Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) CAS 110-46-3

1) CAS 544-16-1

1) CAS 540-80-7

1) CAS 109-95-5

1) CAS 542-56-3

1) CAS 115216-77-8

1) CAS 7758-09-0

1) CAS 7783-99-5

1) CAS 7632-00-0

1) NITRITE, INORGANIC, N.O.S
2) NITRITES AND RELATED AGENTS

Available Forms Sources

A)

1) SODIUM NITRITE - Sterile sodium nitrite (300 milligrams/10 milliliter ampule) is available in the Cyanide Antidote Kit.

B)

1) Nitrates are converted to nitrites by bacteria in the mouth. The kinetics of conversion are quite complex and are not directly related to the nitrate level in the medium or the amount of microbial growth (Tannenbaum et al, 1974).
2) HIGH INORGANIC NITRITE (KNO2, NaNO2) levels are found in well-water contaminated by septic tanks, municipal sewage, fertilizers, and feed lots where bacteria reduce nitrates to nitrites (Ellenhorn & Barceloux, 1988).

C)

1) INDUSTRIAL

a) Used in manufacture of diazo dyes, potassium salts, nitroso compounds, and nitrogen oxide; dyeing and printing textile fabrics; bleaching flax, silk, and linen; photography (ITI, 1988; Budavari, 1996)
b) Also used in meat curing, coloring, and preserving, where nitrites are legally present in amounts of up to 200 ppm (Baselt, 2000); in processing smoked chub (Budavari, 1996).
c) Used as reagents in analytical chemistry (Budavari, 1996).
d) Chemical in metal treatment and finishing operations; corrosion inhibitor; component of detinning solution and multi-purpose greases (HSDB , 2000).

2) MEDICINAL

a) SODIUM NITRITE

1) One gram tablets of sodium nitrite are supplied to medical and dental professionals as an adjunct to disinfectant fluids such as chlorhexidine. Sodium nitrite, a strong oxidizing agent, prevents rusting of the instruments being disinfected (Gowans, 1990).
2) Used in combination with amyl nitrite and sodium thiosulfate as an antidote for cyanide poisoning (Chen et al, 1933; Chen & Rose, 1952; Hall & Rumack, 1986). It may also be efficacious in hydrogen sulfide poisoning (Stine et al, 1976; Peters, 1981).
3) Formerly administered orally as a vasodilator for the treatment of angina pectoris (Baselt, 2000). This use has been rendered obsolete by the presence of more efficacious and less toxic vasodilators (Gilman et al, 1985).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Nitrites are commonly found in the manufacturing industry; they are used in the manufacture of diazo dyes, potassium salts, nitroso compounds, and nitrogen oxide, dyeing and printing textile fabrics, in photography, as reagents in analytical chemistry, as a key chemical in metal treatment and finishing operations, and bleaching flax, silk, and linen. Nitrites are also used in meat curing and preserving, and high inorganic nitrite (KNO2, NaNO2) levels may be found in well water contaminated by septic tanks, municipal sewage, fertilizers, and feed lots where bacteria reduce nitrates to nitrites. Medically, sodium nitrite is used as an adjunct to disinfectant fluids to prevent rusting of the instruments. Sodium nitrite is also used as an antidote to cyanide poisoning in combination with sodium thiosulfate. Please refer to "SODIUM NITRITE" management for more information.
B) PHARMACOLOGY: Sodium nitrite acts as a vasodilator and relaxes maximally contracted smooth muscles, especially at the level of the small blood vessels. In the setting of cyanide toxicity, sodium nitrite has its therapeutic effect by creating methemoglobin which scavenges cyanide and possibly by increasing hepatic blood flow. Nitrites oxidize normal (ferrous) hemoglobin to ferric hemoglobin (methemoglobin).
C) TOXICOLOGY: Toxic effects of sodium nitrite are caused by an extension of therapeutic mechanisms. Significant vasodilation may cause hypotension and end-organ hypoperfusion. Excess methemoglobinemia may lead to functional hypoxia. The toxic effects of other nitrites are similar to sodium nitrite's effects.
D) EPIDEMIOLOGY: Overdose is rare.
E) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Hypotension with syncope and tachycardia are common findings in toxicity. Cyanosis may also be noted due to methemoglobinemia. Other common symptoms include headache, nausea, vomiting, and abdominal pain.
2) SEVERE TOXICITY: In cases of severe toxicity, patients may develop severe hypotension, distributive shock, coronary ischemia, cerebrovascular disease, and seizures. Profound methemoglobinemia may lead to respiratory depression, and coma. Death due to nitrite poisoning is caused by uncontrolled vasodilation and hypoperfusion, or by profound methemoglobinemia and functional hypoxia.

