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4,6-DINITRO-O-CRESOL AND SALTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) 4,6-dinitro-o-cresol is a dinitrophenol compound.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C7-H6-N2-O5 (4,6-DINITRO-o-CRESOL)
    2) C7-H6-N2-O4.C4-H11-N (4,6-DINITRO-o-CRESOL DIETHYLAMINE SALT)
    3) C7-H5-N2-O5.Na (4,6-DINITRO-o-CRESOL SODIUM SALT)

Available Forms Sources

    A) FORMS
    1) Dinitro-o-cresol (DNOC) is an odorless yellowish, prismatic crystalline solid (HSDB , 1993). It is soluble in ethanol, benzene, chloroform, and acetone, and is sparingly soluble in water (HSDB , 1993). In aqueous solution, dinitro-o-cresol is colorless; it turns yellow when alkaline (OHM/TADS, 1993).
    2) The sodium salt of dinitro-o-cresol is a reddish powder (OHM/TADS, 1993). No description of the diethylamine salt was found in available references at the time of this review.
    3) DINITROPHENOLS act by uncoupling oxidative phosphorylation at the cellular level, leading to increased oxygen uptake and diversion of available energy into production of heat, resulting in an increase in body temperature (EPA, 1988; (Fikes et al, 1989; Finkel, 1983; Morgan, 1989).
    B) USES
    1) Dinitro-o-cresol was formerly used as a selective herbicide and an ovicidal insecticide spray for dormant fruit trees (Budavari, 1989; Sax & Lewis, 1989; Sax & Lewis, 1987; EPA, 1985) ACGIH, 1986; (HSDB , 1993; Sittig, 1985; Anon, 1980). It has also been used as a broadleaf herbicide, acaricide, defoliant, fungicide, blossom thinner, for scab apple control, in the dyestuff industry, and to prevent alternate bearing on fruit trees (OHM/TADS, 1993; (HSDB , 1993; Sittig, 1985; Anon, 1980). It is too phytotoxic to be applied on actively growing plants (Sax & Lewis, 1987) OHM/TADS, 1993). It was formerly used in humans to promote weight loss.
    2) DINOTERB, a closely related compound, was formerly used as a pre-emergence herbicide to control annual weeds in vegetable and cereal fields (HSDB , 1993). As dinoterb acetate, it was also used on grapevines and fruit trees as an insecticide and acaricide (HSDB , 1993). As a rodenticide, it was particularly effective against rats and mice (HSDB , 1993). All US EPA registrations for this agent were suspended in 1986 under emergency action to mitigate human exposures (EPA, 1988; (Crawford, 1986) Fikes et al, 1986; (HSDB , 1993).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Dinitro-o-cresol was formerly used as a selective herbicide and insecticide, and is a cumulative poison. Its toxicity is similar to that seen with dinitrophenol, but it is more potent.
    1) Systemic poisoning symptoms can include nausea; vomiting; headache; restlessness; a sensation of heat; flushed skin; fever; diaphoresis; yellow pigmentation of the skin, sclera, and hair; hyperpnea with shortness of breath; cyanosis; tachycardia; convulsions; and coma.
    2) Hepatotoxicity and nephrotoxicity may occur. Following inhalation exposure, coughing, fever, tachycardia, and shortness of breath are most common. Fatalities are usually due to hyperthermia. Local necrosis and systemic absorption may occur following dermal contact. Eye irritation may occur. Toxic psychosis be seen.
    B) Chronic exposure may result in fatigue, anxiety, restlessness, diaphoresis, fever, tachycardia, shortness of breath, cough, and excessive thirst. Nail damage and painless paronychiae have occurred in individuals who chronically handled this material. Chronic ingestion of dinitro-o-cresol as an ill-advised weight loss agent in the past has caused cataracts in humans; occupational exposure has not been reported to cause cataracts.
    1) Workers exposed to a dinitro-o-cresol concentration of 4.7 mg/m(3) developed symptoms of fever, elevated basal metabolic rate, tachycardia, tachypnea, diaphoresis, shortness of breath, and cough. The symptoms cleared when the airborne concentration was decreased to 2.5 mg/m(3).
    2) The risk of significant poisoning is increased when exposure occurs during hot weather. The clinical presentation may mimic thyroid storm. Hyperthermia, hyperpnea, and coma are commonly seen in fatalities due to occupational exposure. Pulmonary edema may be found at autopsy. Yellow skin and appendage staining is most common with dermal contact.
    C) Liver and kidney injury and moderate methemoglobinemia were noted in sheep chronically fed 70 mg/kg. Symptoms noted before death in chronically exposed cats were sluggishness, loss of muscle tone, dyspnea, decreased hemoglobin and RBC counts, elevated WBC counts, and increased blood glucose.
    D) The mechanism of acute toxicity is uncoupling of oxidative phosphorylation by prevention of the conversion of ADP to ATP, resulting in cellular biochemical changes that lead to increased oxygen uptake, increased permeability of mitochondrial membranes to hydrogen ions, and diverting of energy available from metabolism into heat production which raises body temperature.
    0.2.3) VITAL SIGNS
    A) An elevated respiratory rate and temperature with diaphoresis are commonly seen. Tachycardia frequently occurs in acute poisoning.
    0.2.4) HEENT
    A) Dinitro-o-cresol causes eye irritation and yellow scleral staining.
    0.2.5) CARDIOVASCULAR
    A) Systemic dinitro-o-cresol poisoning may be manifested by tachycardia. Cardiac arrhythmias may occur.
    0.2.6) RESPIRATORY
    A) Tachypnea, labored breathing and cyanosis may develop in serious poisoning cases. Coughing and shortness of breath are common. Pulmonary edema may be found at autopsy in fatal cases.
    0.2.7) NEUROLOGIC
    A) Headache, lassitude, confusion, apprehension, and manic behavior may be seen in acute poisoning. Coma and seizures may develop.
    0.2.8) GASTROINTESTINAL
    A) Systemic poisoning symptoms can include nausea and vomiting. The stools may be a bright yellow color.
    0.2.9) HEPATIC
    A) Dinitro-o-cresol can cause hepatic injury.
    0.2.10) GENITOURINARY
    A) Renal tubular injury may occur in acute dinitro-o-cresol poisonings.
    0.2.11) ACID-BASE
    A) Acidosis may be seen in acute poisonings.
    0.2.12) FLUID-ELECTROLYTE
    A) Excessive thirst is common in acute poisonings.
    0.2.13) HEMATOLOGIC
    A) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants. This effect has not been reported in exposed humans.
    0.2.14) DERMATOLOGIC
    A) Yellow staining of the skin, hair, and nails may be seen if direct contact occurs. Profuse sweating or shivering may be noted. Systemic poisoning may be manifested by facial flushing.
    B) Local necrosis and systemic absorption may occur following dermal contact.
    0.2.16) ENDOCRINE
    A) Glucose intolerance after exposure to dinitro-o-cresol compounds has been described.
    0.2.17) METABOLISM
    A) The mechanism of acute toxicity is uncoupling of oxidative phosphorylation by prevention of the conversion of ADP to ATP, resulting in cellular biochemical changes that lead to increased oxygen uptake, increased permeability of mitochondrial membranes to hydrogen ions, and diverting of energy available from metabolism into heat production which raises body temperature.
    B) Basal metabolic rate is greatly increased after exposure secondary to uncoupling of oxidative phosphorylation.
    0.2.18) PSYCHIATRIC
    A) Toxic psychosis may occur. A sense of well-being may occur prior to signs of toxicity.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    B) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    C) Dinitro-o-cresol inhibited the motility of human sperm in an in vitro experiment. Aspermatogenesis has occurred in male rats.
    D) No developmental effects occurred in mice given dinitro-o-cresol from days 11 to 14 of gestation; the numbers for corpora lutea, implantations, resorbed embryos, pre- and post-implantation mortality, and malformations did not differ significantly from controls.
    E) When injected intraperitoneally in male rats at a dose of 0.6 milligrams/kilogram twice weekly for 5 weeks, a 50% dinitro-o-cresol containing pesticide did not significantly increase the number of chromosomal abnormalities in the gonads and germ cells, although a somewhat increased number of autosomal univalents was noted after 3 weeks.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of dinitro-o-cresol in humans.

