Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1.2.1) MOLECULAR FORMULA
1) C7-H6-N2-O4

Available Forms Sources

A)

1) There are six isomers of dinitrotoluene (ACGIH, 1991):

1) 2,3-Dinitrotoluene
2) 2,4-Dinitrotoluene
3) 2,5-Dinitrotoluene
4) 2,6-Dinitrotoluene
5) 3,4-Dinitrotoluene
6) 3,5-Dinitrotoluene

2) The commercial grade of dinitrotoluene is a mixture composed of approximately 76% of 2,4-dinitrotoluene, 19% of 2,6-dinitrotoluene, and 5% of the other four isomers (ACGIH, 1991).

B)

1) The major use of dinitrotoluene is in the production of toluene diisocyanate and toluenediamine, intermediates for polyurethane foams and polymers. 2,4-Dinitrotoluene is used in the formulation of dyes, in the munitions industry as a modifier for smokeless powders, and as a gelatinizing and waterproofing agent in military and commercial explosive compositions (ACGIH, 1991).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) Dinitrotoluene (DNT) can be absorbed in harmful amounts by the oral, inhalation, or dermal routes.
B) Acute toxic effects of dinitrotoluene exposure are mainly due to its ability to induce methemoglobinemia, which decreases the oxygen-carrying capacity of the blood. Methemoglobinemia results in cyanosis accompanied by headache, irritability, dizziness, weakness, nausea, vomiting, dyspnea, drowsiness, unconsciousness, and possible death. Prolonged exposure can cause hemolytic anemia.
C) Epidemiological studies of explosives workers expected to have substantial exposure to technical-grade dinitrotoluene revealed no correlation between human exposure and development of hepatic cancer. However, an unsuspected excess of mortality from ischemic heart disease was detected in the workers, correlated with exposure to dinitrotoluenes.
D) In experimental animal studies, chronic exposure to the 2,6-dinitrotoluene isomer has been associated with hepatocellular carcinomas.
E) Experimental tumorigenic and teratogenic data exist. Experimental reproductive effects have been documented. Mutation data have been reported for dinitrotoluene.
F) Reported effects from acute exposure in animals include methemoglobinemia, respiratory depression, and seizures.

0.2.3)

A) Respiratory depression secondary to hypoxia may occur.

0.2.4)

A) Headache can occur.

0.2.7)

A) CNS depression is secondary to hypoxia from methemoglobinemia.

0.2.8)

A) Nausea and vomiting may be secondary to methemoglobinemia.

0.2.11)

A) Metabolic acidosis can be a consequence of severe methemoglobinemia.

0.2.13)

A) Methemoglobinemia is the main acute toxic effect; onset of symptoms may be delayed.

0.2.15)

A) Joint pain has been reported.

0.2.20)

A) DNT was NOT teratogenic in rats, and had no effects in a 3-generation study in rats. Testicular effects have been seen in laboratory animals, but not in exposed workers.

0.2.21)

A) No increased risk of cancer mortality has been seen in workers exposed to DNT.

0.2.22)

A) The inhalation, dermal, oral, and ocular routes are all important modes of entry. Alcohol may increase susceptibility. Toxic fumes of nitrogen oxides can be emitted in thermal decomposition.

Laboratory Monitoring

A)

B)

C)

D)

E)

F)

G)

Treatment Overview

0.4.2)

A) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting.
B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
C) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.

1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.

D) OXYGEN - Administer oxygen to all cyanotic patients.
E) METHEMOGLOBINEMIA: 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.
F) 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) 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.
H) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).

1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

I) SHOCK AND CARDIAC ARREST - Treat with standard therapy.
J) ADJUNCTIVE THERAPY - Exchange transfusions and hyperbaric oxygen may be useful cases of in severe methemoglobinemia.

0.4.3)

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.
B) OXYGEN - Administer oxygen to all cyanotic patients.
C) METHEMOGLOBINEMIA: 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.
D) 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.
E) 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.
F) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).

1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

G) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
H) SHOCK AND CARDIAC ARREST - Treat with standard therapy.
I) ADJUNCTIVE THERAPY - Exchange transfusions and hyperbaric oxygen may be useful in cases of severe methemoglobinemia.