0.2.20)

A) Behavioral deficits were observed in the adult offspring of rats who received sodium nitrite prenatally.

0.2.21)

A) Sodium nitrite has shown a potential for carcinogenicity in animals.

Laboratory Monitoring

A)

B)

C)

D)

E)

F)

G)

H)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment of mild to moderate toxicity consists of predominantly symptomatic and supportive care. Patients with mild hypotension should be treated with IV fluid hydration.

B) MANAGEMENT OF SEVERE TOXICITY

1) Patients who develop severe hypotension should be treated first with aggressive IV fluid hydration. Vasopressors should be used with caution as they intensify the arteriolar constriction that is generated by spontaneous reflexes in the nitrite-poisoned patient, thereby further compromising tissue blood flow. METHEMOGLOBINEMIA: Symptomatic patients should be treated with methylene blue. Rarely, pediatric patients with severe methemoglobinemia not responsive to methylene blue therapy may require exchange transfusion; patients may be temporized while awaiting transfusion with hyperbaric oxygen therapy. SEIZURES: Treat seizures with benzodiazepines; add barbiturates if seizures persist.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
2) HOSPITAL: Gastrointestinal decontamination with single-dose activated charcoal may be considered in patients with a recent (within 1 hour) potentially life-threatening ingestion of sodium nitrite who are awake and able to protect their airway.

D) AIRWAY MANAGEMENTS

1) Patients with nitrite toxicity may require intubation for respiratory failure associated with altered mental status due to hypotension or functional hypoxia due to methemoglobinemia.

E) ANTIDOTE

1) There is no specific antidote for treatment of nitrite toxicity. However, patients who develop significant methemoglobinemia (symptomatic patients or patients with a methemoglobin level of greater than 30%) should be treated with methylene blue. Contraindications to treatment with methylene blue include known G-6-PD deficiency (may cause hemolysis), known hypersensitivity to methylene blue, and methemoglobin reductase deficiency.

F) 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.

G) ENHANCED ELIMINATION

1) Hemodialysis is typically not useful for treatment of nitrite toxicity. Exchange transfusion may be considered in severely symptomatic patients, especially neonatal and pediatric patients, if the methemoglobinemia is not responsive to methylene blue therapy. It may also be useful in patients with known G-6-PD deficiency or NADPH-dependent methemoglobin reductase deficiencies. Exchange transfusions are of limited applicability in adults due to the inherent risks of large blood volumes required in adults. Although there is limited data in humans, hyperbaric oxygen (HBO) may be considered as a supportive measure while preparations for exchange transfusion are being made. HBO may provide sufficient oxygen to maintain life with dissolved oxygen in blood, and temporarily obviates the need for functional hemoglobin.

H) PATIENT DISPOSITION

1) OBSERVATION CRITERIA: Patients with deliberate or significant exposure should be sent to a healthcare facility for evaluation, treatment, and observation. Patients who are asymptomatic with normal methemoglobin concentrations can be discharged after 6 hours of observation.
2) ADMISSION CRITERIA: Patients who develop significant hypotension, or signs and symptoms of methemoglobinemia should be admitted to an intensive care unit.
3) CONSULT CRITERIA: Contact a local poison center for a toxicology consult for any patient with suspected symptomatic nitrite toxicity.

I) PITFALLS

1) The arterial pO2 is usually normal despite significant methemoglobinemia. Pulse oximetry may overestimate oxygen saturation in patients with significant methemoglobinemia and should not be used to reflect arterial oxygen content or tissue oxygen delivery. Ongoing absorption can lead to recurrent methemoglobinemia.

J) PHARMACOKINETICS

1) Simple aliphatic nitrites such as ethyl nitrite, isobutyl nitrite, and amyl nitrite are volatile liquids readily absorbed through the lungs. Sodium nitrite is readily absorbed through the GI tract after ingestion, and is commonly given medically intravenously. Approximately 60% of nitrite ions are metabolized, with ammonia as one of the end products; 40% of nitrite is excreted unchanged in the urine.