Laboratory Monitoring

    A) The dinitro-o-cresol compounds can be identified in the serum or urine by a gas-liquid chromatographic method. Such analyses may be useful to confirm the etiology of the poisoning, but are not useful for patient management in acute poisonings. A colorimetric procedure is available for the assay of dinitro-o-cresol in blood. Serum levels of 10 mcg/mL or greater are usually seen when acute toxicity is present.
    1) See Main Document under LABORATORY for a discussion of dinitro-o-cresol levels in occupational biological monitoring.
    B) Glucose intolerance after exposure to dinitro-o-cresol compounds has been described. Monitor blood sugar in significantly exposed patients.
    C) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants. This effect has not been reported in exposed humans.
    1) If cyanosis is present, obtain methemoglobin level and monitor if abnormal.
    D) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count and liver and kidney function tests is suggested for patients with significant exposure.
    E) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.
    F) Pulse oximetry monitoring is an alternative to arterial blood gases.
    G) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    H) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.
    I) If respiratory tract irritation is present, monitor chest x-ray.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Caution may be indicated in substantial recent ingestions because the patient may rapidly become obtunded, comatose, or convulsing, thereby at risk of aspiration of gastric contents into the lungs.
    B) 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.
    C) Significant esophageal or gastrointestinal tract irritation or burns may occur following ingestion. The possible benefit of early removal of some ingested material by cautious gastric lavage must be weighed against potential complications of bleeding or perforation.
    D) 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.
    E) 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.
    F) MONITORING PARAMETERS - Monitor hepatic and renal function tests.
    1) Fluid, electrolyte, blood glucose, and acid-base status should be monitored and abnormalities corrected as indicated.
    G) All intravenous solutions should contain adequate amounts of glucose to supply the requirements of increased metabolism.
    H) HYPERTHERMIA
    1) Reduction of hyperthermia with tepid water baths is superior to alcohol sponging or ice packs which tend to constrict the peripheral circulation and could result in heat retention.
    2) A rectal electrode thermometer, if available, should be used to monitor core temperature.
    3) If tepid bathing is not sufficient, a cooling blanket or bath should be considered.
    4) Administration of SALICYLATES to reduce hyperpyrexia is probably CONTRAINDICATED. Aspirin is also an oxidative phosphorylation uncoupler and may aggravate the hyperpyrexia.
    I) 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.
    J) Atropine SHOULD NOT BE ADMINISTERED as it could exacerbate hyperthermia.
    K) Administration of oxygen may assist in minimizing tissue hypoxia.
    L) Agitation should be controlled with such agents as diazepam to prevent further metabolic heat generation which could aggravate the hyperpyrexia.
    M) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants. This effect has not been reported in exposed humans.
    1) If cyanosis is present, obtain methemoglobin level and monitor if abnormal.
    2) 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.
    3) 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.
    4) 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.
    N) Hemodialysis and forced diuresis have not been shown to be effective in poisoning with these agents. Hemoperfusion has not been sufficiently tested to state whether or not it could have any beneficial effect.
    O) NOTE: See treatment of oral exposure in the main body of this document for complete information.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
    C) Respiratory tract irritation, if severe, can progress to pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.
    D) 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.
    E) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    F) MONITORING PARAMETERS -
    1) Monitor hepatic and renal function tests.
    2) Fluid, electrolyte, blood glucose, and acid-base status should be monitored and abnormalities corrected as indicated.
    G) All intravenous solutions should contain adequate amounts of glucose to supply the requirements of increased metabolism.
    H) HYPERTHERMIA -
    1) Reduction of hyperthermia with tepid water baths is superior to alcohol sponging or ice packs which tend to constrict the peripheral circulation and could result in heat retention.
    2) A rectal electrode thermometer, if available, should be used to monitor core temperature.
    3) If tepid bathing is not sufficient, a cooling blanket or bath should be considered.
    4) Administration of SALICYLATES to reduce hyperpyrexia is probably CONTRAINDICATED. Aspirin is also an oxidative phosphorylation uncoupler and may aggravate the hyperpyrexia.
    I) 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.
    J) Atropine SHOULD NOT BE ADMINISTERED as it could exacerbate hyperthermia.
    K) Administration of oxygen may assist in minimizing tissue hypoxia.
    L) Agitation should be controlled with such agents as diazepam to prevent further metabolic heat generation which could aggravate the hyperpyrexia.
    M) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants. This effect has not been reported in exposed humans.
    1) If cyanosis is present, obtain methemoglobin level and monitor if abnormal.
    2) 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.
    3) 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.
    4) 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.
    N) Hemodialysis and forced diuresis have not been shown to be effective in poisoning with these agents. Hemoperfusion has not been sufficiently tested to state whether or not it could have any beneficial effect.
    O) NOTE: See treatment of inhalation exposure in the main body of this document for complete information.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    B) No cases of systemic toxicity in humans following ocular exposure to this compound have been reported. Should systemic toxicity develop following eye exposure:
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Cutaneous exposure is usually accompanied by a yellowish discoloration which does not have to be removed entirely to prevent absorption.
    3) Severe systemic dinitrophenol poisoning can occur from dermal exposure; hence aggressive and immediate skin decontamination must be undertaken and a physician consulted as soon as possible.
    4) MONITORING PARAMETERS -
    a) Monitor hepatic and renal function tests.
    b) Fluid, electrolyte, blood glucose, and acid-base status should be monitored and abnormalities corrected as indicated.
    5) All intravenous solutions should contain adequate amounts of glucose to supply the requirements of increased metabolism.
    6) HYPERTHERMIA -
    a) Reduction of hyperthermia with tepid water baths is superior to alcohol sponging or ice packs which tend to constrict the peripheral circulation and could result in heat retention.
    b) A rectal electrode thermometer, if available, should be used to monitor core temperature.
    c) If tepid bathing is not sufficient, a cooling blanket or bath should be considered.
    d) Administration of SALICYLATES to reduce hyperpyrexia is probably CONTRAINDICATED. Aspirin is also an oxidative phosphorylation uncoupler and may aggravate the hyperpyrexia.
    7) 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.
    8) Atropine SHOULD NOT BE ADMINISTERED as it could exacerbate hyperthermia.
    9) Administration of oxygen may assist in minimizing tissue hypoxia.
    10) Agitation should be controlled with such agents as diazepam to prevent further metabolic heat generation which could aggravate the hyperpyrexia.
    11) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants. This effect has not been reported in exposed humans.
    a) If cyanosis is present, obtain methemoglobin level and monitor if abnormal.
    b) 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.
    c) 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.
    d) 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.
    12) Hemodialysis and forced diuresis have not been shown to be effective in poisoning with these agents. Hemoperfusion has not been sufficiently tested to state whether or not it could have any beneficial effect.
    13) NOTE: See treatment of dermal exposure in the main body of this document for complete information.