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) OXYGEN - Administer oxygen to all cyanotic patients.
3) METHEMOGLOBINEMIA: 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.
4) 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.
5) 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.
6) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).

a) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
b) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

7) SHOCK AND CARDIAC ARREST - Treat with standard therapy.
8) ADJUNCTIVE THERAPY - Exchange transfusions and hyperbaric oxygen may be useful in cases of severe methemoglobinemia.

Range Of Toxicity

A)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

F)

Vital Signs

3.3.1)

A) Respiratory depression secondary to hypoxia may occur.

3.3.2)

A) RESPIRATORY DEPRESSION - May be secondary to hypoxia from methemoglobinemia (Clayton & Clayton, 1994). Respiratory depression has been seen in experimental animals (ACGIH, 1991).

Heent

3.4.1)

A) Headache can occur.

3.4.2)

A) HEADACHE and dizziness may be secondary to hypoxia caused by methemoglobinemia (Sittig, 1985).

3.4.3)

A) IRRITATION POTENTIAL - All 6 isomers were nonirritating to the eye (ACGIH, 1991). Immediate eye irritant (HSDB, 1995).
B) DECREASED VISUAL ACUITY - In one case, vision deteriorated from 20/40 to 6/200 after 3 years of occupational exposure to DNT and mononitrotoluene. Improvement was seen 1 year after discontinuance of exposure (Grant, 1986).

Neurologic

3.7.1)

A) CNS depression is secondary to hypoxia from methemoglobinemia.

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) CNS depression including headache, weakness, dizziness, irritability, narcosis, and unconsciousness, are secondary to hypoxia resulting from methemoglobinemia (Sittig, 1985).

3.7.3)

A) ANIMAL STUDIES

a) Seizures occurred in mice exposed to lethal doses by the oral route (RTECS, 1995). This effect has not been reported in exposed humans.

2) TREMOR

a) Tremors and extensor rigidity were seen in a dog exposed to 10 mg/kg/day of the 2,4- isomer for 8 weeks (ACGIH, 1991; Hathaway et al, 1991).

1) Enlarged astrocytes, encephalomalacia, and hypertrophy of endothelial cells were seen in the dog's cerebellum (ACGIH, 1991).

Gastrointestinal

3.8.1)

A) Nausea and vomiting may be secondary to methemoglobinemia.

3.8.2)

A) NAUSEA AND VOMITING

1) Nausea and vomiting are results of CNS depression from methemoglobinemia (Sittig, 1985).

Hepatic

3.9.3)

A) ANIMAL STUDIES

a) Degenerative and proliferative changes were seen in hepatocytes of rats given 14 or 35 mg/kg/day technical grade DNT in the diet for 26 weeks (ACGIH, 1991).

Acid-Base

3.11.1)

A) Metabolic acidosis can be a consequence of severe methemoglobinemia.

3.11.2)

A) ACIDOSIS

1) Acidosis can be seen when levels of methemoglobin exceed 50 percent.

Hematologic

3.13.1)

A) Methemoglobinemia is the main acute toxic effect; onset of symptoms may be delayed.

3.13.2)

A) METHEMOGLOBINEMIA

1) Methemoglobinemia is the major concern from acute exposures to DNT. Methemoglobinemia can occur following systemic absorption by the oral, dermal, or inhalation routes (Sittig, 1985; ACGIH, 1991; Clayton & Clayton, 1994).

3.13.3)

A) ANIMAL STUDIES

a) Methemoglobinemia, reticulocytosis, anemia, and Heinz bodies have been seen in experimental animals (Hathaway et al, 1991).

1) Methemoglobinemia increased 7-fold in rats given 0.5% DNT in the diet for 6 months (ACGIH, 1991).
2) Hemolytic anemia was reported in dogs exposed to 10 mg/kg/day (2,4- isomer), and in rats given 35 mg/kg/day (technical grade) in the diet for 3 months (ACGIH, 1991).
3) Hematological parameters returned to normal in dogs and rats within 1 month after cessation of exposure (ACGIH, 1991).

Dermatologic

3.14.3)

A) ANIMAL STUDIES

a) The 2,4-, 2,6- and 3,5- isomers were not irritating to the skin of rabbits, while the 2,3-, 3,4-, and 2,5- isomers were mild irritants (ACGIH, 1991; Hathaway et al, 1991).
b) The 2,6- isomer was a mild sensitizer in guinea pigs, while the other 5 isomers were inactive (ACGIH, 1991).