K) DIFFERENTIAL DIAGNOSIS

1) The differential for nitrite toxicity includes other causes of vasodilatory hypotension, other causes of methemoglobinemia, and in the setting of sodium nitrite treatment for cyanide poisoning, includes the underlying cyanide toxicity.

0.4.3)

A) Move patient to fresh air. Monitor for respiratory distress. Administer oxygen and assist ventilation as required.

0.4.4)

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)

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)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) MILD TO MODERATE TOXICITY: Hypotension with syncope and tachycardia are common findings in toxicity. Cyanosis may also be noted due to methemoglobinemia. Other common symptoms include headache, nausea, vomiting, and abdominal pain.
2) SEVERE TOXICITY: In cases of severe toxicity, patients may develop severe hypotension, distributive shock, coronary ischemia, cerebrovascular disease, and seizures. Profound methemoglobinemia may lead to respiratory depression, and coma. Death due to nitrite poisoning is caused by uncontrolled vasodilation and hypoperfusion, or by profound methemoglobinemia and functional hypoxia.

Heent

3.4.3)

A) VISUAL DISTURBANCES

1) Temporary darkening of the whole visual field of both eyes was reported by one patient who took 14.5 grams of sodium nitrite orally (Vetter, 1951).
2) Application of a 0.08 M solution of sodium nitrite on rabbit corneas has caused no local injury (Grant & Schuman, 1993).

Cardiovascular

3.5.2)

A) VASODILATATION

1) Peripheral vasodilation presents as headache, nausea, vomiting, postural lightheadedness, warm flushed sweaty skin that later becomes cold and cyanotic, syncope, and tachycardia (Gosselin et al, 1984; Ellenhorn & Barceloux, 1988; HSDB , 2000).
2) Peripheral vasodilation produces hypotension, syncope, decreased peripheral vascular resistance, cardiovascular collapse, seizures, and coma in severe toxicity (Gosselin et al, 1984; Ellenhorn & Barceloux, 1988; HSDB , 2000).
3) Fourteen people died as a result of circulatory failure, with peripheral cyanosis noted, due to food poisoning with sodium nitrite and potassium arsenate (Gautami et al, 1995).
4) CASE REPORT: Following ingestion of approximately 0.7 g sodium nitrite in contaminated drinking water, a 34-year-old female developed cyanosis and a sinus tachycardia of 108/min associated with a methemoglobin level of 49% (Bradberry et al, 1993).

Respiratory

3.6.2)

A) CYANOSIS

1) Cyanosis occurs when oxygen binds to methemoglobin which keeps the oxygen bound without releasing it to the tissues. Suspect methemoglobinemia in all cyanotic patients who do not improve with supplemental oxygen.
2) CASE REPORT: 3 phenylpropanolamine production workers presented to the ED with cyanosis and with MetHb levels of 35.8%, 46.3%, and 68.0%, respectively. All were exposed to methyl nitrite (Ger et al, 1996).

Neurologic

3.7.2)

A) HEADACHE

1) Throbbing headache is common secondary to CNS hypoxia and often occurs when the methemoglobin level is 20% to 45% (Shih et al, 1995).

B) SEIZURE

1) Seizures have been reported following severe intoxication.
2) Peripheral vasodilation produces hypotension, syncope, decreased peripheral vascular resistance, cardiovascular collapse, seizures, and coma in severe toxicity (Gosselin et al, 1984; Ellenhorn & Barceloux, 1988; HSDB , 2000).

C) COMA

1) WITH POISONING/EXPOSURE

a) Peripheral vasodilation produces hypotension, syncope, decreased peripheral vascular resistance, cardiovascular collapse, seizures, and coma in severe toxicity (Gosselin et al, 1984; Ellenhorn & Barceloux, 1988; HSDB , 2000).

3.7.3)

A) ANIMAL STUDIES

1) THINKING ABNORMAL

a) Acute intoxication with sodium nitrite, probably due to hypoxic effects, was reported to provoke damage to the hippocampus and to impair acquisition and performance of several learning tasks in experimental animals (Isaacson & Fahey, 1987; Viveiros & Tondat, 1978).

Gastrointestinal

3.8.2)

A) GASTROENTERITIS

1) Initial effects of nitrite poisoning usually include nausea, vomiting, abdominal pain and diarrhea (Bradberry et al, 1993).

B) ABDOMINAL PAIN

1) Severe abdominal spasms have been prominent in fatal cases of sodium nitrite poisoning.