Range Of Toxicity

    A) Normal volunteers developed no symptoms following a single oral dose of 75 milligrams of dinitro-o-cresol. When this same dose was taken daily for 5 or more days, symptoms of malaise, headache, and lassitude developed, and were associated with average blood levels of 20 ppm (peak levels 40 and 48 ppm).
    B) A worker exposed to a dinitro-o-cresol concentration of 4.7 mg/m(3) developed symptoms of fever, elevated basal metabolic rate, tachycardia, tachypnea, diaphoresis, shortness of breath, and cough. The symptoms cleared when the airborne concentration was decreased to 2.5 mg/m(3).
    1) Chronic handling of dinitro-o-cresol resulted in nail damage and painless paronychiae.

Clinical Effects

Summary Of Exposure

    A) Dinitro-o-cresol was formerly used as a selective herbicide and insecticide, and is a cumulative poison. Its toxicity is similar to that seen with dinitrophenol, but it is more potent.
    1) Systemic poisoning symptoms can include nausea; vomiting; headache; restlessness; a sensation of heat; flushed skin; fever; diaphoresis; yellow pigmentation of the skin, sclera, and hair; hyperpnea with shortness of breath; cyanosis; tachycardia; convulsions; and coma.
    2) Hepatotoxicity and nephrotoxicity may occur. Following inhalation exposure, coughing, fever, tachycardia, and shortness of breath are most common. Fatalities are usually due to hyperthermia. Local necrosis and systemic absorption may occur following dermal contact. Eye irritation may occur. Toxic psychosis be seen.
    B) Chronic exposure may result in fatigue, anxiety, restlessness, diaphoresis, fever, tachycardia, shortness of breath, cough, and excessive thirst. Nail damage and painless paronychiae have occurred in individuals who chronically handled this material. Chronic ingestion of dinitro-o-cresol as an ill-advised weight loss agent in the past has caused cataracts in humans; occupational exposure has not been reported to cause cataracts.
    1) Workers exposed to a dinitro-o-cresol concentration of 4.7 mg/m(3) developed symptoms of fever, elevated basal metabolic rate, tachycardia, tachypnea, diaphoresis, shortness of breath, and cough. The symptoms cleared when the airborne concentration was decreased to 2.5 mg/m(3).
    2) The risk of significant poisoning is increased when exposure occurs during hot weather. The clinical presentation may mimic thyroid storm. Hyperthermia, hyperpnea, and coma are commonly seen in fatalities due to occupational exposure. Pulmonary edema may be found at autopsy. Yellow skin and appendage staining is most common with dermal contact.
    C) Liver and kidney injury and moderate methemoglobinemia were noted in sheep chronically fed 70 mg/kg. Symptoms noted before death in chronically exposed cats were sluggishness, loss of muscle tone, dyspnea, decreased hemoglobin and RBC counts, elevated WBC counts, and increased blood glucose.
    D) The mechanism of acute toxicity is uncoupling of oxidative phosphorylation by prevention of the conversion of ADP to ATP, resulting in cellular biochemical changes that lead to increased oxygen uptake, increased permeability of mitochondrial membranes to hydrogen ions, and diverting of energy available from metabolism into heat production which raises body temperature.

Vital Signs

    3.3.1) SUMMARY
    A) An elevated respiratory rate and temperature with diaphoresis are commonly seen. Tachycardia frequently occurs in acute poisoning.
    3.3.2) RESPIRATIONS
    A) An elevated respiratory rate is commonly seen in acute poisoning (Morgan, 1993; HSDB, 1998).
    3.3.3) TEMPERATURE
    A) An elevated temperature may be seen following exposure (Smith, 1981; Hathaway et al, 1996; Lewis, 1998). Fatal hyperpyrexia may occur (Finkel, 1983).
    1) Elevated temperature with profuse diaphoresis is virtually always found after acute toxic exposure (Birdstrup & Payne, 1951; MacBryde & Taussig, 1935).
    3.3.5) PULSE
    A) A rapid pulse is frequently seen in acute poisoning (Morgan, 1993; HSDB, 1998; Sittig, 1991; (Budavari, 1996).