Musculoskeletal

3.15.1)

A) Joint pain has been reported.

3.15.2)

A) JOINT PAIN

1) Joint pain has been reported (Clayton & Clayton, 1994).

Immunologic

3.19.3)

A) ANIMAL STUDIES

a) The 2,6- isomer was a mild sensitizer in guinea pigs, while the other 5 isomers were inactive (ACGIH, 1991).

Reproductive

3.20.1)

A) DNT was NOT teratogenic in rats, and had no effects in a 3-generation study in rats. Testicular effects have been seen in laboratory animals, but not in exposed workers.

3.20.2)

A) ANIMAL STUDIES

1) LACK OF EFFECT

a) DNT was not teratogenic in rats given oral doses as high as 150 mg/kg/day on days 7 through 20 of gestation (76% 2,4-DNT, 19% 2,6-DNT, 2.4% 3,4-DNT, 1.5% 2,3-DNT, and < 1% other isomers) (Price et al, 1985) Schardein, 1994).

1) Increased resorptions (not statistically significant) were seen in the highest dose group, where maternal toxicity was also present (Price et al, 1985).

b) The technical grade was not teratogenic or embryotoxic in rats given oral doses up to 100 mg/kg/day from day 7 to 20 of gestation, or through parturition, where signs of maternal toxicity (methemoglobinemia) were present (Wolkowski-Tyl et al, 1981).
c) No effects were seen in a 3-generation study in rats given 34 mg/kg/day (males) or 45 mg/kg/day (females) (Clayton & Clayton, 1994).

3.20.3)

A) ABORTION

1) A slight increase in spontaneous abortions was seen in a group of wives of 30 workers exposed to DNT (Hathaway et al, 1991). This was not confirmed in another study of 20 workers, however (ACGIH, 1991).

B) METHEMOGLOBINEMIA

1) The fetus may be at special risk from methemoglobin inducers, because of its more critical need for oxygen and because fetal methemoglobin has a longer half-life than the adult form.

3.20.4)

A) LACK OF INFORMATION

1) No studies were found to assess the potential effects of DNT on lactation.

3.20.5)

A) ANIMAL STUDIES

1) FERTILITY DECREASED MALE

a) Nonfunctional ovaries were seen in mice. Testicular effects, including reduced fertility, have been seen in several experimental species. Reported increases in spontaneous abortions and reduced sperm counts in humans have not been confirmed.

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS25321-14-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) No increased risk of cancer mortality has been seen in workers exposed to DNT.

3.21.3)

A) HEPATIC CARCINOMA

1) An excess of hepatobiliary cancer was found in a mortality study of 4989 DNT-exposed workers; an exposure-response relationship between DNT exposure duration and hepatobiliary cancer mortality was not demonstrated, however (Stayner et al, 1993).

B) BLADDER CANCER

1) Three of 60 workers employed in the manufacturing of nitrotoluene explosives developed urothelial carcinoma of the urinary bladder. The data suggested that the bladder cancers were associated with long-term, high-dose exposures (Harth et al, 2005).

C) LACK OF EFFECT

1) No evidence of carcinogenicity was seen in a group of munitions workers exposed to DNT (Hathaway et al, 1991; HSDB , 1996).

3.21.4)

A) HEPATIC CARCINOMA

1) Dinitrotoluene was an equivocal tumorigenic agent in rats. It induced liver tumors at a total oral dose of 12,775 mg/kg/year (RTECS, 1995).
2) Hepatocellular carcinomas were induced by the 2,6- isomer in rats given 7 or 14 mg/kg/day for 1 year (ACGIH, 1991; Hathaway et al, 1991).
3) Induction of hepatocellular carcinomas was specific to the 2,6-isomer. Doses of 2,4-DNT up to 27 mg/kg/day in the diet for 1 year were not carcinogenic (ACGIH, 1991; Hathaway et al, 1991).
4) A mixture of the 2,4- and 2,6- isomers (76%:18%) gave an intermediate incidence of hepatocellular tumors: 35 mg/kg/day produced tumors in 47% of the animals (Hathaway et al, 1991).
5) Inconsistent results of 4 different carcinogenicity studies can be explained on the basis of varying proportions of this isomer in the test material.