Hematologic

3.13.2)

A) METHEMOGLOBINEMIA

1) Cyanosis that minimally responds to oxygen therapy may be noted and is indicative of probable methemoglobinemia.
2) Nitrite-generated methemoglobinemia presents as cyanosis of the lips and the mucous membranes at methemoglobin levels as low as 1.5 grams/deciliter (10% saturation in a patient with normal hemoglobin levels) (Ellenhorn & Barceloux, 1988).
3) If nitrite-induced, methemoglobinemia is characterized by delayed onset and sustained circulating levels (Smith et al, 1967).
4) CASE REPORTS: 2 cases of methyl nitrite-induced methemoglobinemia occurred in workers exposed accidentally to the gas used in the synthesis of phenylpropanolamine. Measured methemoglobin levels were 31.3% and 58.9%. The latter worker had worn an organic filter mask to clean up a methyl nitrite spill and had an 80 minute delay in symptomatology, suggesting an enteric route of exposure other than inhalation. The authors suggest a possible contribution of dermal absorption. Both workers recovered after receiving methylene blue 1 mg/kg IV (Wax & Hoffman, 1994).
5) CASE REPORTS: 3 cases of methyl nitrite-induced methemoglobinemia were reported in pharmaceutical phenylpropanolamine production workers. All 3 presented to the ED with general weakness, chest tightness, dizziness and cyanosis. MetHb levels were 35.8%, 46.3%, and 68.0% respectively. Death occurred in one of the workers due to a shortage of methylene blue during transportation to the hospital (Ger et al, 1996).
6) CASE SERIES: An outbreak of methemoglobinemia was reported following contamination of soup in a school cafeteria from nitrites used in boiler water treatment solutions. Cyanosis was reported in many of the children. Fourteen children were treated with supplemental oxygen and IV methylene blue for methemoglobinemia. Recovery was complete for all children within 36 hours (Askew et al, 1994).

Dermatologic

3.14.2)

A) CYANOSIS

1) Cyanosis, minimally responding to oxygen, has been noted and is indicative of probable methemoglobinemia.
2) ACROCYANOSIS has been reported in a 28-year-old HIV-infected male who admitted to inhalational abuse of butyl nitrite over a 2 week period prior to onset of symptoms. No other vasoactive agents were used. Symptoms included increasing, painless, livid to gray bluish macules with edema of the nose, ears, and back of hands in a symmetrical pattern. Methemoglobin levels were normal. The patient returned to normal after stopping butyl nitrite abuse (Hoegl et al, 1999).

Reproductive

3.20.1)

A) Behavioral deficits were observed in the adult offspring of rats who received sodium nitrite prenatally.

3.20.2)

A) ANIMAL STUDIES

1) There is no evidence of teratogenicity from animal data using acceptable nitrate or nitrite ingestions.
2) Adverse effects (decreased weight gain, alopecia, stillbirth) were reported in animals at maternal doses 1000 times higher than estimated human intake (Fan et al, 1987; Grant & Butler, 1989).
3) ANIMAL DATA indicate that sodium nitrite crosses the placenta and can induce methemoglobinemia in the fetus (Gruener et al, 1973).

a) 2 grams/liter of sodium nitrite given to rats throughout the second half of pregnancy caused inferior auditory and visual discrimination and impaired passive avoidance response among the male adult offspring (Nyakas et al, 1990).
b) These behavioral deficits were eliminated with the calcium antagonist, nimodipine, which was given daily to the pregnant rats at a dose of 10 mg/kg orally.

Carcinogenicity

3.21.2)

A) Sodium nitrite has shown a potential for carcinogenicity in animals.

3.21.3)

A) HUMANS

1) Sodium nitrite was detected in a human promyeloleukemia cell line and was shown to have a cell-transforming activity by itself.
2) Formation of carcinogenic N-nitrosamines was not observed (Tsuda & Hasegawa, 1990) in contrast to earlier studies attributing carcinogenicity to production of nitrosamines (Mokhtar et al, 1988; Wang et al, 1988).

B) ANIMAL STUDIES

1) The potential of sodium nitrite to induce tumor growth has been inferred in animal studies where sodium nitrite was made to react with both endogenous and exogenous substances (Kikugawa & Kato, 1988) Yamamoto et al, 1989; (Hoorn, 1989; Robbiano et al, 1990).
2) This carcinogenicity was not observed in the long-term feeding of rats for up to 115 weeks (Grant & Butler, 1990).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Serum nitrite concentrations are not widely available or clinically useful.
B) Determine CBC and methemoglobin concentration in all cyanotic patients or patients with dyspnea or other signs of respiratory distress.
C) Arterial blood gases should be monitored in symptomatic or cyanotic patients. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.
D) Monitor vital signs.
E) Monitor renal function in symptomatic patients.
F) Monitor serum electrolyte status in patients with significant vomiting.
G) Monitor mental status and perform a neurologic exam in symptomatic patients.
H) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.