Heent

    3.4.1) SUMMARY
    A) Dinitro-o-cresol causes eye irritation and yellow scleral staining.
    3.4.3) EYES
    A) SCLERAL STAINING - In acute poisoning, the sclera may be stained yellow (Morgan, 1993; (Hathaway et al, 1996).
    B) IRRITATION - Eye irritation may occur (Lewis, 1996; Grant, 1993).
    C) CATARACTS - Use of dinitro-o-cresol compounds as obesity control agents in the past resulted in development of cataracts following chronic ingestion (Finkel, 1983; Kurt et al, 1986; Grant, 1993; Sittig, 1985).
    1) No cataracts due to occupational dinitro-o-cresol exposure have been reported (Hathaway et al, 1996; Sittig, 1985).
    D) GLAUCOMA - Glaucoma has developed secondary to the cataracts (Grant, 1993).

Cardiovascular

    3.5.1) SUMMARY
    A) Systemic dinitro-o-cresol poisoning may be manifested by tachycardia. Cardiac arrhythmias may occur.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) A rapid pulse is frequently seen in acute poisoning (Morgan, 1993; HSDB, 1998; (Lewis, 1998; Budavari, 1996).
    B) CONDUCTION DISORDER OF THE HEART
    1) Cardiac arrhythmias may be noted (Sittig, 1991).

Respiratory

    3.6.1) SUMMARY
    A) Tachypnea, labored breathing and cyanosis may develop in serious poisoning cases. Coughing and shortness of breath are common. Pulmonary edema may be found at autopsy in fatal cases.
    3.6.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) Tachypnea, labored breathing and cyanosis may develop in serious poisoning cases (Morgan, 1993).
    B) HYPERVENTILATION
    1) An elevated respiratory rate is commonly seen in acute poisoning (Morgan, 1993; HSDB, 1998; (Hathaway et al, 1996).
    C) COUGH
    1) Following inhalation exposure, coughing and shortness of breath are common (EPA, 1985; ILO, 1998).
    D) ACUTE LUNG INJURY
    1) Pulmonary edema may be found at autopsy in fatal cases (Baselt & Cravey, 1995).

Neurologic

    3.7.1) SUMMARY
    A) Headache, lassitude, confusion, apprehension, and manic behavior may be seen in acute poisoning. Coma and seizures may develop.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) Headache, lassitude, confusion, apprehension, and manic behavior may be seen in acute poisoning (Morgan, 1993; (Lewis, 1996).
    B) COMA
    1) Coma may develop in serious poisonings (Morgan, 1993; (ILO, 1998).
    C) SEIZURE
    1) Convulsions may be noted in seriously poisoned patients (Morgan, 1993).

Gastrointestinal

    3.8.1) SUMMARY
    A) Systemic poisoning symptoms can include nausea and vomiting. The stools may be a bright yellow color.
    3.8.2) CLINICAL EFFECTS
    A) STOOL FINDING
    1) Stools may be a bright yellow color (Smith, 1981).
    B) NAUSEA AND VOMITING
    1) Systemic poisoning symptoms can include nausea and vomiting (EPA, 1985) Morgan, 1993; Sittig, 1991; (Birdstrup & Payne, 1951).

Hepatic

    3.9.1) SUMMARY
    A) Dinitro-o-cresol can cause hepatic injury.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) Dinitro-o-cresol can cause hepatic injury with associated jaundice (HSDB, 1998; (Birdstrup & Payne, 1951) Sittig, 1991).

Genitourinary

    3.10.1) SUMMARY
    A) Renal tubular injury may occur in acute dinitro-o-cresol poisonings.
    3.10.2) CLINICAL EFFECTS
    A) RENAL TUBULAR DISORDER
    1) Renal tubular injury may occur in acute poisonings (Morgan, 1989) HSDB, 1998; (Birdstrup & Payne, 1951).
    B) RENAL FAILURE SYNDROME
    1) Dinitro-o-cresol can cause kidney failure (Sittig, 1991).

Acid-Base

    3.11.1) SUMMARY
    A) Acidosis may be seen in acute poisonings.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Acidosis may be seen in acute poisonings (HSDB, 1998).

Hematologic

    3.13.1) SUMMARY
    A) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants. This effect has not been reported in exposed humans.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants (Froslie & Karlog, 1970; Froslie, 1973; Hayes, 1982). This effect has not been reported in exposed humans.

Dermatologic

    3.14.1) SUMMARY
    A) Yellow staining of the skin, hair, and nails may be seen if direct contact occurs. Profuse sweating or shivering may be noted. Systemic poisoning may be manifested by facial flushing.
    B) Local necrosis and systemic absorption may occur following dermal contact.
    3.14.2) CLINICAL EFFECTS
    A) DISCOLORATION OF SKIN
    1) Yellow staining of the skin, hair, and nails may be seen if direct contact occurs (Smith, 1981) Morgan, 1993; (Leftwich et al, 1982; Hathaway et al, 1996).
    B) EXCESSIVE SWEATING
    1) Profuse sweating may be noted (Smith, 1981; Hathaway et al, 1996; Budavari, 1996).
    C) CHILL
    1) Shivering may be noted (Smith, 1981).
    D) FLUSHING
    1) Systemic poisoning symptoms can include a sensation of heat; flushed skin; diaphoresis; yellow pigmentation of the skin, sclera, and hair; and cyanosis (EPA, 1985; ACGIH, 1991; Baselt & Cravey, 1995) Morgan, 1993; Sittig, 1991; (Birdstrup & Payne, 1951).
    E) SKIN NECROSIS
    1) Local necrosis and systemic absorption may occur following dermal contact (Baselt & Cravey, 1995; Hathaway et al, 1996).