B) CARCINOMA

1) In a National Cancer Institute study, rats given >95% pure 2,4-DNT in the diet for 18 months developed subcutaneous fibromas in the males and mammary fibroadenomas in the females. No evidence of carcinogenicity was seen in mice of either sex (ACGIH, 1991).

C) LACK OF EFFECT

1) The 2,6- isomer did not induce pulmonary tumors in mice at the maximum-tolerated dose of 125 mg/kg intraperitoneally or 250 mg/kg orally (ACGIH, 1991).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Blood or urine levels are not clinically useful. Laboratory should be directed toward managing metabolic acidosis and methemoglobinemia.
B) If patient is cyanotic, obtain CBC, electrolytes, arterial blood gases, chest x-ray, EKG, and methemoglobin level.
C) If O2 saturation on blood gases can be measured instead of calculated, this should be done.
D) If patient is not cyanotic but has ingested or been exposed to a methemoglobin producing substance, methemoglobin level may be drawn as a baseline.
E) If chronic cyanosis not due to pulmonary disease (especially if family history of cyanosis is present), hemoglobin electrophoresis, methemoglobin reductase level, and/or G-6-PD activity measurement may be indicated.
F) NOTE - METHEMOGLOBIN LEVELS will be ARTIFICIALLY LOW if BLOOD is NOT ANALYZED RAPIDLY (FEW HOURS). Bedside determination can be made by placing a drop of blood on filter paper with a control drop of blood nearby. With greater than 15% methemoglobinemia, the affected blood will have a chocolate brown color in comparison with the control blood.
G) Monitor liver and kidney function tests in patients with chronic exposure.

4.1.2)

A) ACID/BASE

1) Arterial blood gases should be obtained in cyanotic patients; metabolic acidosis may occur.
2) There may be a significant disparity between the calculated and measured O2 saturation values due to the presence of methemoglobin.

a) pO2 is usually normal, even in the presence of severe methemoglobinemia.

3) Metabolic acidosis is secondary to tissue hypoxia and mandates immediate treatment.

a) Methemoglobin is incapable of reversibly binding oxygen. Metabolic acidosis occurs when the methemoglobin level is high enough to result in tissue hypoxia (generally >50%).
b) Partial respiratory compensation for the metabolic acidosis usually occurs.

4) The PO2 and O2 saturation percentages are usually normal, even in severe methemoglobinemia, reflecting normal pulmonary function.

a) PO2 is a measurement of the partial pressure of oxygen in plasma and is not a direct measurement of oxygen bound to hemoglobin, and O2 saturation when CALCULATED is merely extrapolated from the PO2 and assumes normal hemoglobin is present.
b) Therefore, in disease states in which hemoglobin is abnormal (eg, methemoglobinemia, carbon monoxide poisoning), the arterial blood gas measurements are extremely unreliable. However, if oxygen saturations are MEASURED directly, then a discrepancy between measured and calculated oxygen saturations will be seen.
c) Whenever there is a marked difference between measured and calculated O2 saturations, methemoglobinemia or carbon monoxide poisoning should be suspected.
d) Hypoxia may result from loss of respiratory drive if the patient is comatose.

5) A disparity between the oxygen saturation calculated from PaO2 values and pulse oximetry readings may provide an important clue to the presence of methemoglobinemia.

a) Pulse oximetry overestimates oxygen saturation and should not be used to reflect arterial oxygen content or tissue oxygen delivery, but SpO(2) reading must be interpreted correctly (Watcha et al, 1989; Bardoczky et al, 1990; Barker et al, 1989) Rieder, 1989).

6) Treatment of methemoglobinemia should be guided by direct measurements of oxyhemoglobin using a cooximeter and not on the basis of measurements using pulse oximetry or on estimates of saturations calculated from the PaO2 and the oxyhemoglobin dissociation curve (Watcha et al, 1989).

B) HEMATOLOGIC

1) Hemoglobin Level should be obtained. Anemic patients may have greater symptoms and require treatment at lower methemoglobin levels.
2) Chronic familial methemoglobinemia should prompt a search for an abnormal hemoglobin or enzyme deficiency. Hemoglobin electrophoresis, methemoglobin reductase activity, and G-6-PD activity measurements may be diagnostic.

C) BLOOD/SERUM CHEMISTRY

1) Plasma levels generally are not useful (Hall et al, 1986).