4.1.2)

A) HEMATOLOGIC

1) Monitor CBC and methemoglobin levels in symptomatic patients.

B) ACID/BASE

1) Arterial blood gases should be monitored in symptomatic or cyanotic patients.
2) 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).
3) Arterial blood will be blue or "chocolate brown" even after exposure to oxygen (Forsyth & Moulden, 1991).

Methods

A)

1) BLOOD METHEMOGLOBIN LEVELS should be determined for diagnostic and therapeutic monitoring.
2) Results may be expressed as grams of methemoglobin per deciliter (g/dL) or as a percentage (percent of hemoglobin that has been converted to methemoglobin).
3) CALCULATIONS - To calculate percent methemoglobin, determine the ratio of methemoglobin/hemoglobin in grams (eg, 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) METHEMOGLOBIN LEVELS WILL BE REDUCED if blood is not analyzed rapidly (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)

1) Confirmation of exposure to NITROBENZENE can be made by gas chromatographic analysis of expired air collected in a saran bag.
2) Quantitative measurement of TRINITROGLYCERIN can be performed by gas-liquid chromatography (Wei & Reid, 1979).
3) NITRITE may be determined in biological fluids:

a) By a sulfanilic acid-alpha-naphthylamine colorimetric diazotization technique (Baselt, 1980);
b) With the use of an ion-selective electrode (Choi & Fung, 1980);
c) With high-pressure liquid chromatography (Thayer & Huffaker, 1980).
d) Urine strips have been developed using the Griess nitrite-specific diazonium ion salt reaction. The sensitivity is 0.5 mcg NO2/mL in plasma and water (Rodriguez et al, 1992).

Treatment

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Treatment of mild to moderate toxicity consists of predominantly symptomatic and supportive care. Patients with mild hypotension should be treated with IV fluid hydration.

2) MANAGEMENT OF SEVERE TOXICITY

a) Patients who develop severe hypotension should be treated first with aggressive IV fluid hydration. Vasopressors should be used with caution as they intensify the arteriolar constriction that is generated by spontaneous reflexes in the nitrite-poisoned patient, thereby further compromising tissue blood flow. METHEMOGLOBINEMIA: Symptomatic patients should be treated with methylene blue. Rarely, pediatric patients with severe methemoglobinemia not responsive to methylene blue therapy may require exchange transfusion; patients may be temporized while awaiting transfusion with hyperbaric oxygen therapy. SEIZURES: Treat seizures with benzodiazepines; add barbiturates if seizures persist.

B) MONITORING OF PATIENT

1) Serum nitrite concentrations are not widely available or clinically useful.
2) Determine CBC and methemoglobin concentration in all cyanotic patients or patients with dyspnea or other signs of respiratory distress.
3) Arterial blood gases should be monitored in symptomatic or cyanotic patients. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.
4) Monitor vital signs.
5) Monitor serum electrolyte status in patients with significant vomiting.
6) Monitor CBC and renal function in symptomatic patients.
7) Monitor mental status and perform a neurologic exam in symptomatic patients.
8) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.

C) 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.

D) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

E) HYPOTENSIVE EPISODE

1) Vasopressors should be used only when needed and with utmost CAUTION as they intensify the arteriolar constriction that is generated by spontaneous reflexes in the nitrite-poisoned patients, thereby further compromising tissue blood flow (Gosselin et al, 1984).
2) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

3) 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).

4) 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).

F) HYPERBARIC OXYGEN THERAPY

1) 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).
2) Although, in human nitrite poisoning, hyperbaric oxygen deserves a clinical trial, insufficient data exist in the literature to support its widespread use. Further studies on the role of hyperbaric oxygen in human nitrate poisoning are indicated (Smith & Gosselin, 1976).
3) Has additive effect with methylene blue in protecting mice against death by nitrite (Sheehy & Way, 1974).