Endocrine

    3.16.1) SUMMARY
    A) Glucose intolerance after exposure to dinitro-o-cresol compounds has been described.
    3.16.2) CLINICAL EFFECTS
    A) ABNORMAL GLUCOSE TOLERANCE TEST
    1) Glucose intolerance after exposure to dinitro-o-cresol compounds has been described (MacBryde & Taussig, 1935).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    B) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    C) Dinitro-o-cresol inhibited the motility of human sperm in an in vitro experiment. Aspermatogenesis has occurred in male rats.
    D) No developmental effects occurred in mice given dinitro-o-cresol from days 11 to 14 of gestation; the numbers for corpora lutea, implantations, resorbed embryos, pre- and post-implantation mortality, and malformations did not differ significantly from controls.
    E) When injected intraperitoneally in male rats at a dose of 0.6 milligrams/kilogram twice weekly for 5 weeks, a 50% dinitro-o-cresol containing pesticide did not significantly increase the number of chromosomal abnormalities in the gonads and germ cells, although a somewhat increased number of autosomal univalents was noted after 3 weeks.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    B) ANIMAL STUDIES
    1) 4,6-dinitro-o-cresol was not teratogenic is mice (Schardein, 1993).
    3.20.3) EFFECTS IN PREGNANCY
    A) LABOR ABNORMAL
    1) DNOC was thought to have induced premature labor in one of 3 pregnant agricultural workers who developed poisoning following 8 hours of dermal exposure (ATSDR, 1995). All three workers delivered healthy infants.
    B) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) No developmental effects occurred in mice given dinitro-o-cresol from days 11 to 14 of gestation; the numbers for corpora lutea, implantations, resorbed embryos, pre- and post-implantation mortality, and malformations did not differ significantly from controls (Hathaway et al, 1996).
    2) DINOSEB, a closely related compound, is embryotoxic, fetotoxic, and teratogenic in experimental animals and has inhibited the development of sperm and male fertility in rats.
    3) METHEMOGLOBINEMIA
    a) DINITROPHENOLS can induce METHEMOGLOBINEMIA in experimental animals. The fetus and newborn may be at special risk from methemoglobinemia (Rayner, 1986; Ross & Desforges, 1959; Harley & Celermajer, 1970; Schmitz, 1961; Rane & Ackermann, 1972). The fetal form of hemoglobin, which is still present at birth, is more easily oxidized to methemoglobin, and levels of methemoglobin reductase are lower in the fetus than in the adult (Ross & Desforges, 1959).
    b) Refer to NITROBENZENE for a more detailed discussion of the effects of methemoglobinemia on the unborn.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS534-52-1 (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) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of dinitro-o-cresol in humans.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) 4,6-Dinitro-o-cresol has caused DNA repair in microorganisms. 4,6-Dinitro-o-cresol and its sodium salt have caused mutations in S. typhimurium. 4,6-Dinitro-o-cresol has caused sex chromosome loss and nondisjunction in D. melanogaster. It was negative in rodent dominant lethal testing. Chromosomal aberrations have been observed in human lymphocytes, rat and mouse bone marrow, and in embryos fathered by treated male mice.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) The dinitro-o-cresol compounds can be identified in the serum or urine by a gas-liquid chromatographic method. Such analyses may be useful to confirm the etiology of the poisoning, but are not useful for patient management in acute poisonings. A colorimetric procedure is available for the assay of dinitro-o-cresol in blood. Serum levels of 10 mcg/mL or greater are usually seen when acute toxicity is present.
    1) See Main Document under LABORATORY for a discussion of dinitro-o-cresol levels in occupational biological monitoring.
    B) Glucose intolerance after exposure to dinitro-o-cresol compounds has been described. Monitor blood sugar in significantly exposed patients.
    C) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants. This effect has not been reported in exposed humans.
    1) If cyanosis is present, obtain methemoglobin level and monitor if abnormal.
    D) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count and liver and kidney function tests is suggested for patients with significant exposure.
    E) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.
    F) Pulse oximetry monitoring is an alternative to arterial blood gases.
    G) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    H) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.
    I) If respiratory tract irritation is present, monitor chest x-ray.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) In normal volunteers who ingested dinitro-o-cresol, symptoms were noted when blood levels exceeded 15 to 20 micrograms/liter (Baselt & Cravey, 1995). This was evidence of cumulative toxicity, as these blood levels could not be obtained with a single daily dose of the amount administered (ACGIH, 1991). Workers exposed by inhalation to a concentration of 0.2 milligrams per cubic meter for 5 to 48 hours had blood levels ranging from 1.4 to 4.3 milligrams/Liter on the day following termination of exposure (Baselt & Cravey, 1995).
    a) When 75 milligrams of dinitro-o-cresol were taken daily for 5 or more days, symptoms of malaise, headache, and lassitude developed, and were associated with average blood levels of 20 ppm (peak levels 40 and 48 ppm) (ACGIH, 1991).
    b) Toxic effects will most likely be seen in individuals with blood levels greater than 40 mcg/gram (milligrams/Liter); those with blood levels between 20 and 40 mcg/gram (milligrams/Liter) may or may not be symptomatic; and those with blood levels less than 20 mcg/gram (milligrams/Liter) are unlikely to be symptomatic (Hathaway et al, 1996).
    c) Serious intoxication in exposed workers has been associated with blood levels of 44 to 60 milligrams/Liter, and a blood level of 75 milligrams/Liter was found in a fatal case (Baselt & Cravey, 1995).
    2) Dinitro-o-cresol compounds can usually be detected in plasma and urine, but these values are of little value in the management of an acutely poisoned patient (Baselt, 1988).
    a) One patient who survived with supportive treatment after poisoning with dinitro-o-cresol had a blood level of 60 mcg/g (milligrams/Liter) (Baselt & Cravey, 1989).
    3) Exposed workers should have weekly blood sampling for dinitro-o-cresol analysis. The samples should be obtained no less than 8 hours after the end of exposure each week, because peak levels may not occur for some time after exposure terminates (Baselt, 1997).
    a) When blood dinitro-o-cresol levels reach 10 milligrams/Liter, corrective action to decrease the exposure should be taken, while at blood levels of 20 milligrams/Liter the affected employee should be removed from further exposure and be under medical observation (Baselt, 1997; Anon, 1980; Birdstrup et al, 1952).
    4) Blood levels of dinitro-ortho-cresol have not correlated with urine levels (Harvey, 1952).
    5) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count and liver and kidney function tests is suggested for patients with significant exposure.
    B) OTHER
    1) Glucose intolerance after exposure to dinitro-o-cresol compounds has been described (MacBryde & Taussig, 1935). Monitor blood sugar in significantly exposed patients.
    C) HEMATOLOGIC - Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants (Froslie & Karlog, 1970; Froslie, 1973; Hayes, 1982). This effect has not been reported in exposed humans.
    1) If cyanosis is present, obtain methemoglobin level and monitor if abnormal.
    D) If symptoms develop or overexposure has occurred, it may be useful to monitor liver and kidney function, examine eyes for cataracts, and examine skin and nails for staining (Sittig, 1991).
    4.1.3) URINE
    A) URINALYSIS
    1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.
    2) MONITORING
    a) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.
    b) The dinitro-o-cresol compounds can be identified in the serum or urine spectrophotometrically or by a gas-liquid chromatographic method. Such analyses may be useful to confirm the etiology of the poisoning, but are not useful for patient management in acute poisoning (Morgan, 1993).