4.1.3)

A) URINALYSIS

1) Patients with significant exposure should have baseline urinalysis with followup as indicated.
2) Urinalysis may show brown or black discoloration, casts, and protein.

4.1.4)

A) OTHER

1) ECG

a) Cardiac monitoring is recommended, especially in patients with underlying diseases known to increase susceptibility.
b) Sinus tachycardia is frequently present and may be secondary to anxiety, tissue hypoxia, or acidosis. If the acidosis and tissue hypoxia are severe enough, ischemic changes, ventricular arrhythmias, and cardiac arrest may result.

2) MONITORING

a) Urinary levels of 2,4-dinitrobenzoic acid increased in end-of-shift samples of workers in an explosives factory (ACGIH, 1991).
b) Methemoglobin determinations should be more clinically useful than monitoring metabolites. Determination of specific metabolites may be useful to confirm exposure to DNT.

Radiographic Studies

A)

1) If respiratory tract irritation is present, monitor chest x-ray.

Methods

A)

1) METHEMOGLOBIN LEVEL (percent of total hemoglobin): Diagnostic; levels >15% usually produce symptoms; cyanosis may be present with level of 15%. Methemoglobin levels will be reduced if blood is not analyzed rapidly (few hours) by endogenous methemoglobin reductase.
2) Serial levels should be obtained because continued absorption of the inducing agent may occur for up to 24 hours (Hall et al, 1986).
3) BEDSIDE TEST - As methemoglobin levels approach 15% to 20%, the blood turns chocolate brown; a drop of the patient's blood placed on filter paper can be compared with that of a control to make the diagnosis while awaiting definitive serum levels.

a) In clinical practice, physicians may delay diagnosis of methemoglobinemia by relying too much on their bedside acumen in detecting chocolate-brown blood. Subtle changes in the appearance of sampled blood may be easily missed if the clinician is not looking specifically for them, and the chocolate-brown color is difficult to identify (Henretig et al, 1988).
b) In an asymptomatic but cyanotic patient in whom methemoglobinemia is suspected, none of the bedside techniques commonly recommended are completely reliable; diagnosis should be pursued with a spectrophotometric analysis.
c) In symptomatic patients, the use of a control for comparison is helpful in identifying darker than normal blood following exposure to air.

4) BUBBLING OXYGEN - Involves bubbling 100% oxygen through a sample of venous blood. While normal hemoglobin will turn bright red, methemoglobin will not.
5) POTASSIUM CYANIDE - Venous blood containing significant methemoglobin concentrations diluted by 1:100 with deionized water will turn bright pink with the addition of a crystal of potassium cyanide, secondary to production of cyanmethemoglobin (Done, 1976).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Any cyanotic or dyspneic patient with clinically significant methemoglobinemia, or any patient with a methemoglobin level >20%, should be admitted to the intensive care unit, even if improvement has occurred after appropriate emergency department management.
B) Patients with significant exposure should probably be admitted and observed for possible delayed development of methemoglobinemia.
C) Patients with altered mental status should be observed continuously on an inpatient basis because of the possibility of mixed ingestion of toxic substances. Sudden deterioration may occur in cases of toxic ingestion.
D) In less severe cases of methemoglobinemia, the possibility of continued absorption of the toxic agent must be ruled out before the patient may be safely discharged. When doubt exists, it is probably best to admit the patient.

6.3.3)

6.3.3.1) ADMISSION CRITERIA/INHALATION

A) All patients demonstrating cyanosis with symptoms, or methemoglobin levels greater than 20 percent, should be admitted. In less severe cases of methemoglobinemia, the possibility of continued absorption of the toxic agent must be ruled out before the patient may be safely discharged. When doubt exists, it is probably best to admit the patient.
B) Patients exposed to thermal decomposition products should probably be admitted for observation.

6.3.5)

6.3.5.1) ADMISSION CRITERIA/DERMAL

A) All patients demonstrating cyanosis with symptoms, or methemoglobin levels greater than 20 percent, should be admitted. In less severe cases of methemoglobinemia, the possibility of continued absorption of the toxic agent must be ruled out before the patient may be safely discharged. When doubt exists, it is probably best to admit the patient.

Monitoring

A)

B)

C)

D)

E)

F)

G)

Oral Exposure

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).

B) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) OXYGEN

1) 100% oxygen should be administered to all cyanotic patients. Cyanosis secondary to methemoglobinemia will not respond to oxygen therapy. Lack of response to oxygen therapy is diagnostic of methemoglobinemia.

B) METHEMOGLOBINEMIA

1) Profound cyanosis may occur in individuals with methemoglobinemia who appear to be in no respiratory distress. The blood should be examined and compared to normal blood to identify chocolate-brown color, signifying a methemoglobin level of at least 15%.
2) 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.

3) 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).

4) 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.

5) METHYLENE BLUE/PRECAUTIONS

a) METHEMOGLOBINEMIA - Although methylene blue has been reported to itself cause methemoglobin formation up to about 7% of total hemoglobin (Whitwam et al, 1979; Goluboff & Wheaton, 1961; Nadler et al, 1934), this hypothesis has been disputed (Stossel & Jennings, 1966; Rentsch & Wittekind, 1967) and the amounts said to be induced are clinically insignificant (Hall et al, 1986).
b) HEMOLYSIS - Repeated large doses (up to 15 milligrams/kilogram) may cause hemolysis (Jaffe, 1979; Harvey & Keitt, 1983) particularly in the presence of G-6-PD deficiency. The dangers of repeated appropriate doses of methylene blue (1 to 2 milligrams/kilogram) are uncertain, but it is recommended that with rare exceptions the total dosage should not exceed 7 milligrams/kilogram (Wintrobe, 1974; Harvey & Keitt, 1983). Methylene blue may be ineffective in patients with G-6-PD deficiency (Rosen et al, 1971).
c) OTHER - reported adverse effects from high doses of methylene blue include chest pain, dyspnea, anxiety, and tremors (Nadler et al, 1934).
d) FALSE POSITIVE CO-OXIMETER RESULTS - Methylene blue may cause a false positive methemoglobin level when measuring arterial blood gases using a co-oximeter (Kirlangitis et al, 1990).

C) 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).

D) HYPERBARIC OXYGEN THERAPY

1) If the patient is not responsive to methylene blue, hyperbaric oxygen has been recommended as adjunctive therapy in severe cases (Donovan, 1983). In animals, HBO has been shown to decrease mortality alone and in combination with methylene blue (Sheehy & Way, 1974; Goldstein & Doull, 1971).
2) In life-threatening cases, hyperbaric oxygen therapy allows dissolving of sufficient oxygen in the blood to maintain life, even without the oxygen-carrying capacity of hemoglobin.
3) It is indicated as adjunctive therapy in patients with severe symptomatic methemoglobinemia who do not respond to methylene blue as it can sustain life during preparation for exchange transfusion.

E) EXCHANGE TRANSFUSION

1) Should be done immediately if the methemoglobinemia is not responsive to methylene blue and is progressive in a symptomatic individual.
2) Should be considered if the methemoglobin level approaches 70 percent and cannot be controlled by the use of methylene blue.

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.

6.7.2)

A) OXYGEN

1) 100% oxygen should be administered to all cyanotic patients. Cyanosis secondary to methemoglobinemia will not respond to oxygen therapy. Lack of response to oxygen therapy is diagnostic of methemoglobinemia.

B) METHEMOGLOBINEMIA

1) Profound cyanosis may occur in individuals with methemoglobinemia who appear to be in no respiratory distress. The blood should be examined and compared to normal blood to identify chocolate-brown color, signifying a methemoglobin level of at least 15%.
2) 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.

3) 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).

4) 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.

5) METHYLENE BLUE/PRECAUTIONS

a) METHEMOGLOBINEMIA - Although methylene blue has been reported to itself cause methemoglobin formation up to about 7% of total hemoglobin (Whitwam et al, 1979; Goluboff & Wheaton, 1961; Nadler et al, 1934), this hypothesis has been disputed (Stossel & Jennings, 1966; Rentsch & Wittekind, 1967) and the amounts said to be induced are clinically insignificant (Hall et al, 1986).
b) HEMOLYSIS - Repeated large doses (up to 15 milligrams/kilogram) may cause hemolysis (Jaffe, 1979; Harvey & Keitt, 1983) particularly in the presence of G-6-PD deficiency. The dangers of repeated appropriate doses of methylene blue (1 to 2 milligrams/kilogram) are uncertain, but it is recommended that with rare exceptions the total dosage should not exceed 7 milligrams/kilogram (Wintrobe, 1974; Harvey & Keitt, 1983). Methylene blue may be ineffective in patients with G-6-PD deficiency (Rosen et al, 1971).
c) OTHER - reported adverse effects from high doses of methylene blue include chest pain, dyspnea, anxiety, and tremors (Nadler et al, 1934).
d) FALSE POSITIVE CO-OXIMETER RESULTS - Methylene blue may cause a false positive methemoglobin level when measuring arterial blood gases using a co-oximeter (Kirlangitis et al, 1990).