Inhalation Exposure

6.7.1)

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)

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)

A) DERMAL DECONTAMINATION

1) Nitrites may be absorbed through skin, especially if the chemicals are hot.
2) 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)

1) 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).
2) May be useful for patients with known G-6-PD or NADPH-dependent methemoglobin reductase deficiencies (Harrison, 1977).
3) Is limited in applicability because of the inherent risks of large blood volumes required in adults.
4) Has been used successfully, at least once, in nitrite-induced methemoglobinemia (Kirby, 1955).

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who develop significant hypotension, or signs and symptoms of methemoglobinemia should be admitted to an intensive care unit.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Contact a local poison center for a toxicology consult for any patient with suspected symptomatic nitrite toxicity.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate or significant exposure should be sent to a healthcare facility for evaluation, treatment, and observation. Patients who are asymptomatic with normal methemoglobin concentrations can be discharged after 6 hours of observation.

Monitoring

A)

B)

C)

D)

E)

F)

G)

H)

Abstracts

Case Reports

A)

1) SODIUM NITRITE

a) ADULT: A 78-year-old man became comatose, apneic, and asystolic after closed-space smoke inhalation. Suspecting a cyanide component to the poisoning, he was given two 300-mg doses of sodium nitrite, the first one given IV over 5 minutes. He became hypotensive and died despite vasopressors and HBO, and had a blood cyanide level of only 0.34 mcg/mL. Death was most likely from the complications of carbon monoxide poisoning, rather than the adverse effects of the administered sodium nitrite (Hall et al, 1989a)
b) INFANT: The ingestion of 130 mg produced severe poisoning in a 2-month-old infant (Oppe, 1951).
c) INFANT: A 17-month-old child died after 450 mg (32 mg/kg) of sodium nitrite was given intravenously in the mistaken impression of acute cyanide poisoning (Berlin, 1970).

Range Of Toxicity

Summary

A)

Minimum Lethal Exposure

A)

1) SODIUM NITRITE

a) The ESTIMATED LETHAL DOSE of sodium nitrite in adults is 2.6 grams (Ten Brink et al, 1982).
b) A 17-year-old female developed central cyanosis, tachycardia, tachypnea, and cardiac arrhythmias prior to her death following ingestion of a 1 gram tablet of sodium nitrite (Gowans, 1990).

Maximum Tolerated Exposure

A)

1) ACCEPTABLE DAILY INTAKE (excluding infants under 6 months of age):

a) NITRITES: 0.4 mg/kg (WHO, 1965)
b) ADULTS: Estimated ingestion of 700 mg of sodium nitrite from the inadvertent dental addition of an anticorrosive agent to drinking water resulted in severe methemoglobinemia (49%) with full recovery after treatment with methylene blue (Bradberry et al, 1993).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) Roughly equivalent oral doses of the same nitrite preparation have produced serum nitrite concentrations that vary widely between individuals (Gowans, 1990).

2) SPECIFIC SUBSTANCE

a) POTASSIUM OR SODIUM NITRITE -

1) Serum nitrite concentrations of 0.5 to 350 milligrams/liter have been reported in fatal cases of sodium or potassium nitrite ingestion (Naidu & Rao, 1936; (Standefer et al, 1979).

Pharmacology Toxicology

Toxicologic Mechanism

A)

B)

1) Methemoglobinemia is the toxic product of this group of compounds. Cyanosis may be detectable at above 15% conversion of normal hemoglobin to methemoglobin. Nitrites, etc + HbFe++--->MeHbFe+++ + Methylene Blue --->HbFe++
2) In treatment, methylene blue is converted to leucomethylene blue in the patient by accepting a hydrogen ion and 2 electrons.

a) The leucomethylene blue then reacts with the MeHbFe+++ to produce normal hemoglobin.
b) Methylene blue in its blue oxidized state is then apparently regenerated by releasing the hydrogen ion and the one remaining electron.
c) MeHbFe+++ is unable to transport oxygen.

3) NOTE -

a) Nitrate may be converted to nitrites in plants and animals; it is nitrite which causes the greatest toxicity. Cyanosis unresponsive to oxygen leads to consideration of the diagnosis of methemoglobinemia.

Physicochemical

Physical Characteristics

A)

Ph

A)

Molecular Weight

A)

Animal Toxicology

Clinical Effects

11.1.1)

A) Signs include polydipsia, vomiting, diarrhea, and hypothermia. Weakness and death follow rapidly. Cyanosis is easily noted on comb and wattles (Pers Comm, 1988).