Radiographic Studies

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

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) The dinitro-o-cresol compounds can be identified in the serum or urine by a gas-liquid chromatographic method. Such analyses may be useful to confirm the etiology of the poisoning, but are not useful for patient management in acute poisonings. A colorimetric procedure is available for the assay of dinitro-o-cresol in blood. Serum levels of 10 mcg/mL or greater are usually seen when acute toxicity is present.
    1) See Main Document under LABORATORY for a discussion of dinitro-o-cresol levels in occupational biological monitoring.
    B) Glucose intolerance after exposure to dinitro-o-cresol compounds has been described. Monitor blood sugar in significantly exposed patients.
    C) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants. This effect has not been reported in exposed humans.
    1) If cyanosis is present, obtain methemoglobin level and monitor if abnormal.
    D) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count and liver and kidney function tests is suggested for patients with significant exposure.
    E) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.
    F) Pulse oximetry monitoring is an alternative to arterial blood gases.
    G) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    H) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.
    I) If respiratory tract irritation is present, monitor chest x-ray.

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Caution may be indicated in substantial recent ingestions because the patient may rapidly become obtunded, comatose, or convulsing, thereby at risk of aspiration of gastric contents into the lungs.
    B) DILUTION
    1) 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 (Caravati, 2004).
    C) LAVAGE PRECAUTIONS
    1) Significant esophageal or gastrointestinal tract irritation or burns may occur following ingestion. The possible benefit of early removal of some ingested material by cautious gastric lavage must be weighed against potential complications of bleeding or perforation.
    D) 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.
    E) 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) TREATMENT
    A) DILUTION
    1) 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 (Caravati, 2004).
    B) MONITORING OF PATIENT
    1) Monitor hepatic and renal function tests.
    2) Fluid, electrolyte, blood glucose, and acid-base status should be monitored and abnormalities corrected as indicated.
    3) All intravenous solutions should contain adequate amounts of glucose to supply the requirements of increased metabolism.
    C) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Reduction of hyperthermia with tepid water baths is superior to alcohol sponging or ice packs which tend to constrict the peripheral circulation and could result in heat retention.
    2) A rectal electrode thermometer, if available, should be used to monitor core temperature.
    3) If tepid bathing is not sufficient, a cooling blanket or bath should be considered.
    4) Administration of SALICYLATES to reduce hyperpyrexia is probably CONTRAINDICATED. Aspirin is also an oxidative phosphorylation uncoupler and may aggravate the hyperpyrexia.
    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) ATROPINE
    1) Atropine SHOULD NOT BE ADMINISTERED as it could exacerbate hyperthermia (Morgan, 1993).
    F) OXYGEN
    1) Administration of oxygen may assist in minimizing tissue hypoxia (Morgan, 1993).
    G) PSYCHOMOTOR AGITATION
    1) Agitation should be controlled with such agents as diazepam to prevent further metabolic heat generation which could aggravate the hyperpyrexia (Morgan, 1989).
    2) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    3) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) 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 (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) 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 (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    5) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    H) METHEMOGLOBINEMIA
    1) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants (Froslie & Karlog, 1970; Froslie, 1973; Hayes, 1982). This effect has not been reported in exposed humans.
    2) If cyanosis is present, obtain methemoglobin level and monitor if abnormal.
    3) 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.
    4) 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).
    5) 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.
    I) 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).
    J) PULSE OXIMETRY
    1) Pulse oximetry monitoring is an alternative to arterial blood gases.
    K) IRRITATION SYMPTOM
    1) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
    2) Respiratory tract irritation, if severe, can progress to noncardiogenic pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.
    3) There are no controlled studies indicating that early administration of corticosteroids can prevent the development of noncardiogenic pulmonary edema in patients with inhalation exposure to respiratory irritant substances, and long-term use may cause adverse effects (Boysen & Modell, 1989).
    a) However, based on anecdotal experience, some clinicians do recommend early administration of corticosteroids (such as methylprednisolone 1 gram intravenously as a single dose) in an attempt to prevent the later development of pulmonary edema.
    1) Anecdotal experience with dimethyl sulfate inhalation showed possible benefit of methylprednisolone in the TREATMENT of noncardiogenic pulmonary edema (Ip et al, 1989).
    4) Anecdotal experience also indicated that systemic corticosteroids may have possible efficacy in the TREATMENT of drug-induced noncardiogenic pulmonary edema (Zitnik & Cooper, 1990; Stentoft, 1990; Chudnofsky & Otten, 1989) or noncardiogenic pulmonary edema developing after cardiopulmonary bypass (Maggart & Stewart, 1987).
    5) It is not clear from the published literature that administration of systemic corticosteroids early following inhalation exposure to respiratory irritant substances can PREVENT the development of noncardiogenic pulmonary edema. The decision to administer or withhold corticosteroids in this setting must currently be made on clinical grounds.
    6) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    7) PULMONARY EDEMA -
    a) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    b) 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).
    1) 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)
    c) 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).
    d) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    e) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    f) 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).
    g) 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).
    B) MONITORING OF PATIENT
    1) Monitor hepatic and renal function tests.
    2) Fluid, electrolyte, blood glucose, and acid-base status should be monitored and abnormalities corrected as indicated.
    3) All intravenous solutions should contain adequate amounts of glucose to supply the requirements of increased metabolism.
    C) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Reduction of hyperthermia with tepid water baths is superior to alcohol sponging or ice packs which tend to constrict the peripheral circulation and could result in heat retention.
    2) A rectal electrode thermometer, if available, should be used to monitor core temperature.
    3) If tepid bathing is not sufficient, a cooling blanket or bath should be considered.
    4) Administration of SALICYLATES to reduce hyperpyrexia is probably CONTRAINDICATED. Aspirin is also an oxidative phosphorylation uncoupler and may aggravate the hyperpyrexia.
    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) ATROPINE
    1) Atropine SHOULD NOT BE ADMINISTERED as it could exacerbate hyperthermia (Morgan, 1993).
    F) OXYGEN
    1) Administration of oxygen may assist in minimizing tissue hypoxia (Morgan, 1993).
    G) PSYCHOMOTOR AGITATION
    1) Agitation should be controlled with such agents as diazepam to prevent further metabolic heat generation which could aggravate the hyperpyrexia (Morgan, 1989).
    2) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    3) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) 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 (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) 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 (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    5) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    H) METHEMOGLOBINEMIA
    1) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants (Froslie & Karlog, 1970; Froslie, 1973; Hayes, 1982). This effect has not been reported in exposed humans.
    2) If cyanosis is present, obtain methemoglobin level and monitor if abnormal.
    3) 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.
    4) 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).
    5) 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.
    I) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) GENERAL TREATMENT
    1) SYSTEMIC TOXICITY -
    a) No cases of systemic toxicity in humans following ocular exposure to this compound have been reported. Should systemic toxicity develop following eye exposure -
    b) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    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. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).
    B) SKIN DISCOLORATION
    1) Cutaneous exposure is usually accompanied by a yellowish discoloration which does not have to be removed entirely to prevent absorption.
    C) DERMAL ABSORPTION
    1) Severe systemic dinitrophenol poisoning can occur from dermal exposure; hence aggressive and immediate skin decontamination must be undertaken and a physician consulted as soon as possible.
    D) OTHER
    1) DINITROPHENOL COMPOUNDS
    a) The survival doses and lethal doses from application of 3% solutions of various dinitrophenol compounds to guinea pigs is shown below (Spencer et al, 1948) -
    COMPOUNDSURVIVAL DOSE G/KGLETHAL DOSE G/KG
    2-sec-Butyl-4, 6-initrophenol0.10.5
    4,6-Dinitro-o-cresol0.20.5
    2,4-Dinitrophenol0.20.7
    2-Cyclohexyl-4,6- dinitrophenol1.0 or more>1.0
    2-Cyclohexyl-4,6- dinitrophenol compound with dicyclohexylamine1.0 or more>1.0

