointestinal tract, with maximal concentrations occurring 5 to 6 hours postingestion.
    11.5.3) METABOLISM
    A) GENERAL
    1) Herbivores convert significant amounts of nitrates to nitrite in the rumen or cecum, while an insignificant amount is converted by the liver.
    11.5.4) ELIMINATION
    A) GENERAL
    1) Nitrates and nitrites are primarily excreted by the kidney.

Pharmacology Toxicology

    A) GENERAL
    1) Nitrate is minimally toxic except in herbivores, where the reducing environment of the rumen or cecum rapidly converts it to nitrite.
    2) Nitrite oxidizes the iron in hemoglobin from the ferrous to the ferric state, producing methemoglobin, which is unable to accept and transport oxygen, resulting in tissue hypoxia.

Sources

    A) LARGE ANIMALS
    1) Most common sources are feed and/or water with high nitrate and or nitrite levels. Test all sources, because effects of nitrates and nitrites are cumulative.
    a) Feeds that are commonly high in nitrates or nitrites include Sudan grass, Johnson grass, sorghum, corn stalks, and corn silage (Beasley et al, 1989).
    B) SMALL ANIMALS
    1) Most common sources for small animals are ingestion of fertilizers (Beasley et al, 1989).

Other

    A) OTHER
    1) GENERAL
    a) LESIONS -
    1) Common findings include generalized icterus or chocolate brown discoloration of blood, mucous membranes, viscera, and muscles. Agonal changes due to respiratory distress such as pulmonary edema and emphysema, and pulmonary or tracheal hemorrhages may also be present.
    b) SAMPLES -
    1) Serum, aqueous humor, urine, and rumen or stomach contents should all be collected, frozen, and shipped on ice for nitrate and nitrite analysis.
    2) Aqueous humor remains diagnostically significant for 60 hours after death (Boermens, 1990).

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