11.1.5)

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 - Suggested to cause infertility and abortion, stunted growth, immunosupression, and interference with iodine metabolism (Robinson, 1987).

11.1.10)

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)

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 - Suggested to cause infertility and abortion, stunted growth, immunosuppression, and interference with iodine metabolism (Beasley et al, 1989).

Treatment

11.2.1)

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 to terminate exposure.
3) Treatment is aimed at reversing the methemoglobinemia and preventing further absorption of ingested nitrate/nitrite.
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 boarded veterinary toxicologist.
6) ANIMAL POISON CONTROL CENTERS

a) 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
b) 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.
c) 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)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

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 per os.

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 per os. Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram.
2) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) 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/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

2) LARGE ANIMALS

a) DO NOT attempt emesis in ruminants or equids.
b) CATHARTIC - 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. Give 0.5 kilogram sodium sulfate or magnesium sulfate per 400 kilograms of body weight.

1) Dissolve in 0.5 to 1 liter water and give orally via stomach tube. The saline cathartics are especially effective when given 30 to 45 minutes after mineral oil administration.

11.2.5)

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. Although some experimental evidence supports the use of methylene blue to treat methemoglobinemia due to acetaminophen toxicity in cats (Pers Comm, 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; Howard, 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. WHOLE BLOOD TRANSFUSIONS: In adult horses, 4 to 8 liters blood are normally transfused at one time.

a) 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 1:1000 dilution 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)

A) BIRD

1) A 1.5 to 2% 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 body weight (Ley, 1986).

B) CATTLE

1) 330 to 616 milligrams nitrate or 150 to 170 milligrams nitrite per kilogram body weight is a lethal dose for cattle (Humphreys, 1988).

a) Acute poisoning may be expected in cattle when levels exceed 500 milligrams nitrate per liter in the water or 1% (dry matter basis) nitrate in the feed (Howard, 1986).
b) 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).
c) The presence of readily fermentable carbohydrate, 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 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 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) Fetuses and neonates are believed to be more sensitive to nitrite than older animals (Beasley et al, 1989).
2) Carnivores and omnivores are only susceptible to preformed nitrites, because they do not reduce significant amounts of nitrate in their gastrointestinal tract (Beasley et al, 1989).

Continuing Care

11.4.1)

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 to terminate exposure.
3) Treatment is aimed at reversing the methemoglobinemia and preventing further absorption of ingested nitrate/nitrite.
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 boarded veterinary toxicologist.
6) ANIMAL POISON CONTROL CENTERS

a) 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
b) 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.
c) 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)

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 per os.

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 per os. Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram.
2) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) 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/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

2) LARGE ANIMALS

a) DO NOT attempt emesis in ruminants or equids.
b) CATHARTIC - 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. Give 0.5 kilogram sodium sulfate or magnesium sulfate per 400 kilograms of body weight.

1) Dissolve in 0.5 to 1 liter water and give orally via stomach tube. The saline cathartics are especially effective when given 30 to 45 minutes after mineral oil administration.

11.4.3)

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: Serum, urine, gastric lavage fluid, samples of all feed sources, and samples of all water sources should be frozen and submitted on ice for nitrate and nitrite analysis.

a) When interpreting results, the effects of all sources of nitrates and nitrites are cumulative (Beasley et al, 1989).

2) Methemoglobin levels can be quantitated spectrophotometrically on whole blood (Robinson, 1987). Clinical signs appear at 20% and death occurs at 80% methemoglobinemia (Humphreys, 1988).

a) Whole blood must be mixed 1:20 with phosphate buffer (pH 6.6) and frozen to preserve the methemoglobin if the sample can not be tested within 3 hours (Howard, 1986).

Kinetics

11.5.1)

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 post ingestion.

11.5.3)

A) GENERAL

1) Herbivores convert significant amounts of nitrate to nitrite in the rumen or cecum, while an insignificant amount is converted by the liver.

11.5.4)

A) GENERAL

1) Nitrites are primarily excreted by the kidney.

Pharmacology Toxicology

A)

1) 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)

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. 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)

1) The most common source for small animals is ingestion of fertilizer (Beasley et al, 1989).

Other

A)

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 (Boermans, 1990).

References

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FeedBack

NITRITES

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hematologic

Dermatologic

Reproductive

Carcinogenicity

Monitoring Parameters Levels

Methods

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Life Support

Patient Disposition

Monitoring

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Kinetics

Pharmacology Toxicology

Sources

Other

General Bibliography