    6.9.2) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor hepatic and renal function tests.
    2) Fluid, electrolyte, blood glucose, and acid-base status should be monitored and abnormalities corrected as indicated.
    3) All intravenous solutions should contain adequate amounts of glucose to supply the requirements of increased metabolism.
    B) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Reduction of hyperthermia with tepid water baths is superior to alcohol sponging or ice packs which tend to constrict the peripheral circulation and could result in heat retention.
    2) A rectal electrode thermometer, if available, should be used to monitor core temperature.
    3) If tepid bathing is not sufficient, a cooling blanket or bath should be considered.
    4) Administration of SALICYLATES to reduce hyperpyrexia is probably CONTRAINDICATED. Aspirin is also an oxidative phosphorylation uncoupler and may aggravate the hyperpyrexia.
    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) ATROPINE
    1) Atropine SHOULD NOT BE ADMINISTERED as it could exacerbate hyperthermia (Morgan, 1993).
    E) OXYGEN
    1) Administration of oxygen may assist in minimizing tissue hypoxia (Morgan, 1993).
    F) PSYCHOMOTOR AGITATION
    1) Agitation should be controlled with such agents as diazepam to prevent further metabolic heat generation which could aggravate the hyperpyrexia (Morgan, 1989).
    2) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    3) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) 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 (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) 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 (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    5) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    G) METHEMOGLOBINEMIA
    1) Methemoglobinemia has followed administration of dinitro-o-cresol compounds in ruminants (Froslie & Karlog, 1970; Froslie, 1973; Hayes, 1982). This effect has not been reported in exposed humans.
    2) If cyanosis is present, obtain methemoglobin level and monitor if abnormal.
    3) 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.
    4) 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).
    5) 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.
    H) 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).
    I) IRRITATION SYMPTOM
    1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    J) BURN
    1) APPLICATION
    a) These recommendations apply to patients with MINOR chemical burns (FIRST DEGREE; SECOND DEGREE: less than 15% body surface area in adults; less than 10% body surface area in children; THIRD DEGREE: less than 2% body surface area). Consultation with a clinician experienced in burn therapy or a burn unit should be obtained if larger area or more severe burns are present. Neutralizing agents should NOT be used.
    2) DEBRIDEMENT
    a) After initial flushing with large volumes of water to remove any residual chemical material, clean wounds with a mild disinfectant soap and water.
    b) DEVITALIZED SKIN: Loose, nonviable tissue should be removed by gentle cleansing with surgical soap or formal skin debridement (Moylan, 1980; Haynes, 1981). Intravenous analgesia may be required (Roberts, 1988).
    c) BLISTERS: Removal and debridement of closed blisters is controversial. Current consensus is that intact blisters prevent pain and dehydration, promote healing, and allow motion; therefore, blisters should be left intact until they rupture spontaneously or healing is well underway, unless they are extremely large or inhibit motion (Roberts, 1988; Carvajal & Stewart, 1987).
    3) TREATMENT
    a) TOPICAL ANTIBIOTICS: Prophylactic topical antibiotic therapy with silver sulfadiazine is recommended for all burns except superficial partial thickness (first-degree) burns (Roberts, 1988). For first-degree burns bacitracin may be used, but effectiveness is not documented (Roberts, 1988).
    b) SYSTEMIC ANTIBIOTICS: Systemic antibiotics are generally not indicated unless infection is present or the burn involves the hands, feet, or perineum.
    c) WOUND DRESSING:
    1) Depending on the site and area, the burn may be treated open (face, ears, or perineum) or covered with sterile nonstick porous gauze. The gauze dressing should be fluffy and thick enough to absorb all drainage.
    2) Alternatively, a petrolatum fine-mesh gauze dressing may be used alone on partial-thickness burns.
    d) DRESSING CHANGES:
    1) Daily dressing changes are indicated if a burn cream is used; changes every 3 to 4 days are adequate with a dry dressing.
    2) If dressing changes are to be done at home, the patient or caregiver should be instructed in proper techniques and given sufficient dressings and other necessary supplies.
    e) Analgesics such as acetaminophen with codeine may be used for pain relief if needed.
    4) TETANUS PROPHYLAXIS
    a) The patient's tetanus immunization status should be determined. Tetanus toxoid 0.5 milliliter intramuscularly or other indicated tetanus prophylaxis should be administered if required.
    K) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) HEMODIALYSIS -
    a) Hemodialysis has not been shown to be effective in poisoning with these agents (Morgan, 1993).
    2) FORCED DIURESIS -
    a) Forced diuresis has not been shown to be of benefit in reducing the body burden of these agents (Morgan, 1993).
    3) HEMOPERFUSION -
    a) Hemoperfusion has not been sufficiently tested in poisoning with these agents to state whether or not it could have any beneficial effect (Morgan, 1993).