C) 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).

D) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

E) HYPERBARIC OXYGEN THERAPY

1) If the patient is not responsive to methylene blue, hyperbaric oxygen has been recommended as adjunctive therapy in severe cases (Donovan, 1983). In animals, HBO has been shown to decrease mortality alone and in combination with methylene blue (Sheehy & Way, 1974; Goldstein & Doull, 1971).
2) In life-threatening cases, hyperbaric oxygen therapy allows dissolving of sufficient oxygen in the blood to maintain life, even without the oxygen-carrying capacity of hemoglobin.
3) It is indicated as adjunctive therapy in patients with severe symptomatic methemoglobinemia who do not respond to methylene blue as it can sustain life during preparation for exchange transfusion.

F) EXCHANGE TRANSFUSION

1) Should be done immediately if the methemoglobinemia is not responsive to methylene blue and is progressive in a symptomatic individual.
2) Should be considered if the methemoglobin level approaches 70 percent and cannot be controlled by the use of methylene blue.

G) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

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) 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).
2) SPEED IS OF THE UTMOST IMPORTANCE - in preventing absorption of toxic doses.

B) CLOTHING

1) Remove all contaminated clothing and shoes and place into sealed containers for regulated disposal. Take precautions to prevent secondary contamination of emergency response and medical personnel.

6.9.2)

A) OXYGEN

1) 100% oxygen should be administered to all cyanotic patients. Cyanosis secondary to methemoglobinemia will not respond to oxygen therapy. Lack of response to oxygen therapy is diagnostic of methemoglobinemia.

B) METHEMOGLOBINEMIA

1) Profound cyanosis may occur in individuals with methemoglobinemia who appear to be in no respiratory distress. The blood should be examined and compared to normal blood to identify chocolate-brown color, signifying a methemoglobin level of at least 15%.
2) 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.

3) 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).

4) 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.

5) METHYLENE BLUE/PRECAUTIONS

a) METHEMOGLOBINEMIA - Although methylene blue has been reported to itself cause methemoglobin formation up to about 7% of total hemoglobin (Whitwam et al, 1979; Goluboff & Wheaton, 1961; Nadler et al, 1934), this hypothesis has been disputed (Stossel & Jennings, 1966; Rentsch & Wittekind, 1967) and the amounts said to be induced are clinically insignificant (Hall et al, 1986).
b) HEMOLYSIS - Repeated large doses (up to 15 milligrams/kilogram) may cause hemolysis (Jaffe, 1979; Harvey & Keitt, 1983) particularly in the presence of G-6-PD deficiency. The dangers of repeated appropriate doses of methylene blue (1 to 2 milligrams/kilogram) are uncertain, but it is recommended that with rare exceptions the total dosage should not exceed 7 milligrams/kilogram (Wintrobe, 1974; Harvey & Keitt, 1983). Methylene blue may be ineffective in patients with G-6-PD deficiency (Rosen et al, 1971).
c) OTHER - reported adverse effects from high doses of methylene blue include chest pain, dyspnea, anxiety, and tremors (Nadler et al, 1934).
d) FALSE POSITIVE CO-OXIMETER RESULTS - Methylene blue may cause a false positive methemoglobin level when measuring arterial blood gases using a co-oximeter (Kirlangitis et al, 1990).

C) 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).

D) HYPERBARIC OXYGEN THERAPY

1) If the patient is not responsive to methylene blue, hyperbaric oxygen has been recommended as adjunctive therapy in severe cases (Donovan, 1983). In animals, HBO has been shown to decrease mortality alone and in combination with methylene blue (Sheehy & Way, 1974; Goldstein & Doull, 1971).
2) In life-threatening cases, hyperbaric oxygen therapy allows dissolving of sufficient oxygen in the blood to maintain life, even without the oxygen-carrying capacity of hemoglobin.
3) It is indicated as adjunctive therapy in patients with severe symptomatic methemoglobinemia who do not respond to methylene blue as it can sustain life during preparation for exchange transfusion.