Range Of Toxicity

Summary

    A) Normal volunteers developed no symptoms following a single oral dose of 75 milligrams of dinitro-o-cresol. When this same dose was taken daily for 5 or more days, symptoms of malaise, headache, and lassitude developed, and were associated with average blood levels of 20 ppm (peak levels 40 and 48 ppm).
    B) A worker exposed to a dinitro-o-cresol concentration of 4.7 mg/m(3) developed symptoms of fever, elevated basal metabolic rate, tachycardia, tachypnea, diaphoresis, shortness of breath, and cough. The symptoms cleared when the airborne concentration was decreased to 2.5 mg/m(3).
    1) Chronic handling of dinitro-o-cresol resulted in nail damage and painless paronychiae.

Minimum Lethal Exposure

    A) ACUTE
    1) Dinitrocresol is an extremely toxic substance and the probable oral lethal dose is 5 to 50 milligrams per kilogram of body weight in humans (between 7 drops and 1 teaspoonful for a 70 kilogram person) (Sittig, 1991).
    2) Published values (RTECS, 1998) -
    a) 4,6-DINITRO-o-CRESOL
    1) LDLo (UNREPORTED) MAN - 29 mg/kg
    2) LDLo (SKIN) CHILD - 500 mg/kg
    3) LDLo (IP) RAT - 28 mg/kg
    4) LDLo (SKIN) GUINEA PIG - 500 mg/kg
    5) LDLo (IV) DOG - 15 mg/kg
    6) LDLo (IV) PIGEON - 7 mg/kg
    7) TCLo (INHL) HUMAN - 1 mg/m(3)
    8) TDLo (ORAL) MAN - 7500 mcg/kg/7days
    b) 4,6-DINITRO-o-CRESOL DIETHYLAMINE SALT (RTECS, 1998)
    1) LDLo (ORAL) RAT - 50 mg/kg
    c) 4,6-DINITRO-o-CRESOL SODIUM SALT (RTECS, 1998)
    1) LDLo (Subcutaneous) RAT - 20 mg/kg

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.
    B) CASE REPORTS
    1) Normal volunteers developed no symptoms following a single oral dose of 75 milligrams of dinitro-o-cresol; when this same dose was taken for 5 or more days, symptoms of malaise, headache, and lassitude developed, and were associated with average blood levels of 20 parts per million (peak levels of 40 and 48 parts per million) (ACGIH, 1991).
    2) A worker exposed to a Dinitro-o-cresol concentration of 4.7 milligrams per cubic meter developed symptoms of fever, elevated basal metabolic rate, tachycardia, diaphoresis, shortness of breath, and cough; the symptoms cleared when the airborne concentration was decreased to 2.5 milligrams per cubic meter (ACGIH, 1991).
    3) Serious intoxication in exposed workers has been associated with blood levels of 44 to 60 milligrams/Liter, and a blood level of 75 milligrams/Liter was found in a fatal case (Baselt & Cravey, 1995).
    4) Toxic effects will most likely be seen in individuals with blood levels greater than 40 micrograms per gram (milligrams/Liter); those with blood levels between 20 and 40 micrograms per gram (milligrams/Liter) may or may not be symptomatic; and those with blood levels less than 20 micrograms per gram (milligrams/Liter) are unlikely to be symptomatic (Hathaway et al, 1996).
    5) A 4-year-old child died following dermal exposure to 50 grams of a 25% dinitro-o-cresol containing ointment. Ingestion of 50 and 140 grams of dinitro-o-cresol has been fatal in humans (Hathaway et al, 1993).
    C) CONCENTRATION LEVEL
    1) A non-fatal case of intoxication occurred from an air concentration of 4.7 mg/m(3). Symptoms included fever, basal metabolic rate of 400, rapid pulse and respiration, profuse sweating, shortness of breath, and cough. Reduction of the concentration to 2.5 mg/m(3) eliminated the difficulty (ACGIH, 1991).

Workplace Standards

    A) ACGIH TLV Values for CAS534-52-1 (American Conference of Governmental Industrial Hygienists, 2010):
    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) Dinitro-o-cresol
    a) TLV:
    1) TLV-TWA: 0.2 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: Not Listed
    2) Codes: Skin
    3) Definitions:
    a) 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): Basal metab
    d) Molecular Weight: 198.13
    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 CAS534-52-1 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Dinitro-o-cresol
    2) REL:
    a) TWA: 0.2 mg/m(3)
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    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):
    3) IDLH:
    a) IDLH: 5 mg/m3
    b) Note(s): Not Listed

    C) Carcinogenicity Ratings for CAS534-52-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Dinitro-o-cresol
    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): Not Listed ; Listed as: Dinitro-o-cresol
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS534-52-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Dinitro-o-cresol
    2) Table Z-1 for Dinitro-o-cresol:
    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: 0.2
    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) TOXICITY VALUES
    A) References: (RTECS, 1998)
    1) LD50- (SUBCUTANEOUS)RAT:
    a) 36.5 mg/kg
    B) References: (RTECS, 1998)
    1) LD50- (ORAL)RAT:
    a) 26 mg/kg
    2) LD50- (SKIN)RAT:
    a) 200 mg/kg
    C) References: Lewis, 1996 RTECS, 1998)
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 19 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 47 mg/kg (Lewis, 1996)
    b) 21 mg/kg (RTECS, 1998)
    3) LD50- (ORAL)RAT:
    a) 10 mg/kg
    b) 7 mg/kg
    4) LD50- (SKIN)RAT:
    a) 200 mg/kg
    5) LD50- (SUBCUTANEOUS)RAT:
    a) 25.6 mg/kg

Physicochemical

Physical Characteristics

    A) This compound is an odorless, yellow, crystalline solid (HSDB, 1998; (Hathaway et al, 1996).

Molecular Weight

    A) 198.14 (Budavari, 1996)

References

General Bibliography

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    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
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    7) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    9) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    10) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    11) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    12) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
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