E) EXCHANGE TRANSFUSION

1) Should be done immediately if the methemoglobinemia is not responsive to methylene blue and is progressive in a symptomatic individual.
2) Should be considered if the methemoglobin level approaches 70 percent and cannot be controlled by the use of methylene blue.

F) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) No methods of extracorporeal elimination have been shown to be effective with dinitrotoluene.

Abstracts

Range Of Toxicity

Summary

A)

Minimum Lethal Exposure

A)

1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

A)

1) The maximum tolerated human exposure to this agent has not been delineated.

B)

1) Cyanosis was observed in rats administered 60 mg/kg/day of 2,4-dinitrotoluene for 5 days (Hathaway et al, 1991).
2) Severe anemia occurred in dogs administered 25 mg/kg/day and rats administered 206 mg/kg/day for 13 weeks. Mild anemia was seen in mice given 441 mg/kg/day for the same duration (Hathaway et al, 1991).
3) Neurologic signs were noted in one dog receiving 10 mg/kg/day of 2,4-dinitrotoluene for 8 weeks, and consisted of tremors followed by extensor rigidity (Hathaway et al, 1991).
4) Administration of 7 or 14 mg/kg/day of 2,6-dinitrotoluene for 1 year produced hepatocellular carcinomas in 85% and 100% of the animals, respectively. In contrast, a diet of 27 mg/kg/day of 2,4-dinitrotoluene for 1 year caused no tumors (Hathaway et al, 1991).
5) All six isomers have been found to be nonirritating in the eyes of rabbits. Applied to the skin of rabbits, 2,4-, 2,6-, and 3,5-dinitrotoluene were nonirritating, whereas 2,3-, 3,4-, and 2,5- were mildly to moderately irritating (Hathaway et al, 1991).
6) Guinea pig dermal sensitivity studies found a mild response to 2,6-dinitrotoluene, while the five other dinitrotoluene isomers exhibited no sensitizing activity (ACGIH, 1991).

Workplace Standards

A)

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Dinitrotoluene

a) TLV:

1) TLV-TWA: 0.2 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A3
2) Codes: BEI(M), Skin
3) Definitions:

a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
b) BEI(M): The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational. Substances identified as Methemoglobin Inducers (for which methemoglobin is the principal cause of toxicity) are part of this notation.
c) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.

c) TLV Basis - Critical Effect(s): Card impair; repro eff
d) Molecular Weight: 182.15

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS25321-14-6 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Dinitrotoluene
2) REL:

a) TWA: 1.5 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
e) Skin Designation: [skin]

1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.

f) Note(s): See Appendix A

3) IDLH:

a) IDLH: 50 mg/m3
b) Note(s): Ca

1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

C) Carcinogenicity Ratings for CAS25321-14-6 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Dinitrotoluene

a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.

2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Dinitrotoluene

a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).

5) MAK (DFG, 2002): Category 2 ; Listed as: Dinitrotoluenes (mixtures of isomers)

a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.

6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS25321-14-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Dinitrotoluene
2) Table Z-1 for Dinitrotoluene:

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 1.5

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: Yes
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) References: (Lewis, 1992; RTECS, 1994

1) LD50- (ORAL)MOUSE:

a) 750 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

A)

B)

Physicochemical

Physical Characteristics

A)

1) ODOR: Characteristic odor (NIOSH, 1994)
2) COLOR: Yellow (ACGIH, 1991); Orange-yellow (NFPA, 1991) NIOSH, 1994)
3) No information about the taste of dinitrotoluene was found at the time of this review.

B)

1) 2,3-Dinitrotoluene
2) 2,4-Dinitrotoluene
3) 2,5-Dinitrotoluene
4) 2,6-Dinitrotoluene
5) 3,4-Dinitrotoluene
6) 3,5-Dinitrotoluene

C)

D)

Ph

1) No information found at the time of this review.

Molecular Weight

A)

Animal Toxicology

References

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FeedBack

DINITROTOLUENE

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

Vital Signs

Heent

Neurologic

Gastrointestinal

Hepatic

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography