FORMOTHION

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1.2.1) MOLECULAR FORMULA
1) C6-H12-N-O4-P-S2

Available Forms Sources

1) Formothion is an organophosphate compound. It is a viscous yellow oil or crystalline mass; it solidifies at approximately 25 degrees C (HSDB , 2000). It is miscible with xylene, ketones, ether, alcohols, chloroform, and benzene, and is sparingly soluble in water (HSDB , 2000).
2) The effects of many of the organophosphates are similar. This review is based on the properties of organophosphates in general, with effects attributed specifically to formothion noted.

1) Formothion is used as a systemic or contact insecticide and acaricide (Sax & Lewis, 1987; EPA, 1985; Budavari, 1996; HSDB , 2000).
2) The ACGIH has established a Biological Exposure Index (BEI) for organophosphate cholinesterase inhibitors. Refer to the BIOMONITORING section for more information.

Overview

Life Support

Clinical Effects

0.2.1)

A) Formothion is an organophosphate compound. The following are symptoms from organophosphates in general, which are due to the anticholinesterase activity of this class of compounds. All of these effects may not be documented for formothion, but could potentially occur in individual cases.

1) In addition to typical anticholinesterase poisoning symptoms, formothion caused contact sensitization dermatitis with papules, erythema, and edema in one worker following direct skin contact. Irritation was not seen when formothion was instilled directly into the eyes of rabbits.

B) MUSCARINIC (PARASYMPATHETIC) EFFECTS may include bradycardia, bronchospasm, bronchorrhea, salivation, lacrimation, diaphoresis, vomiting, diarrhea, and miosis. NICOTINIC (SYMPATHETIC AND MOTOR) EFFECTS may include tachycardia, hypertension, fasciculations, muscle cramps, weakness, and RESPIRATORY PARALYSIS. CENTRAL EFFECTS may include CNS depression, agitation, confusion, delirium, coma, and seizures.
C) Children may exhibit different predominant signs and symptoms than adults: CNS depression, stupor, flaccidity, dyspnea, and coma are the most common signs in children.

0.2.3)

A) Fever, bradycardia and hypotension, or tachycardia and hypertension may occur.

0.2.4)

A) Miosis, lacrimation, and blurred vision are common; mydriasis may occur in severe poisonings. Opsoclonus has been reported in one case. Salivation commonly occurs.
B) Irritation was NOT seen when formothion was instilled directly into the eyes of rabbits.

0.2.5)

A) Bradycardia, hypotension, and chest pain may occur. Tachycardia and hypertension may also be noted. Dysrhythmias and conduction defects may occur in severe poisonings. Myocarditis may develop.

0.2.6)

A) Dyspnea, rales, bronchorrhea, bronchospasm, or tachypnea may be noted. Noncardiogenic pulmonary edema may occur in severe cases. Chemical pneumonitis may be seen.
B) Bronchospasm may occur in previously sensitized asthmatics or as a pharmacological muscarinic effect.
C) Acute respiratory insufficiency is the main cause of death in acute poisonings.
D) Most organophosphate compounds can release toxic and irritating fumes on thermal decomposition. Exposure to such fumes could cause chemical pneumonitis, bronchospasm, or noncardiogenic pulmonary edema.

0.2.7)

A) Headache, dizziness, muscle spasms and profound weakness are common. Alterations of level of consciousness, anxiety, paralysis, seizures and coma may occur. Seizures may be more common in children.
B) Peripheral neuropathy of the mixed sensory-motor type may be delayed by 6 to 21 days following exposure to some organophosphates. Recovery may be slow or incomplete.
C) Dyskinesias may develop. Abnormal neuropsychiatric tests and EEGs may persist for months after acute exposure.

0.2.8)

A) Vomiting, hypersalivation, diarrhea, fecal incontinence and abdominal pain may occur.
B) Intussusception has been reported in a single pediatric organophosphate poisoning case.
C) Pancreatitis has been reported with organophosphate poisoning.

0.2.10)

A) Increased urinary frequency or, in severe cases, urinary incontinence has occurred.
B) Immune-complex nephropathy with proteinuria and/or amorphous crystalluria may be possible.

0.2.11)

A) Metabolic acidosis has occurred in several severe poisonings.

0.2.13)

A) Alteration in prothrombin time and/or tendency to bleeding may occur. Clinically significant bleeding or hypercoagulability are rare.
B) The hallmark of organophosphate poisoning is the inhibition of plasma pseudocholinesterase or erythrocyte acetylcholinesterase, or both.

0.2.14)

A) Sweating is a consistent but not universal sign.

0.2.15)

A) Muscle weakness, fatiguability and fasciculations are common findings and may be delayed by several days. Paralysis may supervene.

0.2.16)

A) Hyperglycemia and glycosuria without ketosis may be present.

0.2.17)

A) Hyperglycemia and glycosuria without ketosis may occur in severe poisoning.

0.2.18)

A) Decreased vigilance, defects in expressive language and cognitive function, impaired memory, depression, anxiety or irritability and psychosis have been reported, more commonly in persons having other clinical signs of organophosphate poisoning or pre-existing psychological conditions.
B) Psychosis may be noted following acute poisoning.
C) Abnormal neuropsychiatric tests and EEGs may persist for months after acute exposure.

0.2.20)

A) Formothion was not teratogenic or embryotoxic in rabbits at doses of 6 to 30 mg/kg given by gavage from days 6 to 18 of gestation.
B) No information about possible male reproductive effects was found in available references at the time of this review.

0.2.22)

A) Delayed toxicity can occur from acute exposure to highly lipophilic organophosphates.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) Inducing emesis is CONTRAINDICATED because of possible respiratory depression and seizures.
B) 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.

C) 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.
D) Suction oral secretions until atropinization.
E) ATROPINE THERAPY - If symptomatic, administer IV atropine until atropinization is achieved. Adult - 2 to 5 mg every 10 to 15 minutes; Child - 0.05 mg/kg every 10 to 15 minutes. Atropinization may be required for hours to days depending on severity.
F) Treat moderate to severe poisoning (fasciculations, muscle weakness, respiratory depression, coma, seizures) with pralidoxime in addition to atropine; most effective if given within 48 hours. Administer for 24 hours after cholinergic manifestations have resolved. May require prolonged administration.
G) BOLUS DOSE: The WHO currently recommends an initial bolus of at least 30 mg/kg followed by a continuous infusion of more than 8 mg/kg/hour.

1) ALTERNATIVE DOSE: ADULT: An alternative initial dose for adults is 1 to 2 grams diluted in 100 mL of normal saline infused over 15 to 30 minutes.
2) ALTERNATIVE DOSE: CHILD: An alternate initial dose for children is 20 to 50 mg/kg (maximum: 2 grams/dose) infused over 30 minutes as a 5% solution in normal saline

H) CONTINUOUS INFUSION: A continuous infusion of pralidoxime is generally preferred to intermittent bolus dosing. DOSE: ADULT: The WHO recommends an infusion of more than 8 mg/kg/hour following the initial loading dose. An alternative is an infusion of 500 mg/hour as a 2.5% solution OR a 5% solution may be used in patients with pulmonary edema. CHILD: Administer 10 to 20 mg/kg/hour of a solution containing 10 to 20 mg of pralidoxime/mL.
I) MAXIMUM DOSE: ADULT: Maximum recommended dose is pralidoxime 12 grams in 24 hours.
J) CONTRAINDICATIONS - Succinylcholine and other cholinergic agents.
K) 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.

L) 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.
M) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.

0.4.3)

A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
B) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
C) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
D) Suction oral secretions until atropinization.
E) CONTRAINDICATIONS - Succinylcholine and other cholinergic agents are contraindicated.

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
B) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.
C) Suction oral secretions until atropinization.
D) CONTRAINDICATIONS - Succinylcholine and other cholinergic agents are contraindicated.

0.4.5)

A) OVERVIEW

1) Systemic effects can occur from dermal exposure to organophosphates.
2) 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).
3) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
4) CONTRAINDICATIONS - Succinylcholine and other cholinergic agents are contraindicated.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) Fever, bradycardia and hypotension, or tachycardia and hypertension may occur.

3.3.3)

A) Fever occurred in a 5-year-old boy who had ingested a small amount of a mixture of parathion, diazinon and chlordane; it persisted for two days (DePalma et al, 1970).

3.3.4)

A) Bradycardia and hypotension occur following moderate to severe poisoning (Ganendran, 1974). Hypotension (systolic blood pressure less than 90 mmHg) occurred in 20 percent of patients in one study (Bardin et al, 1987).
B) Hypertension can occur as a nicotinic effect of organophosphate poisoning (Lund & Monteagudo, 1986).

3.3.5)

A) Bradycardia and hypotension occur following moderate to severe poisoning (Ganendran, 1974). A heart rate of less than 60 beats/minute occurred in 21 percent of patients in one study (Bardin et al, 1987).
B) Tachycardia is also common (Zwiener & Ginsburg, 1988). A heart rate of greater than 100 beats/minute was reported in 49 percent of patients in one study (Bardin et al, 1987).

Heent

3.4.1)

3.4.3)

A) MIOSIS - Intense miosis (pinpoint pupils) is a typical manifestation, and is useful diagnostically, but is not invariably present (pupils may be normal or dilated). Miosis occurred in 50/61 patients (82 percent) in one study (Bardin et al, 1987). Miosis is one of the muscarinic signs of organophosphate poisoning.
B) MYDRIASIS - Severely poisoned individuals may exhibit mydriasis (dilatation of the pupils) (Dixon, 1957).
C) BLURRED VISION - Lacrimation and blurred vision are commonly present; blurred vision may persist for several months (Milby, 1971; Whorton & Obrinsky, 1983).
D) OPSOCLONUS - One case of opsoclonus (rapid, involuntary saccades) developed 3 days after hospital admission in a patient who ingested malathion in an attempted suicide. It gradually resolved over the following 2 weeks (Pullicino & Aquilina, 1989).
E) LACK OF IRRITATION - Irritation was NOT seen when formothion was instilled directly into the eyes of rabbits (HSDB , 2000).
F) DECREASED VISUAL ACUITY - Fenthion has been reported to produce macular lesions in chronically exposed patients, some resulting in compromised vision (Misra et al, 1985).
G) PHOTOPHOBIA - sometimes persisting for several months, has occurred in persons occupationally exposed to mevinphos and phosphamidon residues on leaves of agricultural crops (Whorton & Obrinsky, 1983; Midtling et al, 1985).

3.4.6)

A) SALIVATION - More than 50 percent of patients in one study had excessive salivation (Bardin et al, 1987). Excessive salivation is a muscarinic sign.

Cardiovascular

3.5.1)

A) Bradycardia, hypotension, and chest pain may occur. Tachycardia and hypertension may also be noted. Dysrhythmias and conduction defects may occur in severe poisonings. Myocarditis may develop.

3.5.2)

A) HYPOTENSIVE EPISODE

1) Bradycardia and hypotension occur following moderate to severe poisoning (Ganendran, 1974). Hypotension (systolic blood pressure less than 90 mmHg) occurred in 20 percent of patients in one study (Bardin et al, 1987).

B) CONDUCTION DISORDER OF THE HEART

1) Cardiac dysrhythmias and conduction defects have been reported in patients with severe organophosphate poisoning (Wren et al, 1981; Kiss & Fazekas, 1982; Chhabra & Sepaha, 1970).
2) EKG abnormalities may include sinus bradycardia, A-V dissociation, idioventricular rhythms, multiform premature ventricular extrasystoles, polymorphic ventricular tachycardia, prolongation of the PR, QRS, and QT intervals, and "Torsade de Pointes" polymorphous ventricular dysrhythmias (Brill et al, 1984; Ludomirsky et al, 1982).

C) MYOCARDITIS

1) Occurrence of a protracted toxic myocarditis has been suspected (Wren et al, 1981; Kiss & Fazekas, 1982; Chhabra & Sepaha, 1970).

D) TACHYARRHYTHMIA

1) Tachycardia is also common (Zwiener & Ginsburg, 1988). A heart rate of greater than 100 beats/minute was reported in 49 percent of patients in one study (Bardin et al, 1987).

E) BRADYCARDIA

1) A heart rate of less than 60 beats/minute occurred in 21 percent of patients in one study (Bardin et al, 1987).

F) HYPERTENSIVE EPISODE

1) Hypertension can occur as a nicotinic effect of organophosphate poisoning (Lund & Monteagudo, 1986).

Respiratory

3.6.1)

3.6.2)

A) DYSPNEA

1) Increased bronchial secretions, bronchospasm, chest tightness, heartburn, and dyspnea occur in severe and moderately severe organophosphate poisonings (Hayes, 1965). Rhonchi or crepitations occurred in 48 percent of patients in one study (Bardin et al, 1987). Hypoventilation occurred in 20 percent of patients in one study (Bardin et al, 1987).

B) ACUTE LUNG INJURY

1) Noncardiogenic pulmonary edema is a manifestation of severe organophosphate poisoning (Chhabra & Sepaha, 1970).

C) BRONCHOSPASM

1) Asthma may occur after the inhalation of nontoxic amounts of some organophosphates in sensitive patients with pre-existing asthma (Bryant, 1985).
2) Bronchospasm may also be a pharmacologic effect from the muscarinic activity of organophosphates (Lund & Monteagudo, 1986).

D) HYPERVENTILATION

1) A respiratory rate greater than 30/minute was reported in 39 percent of patients in one study (Bardin et al, 1987).

E) RESPIRATORY FAILURE

1) Acute respiratory insufficiency, due to any combination of depression of the respiratory center, respiratory paralysis, bronchospasm or increased bronchial secretions, is the main cause of death in many acute organophosphate poisonings (Lerman & Gutman, 1988; Anon, 1984).
2) In one case, a patient had relatively minor symptoms for 48 hours before severe muscle fasciculations and respiratory compromise occurred (Sakamoto et al, 1984).

F) PNEUMONITIS

1) Aspiration of commercial organophosphate preparations which contain hydrocarbon solvents may cause potentially fatal chemical pneumonitis (Lund & Monteagudo, 1986).

G) RESPIRATORY CONDITION DUE TO CHEMICAL FUMES AND/OR VAPORS

1) Formothion releases toxic and irritating fumes of oxides of nitrogen, phosphorus, and sulfur when heated to decomposition (Lewis, 1996). Inhalation exposure to such fumes would be predicted to result in respiratory tract irritation with possible chemical pneumonitis or noncardiogenic pulmonary edema.

H) LACK OF EFFECT

1) Phosphorothioate and phosphorodithioate impurities may be present in malathion; these can cause diffuse interstitial thickening in lungs of rats. However, no cases have been seen of lung damage in humans from these impurities (Imamura & Gandy, 1988).

Neurologic

3.7.1)

3.7.2)

A) ANXIETY

1) The earliest manifestations of poisoning are often referable to the central nervous system: giddiness, uneasiness, restlessness, anxiety and tremulousness (Grob & Garlick, 1950).

B) SEIZURE

1) Seizures may be an early symptom after a significant exposure (Joy, 1982). Children may be more susceptible to seizures than adults. In one series, 8 of 37 (22 percent) had seizures (Zwiener & Ginsburg, 1988).
2) EEG changes similar to patterns present on interictal EEG's of temporal lobe epileptics have been described in cases of mild organophosphate poisoning (Brown, 1971).

C) ATAXIA

1) Initial central nervous system effects are commonly followed by headache, ataxia, drowsiness difficulty in concentrating, mental confusion, and slurred speech (Grob & Garlick, 1950).

D) STUPOR

1) More than 50 percent of patients in one study had a disturbed level of consciousness. Five of 61 patients were confused; 16/61 were confused and unable to sit or stand; 16/61 were stuporous without reaction to speech (Bardin et al, 1987).

E) COMA

1) In severe poisoning, coma supervenes, rarely followed by generalized convulsions (Grob & Garlick, 1950). Deep tendon reflexes are weak or absent.

F) PARALYSIS

1) So-called Type II neurological effects involve paralysis appearing from 12 to 72 hours after exposure; this paralysis is nonresponsive to atropine and may be due to excess acetylcholine at nicotinic receptors (Wadia et al, 1987).
2) Paralytic signs include inability to lift the neck or sit up, ophthalmoparesis, slow eye movement, facial weakness, difficulty swallowing, limb weakness (primarily proximal), areflexia, respiratory paralysis and death (Wadia et al, 1987).
3) Type II paralysis occurred in 49 percent of patients with organophosphate poisoning (Wadia et al, 1987).
4) In Type II paralysis, nerve conduction velocities and distal latencies are normal, but the amplitude of the compound action potential is reduced (Wadia et al, 1987).
5) Paralysis of the diaphragm has occurred in rare cases (Rivett & Potgieter, 1987).

G) SECONDARY PERIPHERAL NEUROPATHY

1) Although most symptoms develop rapidly, subjective improvement may be observed followed by the delayed development of peripheral neuropathy.
2) Delayed neurotoxicity appears to be a rare complication (Wadia et al, 1987), but its incidence may be underestimated (Cherniack, 1988).

a) It is not clear if delayed neurotoxicity can potentially occur with any of the organophosphates, or if it may be caused by only a specific few.

3) It may be either of the motor or sensory-motor type.
4) Typically delayed neurotoxicity appears 6 to 21 days after acute exposure by ingestion, inhalation, or the dermal route and involves progressive distal weakness and ataxia in the lower limbs. Flaccid paralysis, spasticity, ataxia or quadriplegia may ensue (Cherniack, 1988).

a) The mixed sensory-motor neuropathy usually begins in the legs, causing burning or tingling, then weakness (Johnson, 1975).

5) Severe cases progress to complete paralysis, impaired respiration and death. The nerve damage of organophosphate-induced delayed neuropathy is frequently permanent. Mechanism appears to involve phosphorylation of esterases in peripheral nervous tissue (Johnson, 1975) and results in a "dying back" pattern of axonal degeneration (Cavanagh, 1963).
6) Recovery requires weeks to months, and may never be complete (Done, 1979).
7) There seems to be no relationship between the severity of acute cholinergic effects and delayed neurotoxicity (Cherniack, 1986).
8) Delayed neurotoxicity may be potentiated by exposure to n-hexane and/or methyl n-butyl ketone, which have been implicated themselves in causing delayed peripheral neuropathy (Abou-Donia, 1983).
9) Lotti et al (1983) found that monitoring levels of lymphocyte neurotoxic esterase (NTE) in circulating lymphocytes aided in providing early warning for delayed neurotoxicity. They found decreases of 50 percent in this enzyme prior to changes in blood acetycholinesterase, plasma butyrylcholinesterase, or clinical manifestations.

a) This technique currently remains only a research tool, and the assay is not generally available.

H) CEREBELLAR DISORDER

1) A cerebellar disorder manifested as ataxia developed approximately 5 weeks after acute exposure to Bromophos; no acute cholinergic effects and no other delayed neuropathy were evident (Michotte et al, 1989).

I) INTERMEDIATE SYNDROME

1) An "intermediate syndrome" has been described in 10 patients from Sri Lanka who developed profound proximal muscle and cranial nerve weakness 1 to 4 days after exposure to fenothion, dimethoate, methamidophos, or monocrotophos (Senanayake & Karalliedde, 1987).
2) It is unclear that this is a distinct syndrome, as the patients were only treated for 24 to 48 hours with pralidoxime (1 g every 12 hours). Therefore, the syndrome may simply reflect inadequate treatment for severe organophosphate poisoning.

J) DYSKINESIA

1) CHOREOATHETOSIS (ceaseless jerky, sinuous, involuntary movements) which was responsive to atropine developed in a 23-year-old female after ingestion of chlorpyrifos (Joubert et al, 1984). Choreiform dyskinesias developed in 2 patients following accidental ingestion of organophosphate insecticide (Joubert & Joubert, 1988).
2) Other cholinergic symptoms including OPISTHOTONOS (a type of spasm where the head and heels are drawn backward while the trunk is forward) developed in an operator of a hand-held sprayer who was exposed to demeton-s-methyl by inhalation and the dermal route (Smith, 1977).
3) One case of opsoclonus (rapid, involuntary saccades of the eyes) developed 3 days after hospital admission in a patient who ingested malathion in an attempted suicide. It gradually resolved over the following 2 weeks (Pullicino & Aquilina, 1989).

K) SEQUELA

1) A case-control study of 100 adult patients administered neuropsychological testing at least 3 months after acute organophosphate poisoning reported subtle effects that could not be detected via clinical examination or EEG. Although cases had worse scores on neuropsychological tests than controls, they were still within the normal range (Savage et al, 1988).
2) In a comprehensive review of the literature regarding the neurological sequelae of organophosphate poisoning, the U.K. Department of Health; Committee on Toxicity of Chemicals in Food, Consumer Products, and the Environment; Working Group on Organophosphates concluded as follows (Anon, 1999):

a) The committee concluded that "(t)he balance of evidence supports the view that neuropsychological abnormalities can occur as a long-term complication of acute (organophosphate) poisoning, particularly if the poisoning is severe. Such abnormalities have been most evident in neuropsychological tests involving sustained attention and speeded flexible cognitive processing...Current evidence suggests that long-term memory is not affected..."
b) Delayed peripheral neuropathy is recognized as a known complication of organophosphate poisoning. The committee also concluded that organophosphates which do not inhibit the neurotoxic esterase can also give rise to sequelae, although these are usually sub-clinical and recognized only with neurodiagnostic testing.
c) The committee concluded that "(t)he limited evidence available does not allow any firm conclusions to be drawn regarding the risk of developing psychiatric illness in the long term as a consequence of acute poisoning..."
d) The committee did not find the current evidence sufficient to support the occurrence of neuropsychological abnormalities, peripheral neuropathy, or psychiatric illness following prolonged, low-level exposure to organophosphates.

Gastrointestinal

3.8.1)

3.8.2)

A) NAUSEA, VOMITING AND DIARRHEA

1) Nausea, vomiting, diarrhea, abdominal cramps and hypersalivation are common muscarinic signs of organophosphate poisoning. Vomiting and diarrhea occurred in 38 percent and 21 percent of patients, respectively, in one study (Bardin et al, 1987).

B) INCONTINENCE OF FECES

1) Fecal incontinence occurs in severe poisoning (Hayes, 1965).

C) INTUSSUSCEPTION OF INTESTINE

1) A single case of intussusception has been reported following the ingestion of an unspecified organophosphate in a 14-month-old child (Crispen et al, 1985).

D) PANCREATITIS

1) Acute pancreatitis has been reported following the ingestion of parathion, malathion, difonate, coumafos, diazanon, and mevinphos and also following dermal exposure to dimethoate. This is postulated to be due to excessive cholinergic stimulation of the pancreas and the occurrence of ductal hypertension (Hsiao et al, 1996).

Genitourinary

3.10.1)

A) Increased urinary frequency or, in severe cases, urinary incontinence has occurred.
B) Immune-complex nephropathy with proteinuria and/or amorphous crystalluria may be possible.

3.10.2)

A) URINARY INCONTINENCE

1) Involuntary urination occurs in the more severe poisonings. Urinary frequency may be evident (Done, 1979).

B) TOXIC NEPHROPATHY

1) Immune-complex nephropathy with proteinuria may have occurred in one case of malathion poisoning. Amorphous crystalluria with decreased urine output were associated with one case of diazinon poisoning; no serum creatinine or BUN abnormalities were seen (Albright et al, 1983; Wedin et al, 1984).

Acid-Base

3.11.1)

A) Metabolic acidosis has occurred in several severe poisonings.

3.11.2)

A) ACIDOSIS

1) Metabolic acidosis has occurred in several cases of severe poisoning (Hui, 1983; Meller et al, 1981; Moore & James, 1981).

Hematologic

3.13.1)

3.13.2)

A) DEFICIENCY OF CHOLINESTERASE

1) The hallmark of organophosphate poisoning is the inhibition of plasma pseudocholinesterase or erythrocyte acetylcholinesterase, or both (Namba, 1972).

B) BLOOD COAGULATION PATHWAY FINDING

1) Alterations in prothrombin time (shortened or prolonged), and increased or decreased factor VII levels have been described, but clinically significant bleeding or hypercoagulability are rare (Von Kaulla & Holmes, 1961).

C) HEMORRHAGE

1) Tendency to bleeding, probably related to platelet dysfunction, may occur (Ziemen, 1984).

Dermatologic

3.14.1)

A) Sweating is a consistent but not universal sign.

3.14.2)

A) EXCESSIVE SWEATING

1) Profuse sweating may occur as one of the muscarinic signs of organophosphate poisoning (Ganendran, 1974). Sweating was present in 23 percent of patients in one study (Bardin et al, 1987). Pallor is sometimes noted (Done, 1979).

B) DERMATITIS

1) Formothion caused contact sensitization dermatitis with papules, erythema, and edema in one worker following direct skin contact (HSDB , 2000).

Musculoskeletal

3.15.1)

A) Muscle weakness, fatiguability and fasciculations are common findings and may be delayed by several days. Paralysis may supervene.

3.15.2)

A) MUSCLE WEAKNESS

1) Muscle weakness, fatigability and fasciculations occur commonly. Fasciculations were present in 33/61 patients (54 percent) in one study (Bardin et al, 1987).

B) PARALYSIS

1) Muscle paralysis occasionally supervenes (Done, 1979).
2) A case of paralysis of the diaphragm has occurred in a person who ingested malathion; full recovery required 9 months (Rivett & Potgieter, 1987).

C) ONSET OF ILLNESS

1) In one case, the patient had relatively minor symptoms for 48 hours before severe muscle fasciculations and respiratory compromise occurred (Sakamoto et al, 1984).

Endocrine

3.16.1)

A) Hyperglycemia and glycosuria without ketosis may be present.

3.16.2)

A) HYPERGLYCEMIA

1) Hyperglycemia and glycosuria (without ketosis) are present in severe poisoning (Namba, 1972).

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL ANOMALY

1) Although some anticholinesterase compounds are teratogenic, most are not (Hayes, 1982; Schardein, 1985).

B) HUMANS

1) Some reports have linked exposure to organophosphates with birth defects in humans; however, these studies are flawed because of mixed or unidentified exposures and failure to account for other possible causes.

a) Two major malformations (talipes equinovarus) were seen in 50 pregnancies involving prenatal exposure during the first trimester to unspecified insecticides; this incidence was not considered significant. Two other cases were seen in a group of 125 women with exposure later in pregnancy (Nora et al, 1967).
b) There were 3 cases of multiple congenital malformations in children of women exposed to unspecified insecticides and other substances during pregnancy (Hall et al, 1980).
c) Malformations of the extremities and fetal death were seen in 18 cases of high acute maternal exposure to methyl parathion, which had been sprayed in a nearby field (Ogi & Hamada, 1965).
d) In one case-control study which attempted to examine correlations between peak agricultural chemical use and incidence of cleft palate, there was not enough statistical power to detect elevations in this birth defect with exposure to any single pesticide group (Gordon & Shy, 1981).

C) LACK OF EFFECT

1) Formothion was not teratogenic or embryotoxic in rabbits at doses of 6 to 30 mg/kg given by gavage from days 6 to 18 of gestation (Schardein, 1993; HSDB , 2000).

3.20.3)

A) LACK OF EFFECT

1) ANIMAL STUDIES

a) Formothion was not teratogenic or embryotoxic in rabbits at doses of 6 to 30 mg/kg given by gavage from days 6 to 18 of gestation (Schardein, 1993; HSDB , 2000).

2) HUMANS

a) Two patients who ingested organophosphate insecticides with suicidal intent during the second and third trimesters of pregnancy delivered normal healthy term infants after successful management of the cholinergic and intermediate phases of poisoning (Karalliedde et al, 1988).
b) A woman attempted to induce an abortion by the intra-vaginal instillation of formothion (50 mL). The woman was "moderately toxic". Outcome was reportedly good (Sancewicz-Pach et al, 1997).

3.20.4)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS2540-82-1 (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

3.21.4)

A) LACK OF EFFECT

1) LACK OF EFFECT

a) RATS - Chronic feeding studies in rats did NOT show an increased incidence of spontaneous tumors (HSDB , 2000).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Determine plasma and red blood cell cholinesterase activities. While there may be poor correlation between cholinesterase values and clinical effects, depression in excess of 50 percent activity is generally associated with severe symptoms. Correlation between cholinesterase levels and clinical effects in milder poisonings may be poor.
B) If respiratory tract irritation, excessive bronchial secretions, or bronchospasm occur following exposure, monitor arterial blood gases.
C) If respiratory tract irritation, excessive bronchial secretions, or bronchospasm occur following exposure, monitor chest x-ray.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Following plasma levels of the ingested organophosphate may provide a rationale for continued administration of 2-PAM in cases with prolonged high levels of circulating insecticide (Gerkin & Curry, 1987).
2) Considerations for monitoring plasma pseudocholinesterase and erythrocyte acetylcholinesterase levels involve their relationship with adverse clinical effects, kinetics of recovery, and other factors affecting their activity:

a) Plasma ChE appears to be a more sensitive index of exposure, and erythrocyte AChE activity may be better correlated with clinical effects (Muller & Hundt, 1980). Usually this biochemical manifestation of toxicity appears at lower dosage levels than amounts producing symptoms or signs.

1) Symptomatic patients usually show depression of blood cholinesterase activities in excess of 50 percent of the pre-exposure value (Milby, 1971).
2) Depressions in excess of 90 percent may occur in severe poisonings (Klemmer et al, 1978).
3) However, moderate to severe organophosphate poisoning has been diagnosed in patients with "normal" red blood AChE activity (Hodgson & Parkinson, 1985; Midtling et al, 1985; Coye et al, 1987). In these patients, AChE decreased by as much as 50 percent but was still within the normal range.

a) Thirty-one agricultural workers exposed to mevinphos have been described as having symptoms consistent with organophosphate poisoning but with plasma cholinesterase levels within the range of normal (Coye et al, 1986).

4) Therefore, the correlation between plasma cholinesterase levels and onset or extent of clinical effects may be poor, especially if the enzyme assays are done in different laboratories. Comparison with pre-exposure values may be helpful.

3) Many conditions and chemicals can alter the "normal" levels of plasma or erythrocyte cholinesterases and hence may interfere with interpretation of these assays.

a) Iatrogenic causes of reduced acetylcholinesterase activity may be X-ray therapy, cancer chemotherapy, monoamine oxidase inhibitors, oral contraceptives, quinine, ecothiophate iodide, propanidid, neostigmine, chlorpromazine, pancuronium and carbamates (pp 13-17; Wills, 1972; HEW, 1976).
b) Plasma pseudocholinesterase activity may be lowered by such agents as morphine, codeine, thiamine, ether and chloroquine (Wills, 1972). Disease states which may cause lowered levels of this enzyme include parenchymal liver disease, malnutrition, acute infections, some anemias, myocardial infarction, or chronic debilitating conditions (Hayes, 1982).
c) Several clinical conditions can result in "spontaneously" lower than normal levels of acetylcholinesterase and would presumably cause an individual to be more sensitive than the normal person to organophosphates. Among these predisposing conditions are (pp 13-17; Wills, 1972; HEW, 1976):

1) Inherited conditions involving rare defective serum cholinesterase variants such as the CHE phenotype (Prody et al, 1989);
2) Physiological conditions such as liver disease, collagen diseases, myocardial infarction, malnutrition, tuberculosis, hyperpyrexia, myxedema, acute infections, carcinomas, leukemia, multiple myeloma, chronic anemias, shock, and uremia.

d) Elevated levels of erythrocyte acetylcholinesterase may be seen with reticulocytosis due to anemias, hemorrhage or treatment of megaloblastic or pernicious anemias (Hayes, 1982).

4) Plasma cholinesterase activity recovers slowly due to the irreversible nature of organophosphate inhibition.

a) Pralidoxime reverses depressions of blood cholinesterase activities. Without the use of pralidoxime, plasma cholinesterase rose an average of 15.6 percent over fourteen days in one group of organophosphate-exposed workers. The authors suggest that serial levels rather than one initial level may be valuable in diagnosing organophosphate toxicity (Coye et al, 1986).
b) Plasma ChE usually recovers in a few days or weeks; RBC AChE recovers in several days to 4 months depending on severity of depression.

1) Sequential rise of plasma pseudocholinesterase activity every few days for 14 to 28 days may give confirmation of organophosphate exposure in the absence of pre-exposure baseline values (Coye et al, 1987).
2) However, recovery of erythrocyte acetylcholinesterase activity should be used as an indicator of when to return to work because the latter is more closely associated with levels of acetylcholinesterase in nerve tissue (Coye et al, 1987).

5) The poor correlation between AChE levels and clinical effects may mislead clinicians into making incorrect diagnoses of moderate organophosphate poisoning. Sequential postexposure determinations may be necessary to confirm AChE inhibition (Coye et al, 1986; Coye et al, 1987; Tafuri & Roberts, 1987). Initially, AChE should regenerate by 15 to 20 percent within 3 to 5 days (Midtling et al, 1985).
6) Patients should be protected from further organophosphate exposure until sequential erythrocyte AChE determinations have been obtained to confirm that AChE activity has plateaued. Plateau is obtained when sequential tests do not differ by more than 10 percent (Midtling et al, 1985; Coye et al, 1987). This may take 3 to 4 months in severe cases.

B) ACID/BASE

1) BLOOD GASES

a) Monitor arterial blood gases and/or pulse oximetry in patients with significant exposure.

4.1.3)

A) URINARY LEVELS

1) Urine assay for alkyl phosphates may be a sensitive indicator of exposure.

B) URINALYSIS

1) Urinalysis, measurement of urine output, and renal function tests may be advisable in significant organophosphate poisonings (Wedin et al, 1984; Albright et al, 1983).

4.1.4)

A) OTHER

1) MONITORING

a) One recommended monitoring scheme for persons chronically exposed to organophosphates involves measurement of both plasma ChE and red blood cell AChE prior to exposure and every 3 months during exposure (Muller & Hundt, 1980).
b) It is advisable that persons chronically exposed to organophosphates undergo periodic evaluation for subclinical central and peripheral nervous system effects. EEG and EKG monitoring and tests of neuromuscular function may be more sensitive than cholinesterase assays to detect overexposures, but these have not been rigorously documented in occupational studies.

2) PULMONARY FUNCTION TESTS

a) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.

3) OTHER

a) Staining activity for non-specific esterase in monocytes was inhibited in workers exposed to triaryl phosphates at subclinical doses. The relationship of this finding to adverse clinical outcome, in particular to organophosphate-induced delayed neuropathy or possible immunologic suppression, is unknown but is being further investigated (Mandel et al, 1989).
b) In a single case report, a 16 year old boy poisoned with methamidophos developed delayed peripheral neuropathy. The development of neuropathy was accompanied by the development of Ig-G antibodies directed against glial fibrillary acidic protein and neurofiliment 200 protein (McConnell et al, 1999). The diagnostic and prognostic significance of this test is currently unknown.

Radiographic Studies

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

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Following acute poisoning, patients should be precluded from further organophosphate exposure until sequential red cell acetylcholinesterase (AChE) levels have been obtained and confirm that AChE activity has reached a plateau. Plateau has been obtained when sequential determinations differ by no more than 10 percent (Midtling et al, 1985). This may take 3 to 4 months following severe poisoning.

6.3.3)

6.3.3.5) OBSERVATION CRITERIA/INHALATION

A) Following an acute poisoning, patients should be precluded from further organophosphate exposure until sequential red cell acetylcholinesterase (AChE) levels have been obtained and confirm that the AChE activity has reached a plateau. The plateau has been obtained when sequential determinations differ by no more than 10 percent (Midtling et al, 1985). This may take 3 to 4 months following severe poisoning.

6.3.4)

6.3.4.5) OBSERVATION CRITERIA/EYE

6.3.5)

6.3.5.5) OBSERVATION CRITERIA/DERMAL

Monitoring

Oral Exposure

6.5.2)

A) EMESIS/NOT RECOMMENDED

1) The onset of toxicity of many organophosphates is rapid. Patients may have significant symptoms, including CNS depression and seizures (Joy, 1982) before ipecac-induced emesis has terminated.
2) Induction of emesis is CONTRAINDICATED due to potential early coma, seizures and risk of aspiration.
3) Many organophosphates are in a hydrocarbon solvent. Care should be taken to prevent aspiration.

B) GASTRIC LAVAGE

1) Gastric lavage is the preferred method of stomach decontamination.
2) 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.

3) 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.

4) 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.

5) 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).

6) 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.

C) ACTIVATED CHARCOAL

1) Although there is some question about the efficacy of activated charcoal in adsorbing organophosphates, based on studies with malathion (Picchioni et al, 1966; Decker et al, 1968; Hayden and Comstock, 1975), the low toxicity of charcoal and the potential for some adsorption suggest its use.
2) 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.

3) CHARCOAL DOSE

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

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

b) ADVERSE EFFECTS/CONTRAINDICATIONS

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

6.5.3)

A) 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).

B) MONITORING OF PATIENT

1) Measure plasma pseudocholinesterase (ChE) and red cell acetylcholinesterase (AChE) activities. Specimens should be obtained prior to administration of pralidoxime when possible.
2) Cholinesterase levels are useful for confirmation of diagnosis; they should NOT be used to determine dosage of atropine or when to wean from atropine therapy (LeBlanc et al, 1986). There is generally poor correlation between cholinesterase levels and severity of clinical effects (pp 13-17).

a) Plasma cholinesterase appears to be a more sensitive index of exposure, while erythrocyte acetylcholinesterase activity appears to better correlate with clinical effects (Muller & Hunt, 1980).

C) ATROPINE

1) Atropine is primarily effective for the treatment of muscarinic effects of organophosphate poisoning, and will not reverse nicotinic effects (muscular weakness, diaphragmatic weakness, etc).
2) DIAGNOSTIC DOSE

a) Organophosphate-poisoned patients are generally tolerant to the toxic effects of atropine (dry mouth, rapid pulse, dilated pupils, etc). If these findings occur following a DIAGNOSTIC atropine dose, the patient is probably not seriously poisoned.

1) DIAGNOSTIC DOSE - ADULT - 1 milligram intravenously or intramuscularly; CHILD - 0.25 milligram (about 0.01 milligram/kilogram) intravenously or intramuscularly.

3) THERAPEUTIC DOSE

a) Severely poisoned patients may require exceedingly large THERAPEUTIC doses of atropine (up to 100 milligrams over a few hours or several grams over several days) to achieve adequate atropinization (ie: drying of secretions, especially pulmonary) (Golsousidis & Kokkas, 1985). Early and prompt atropinization is of paramount importance in severe poisoning.
b) Organophosphate manufacturers and some medical references grossly underestimate the amount of atropine that may be required in severe poisonings. Recent evidence suggests that low dosages of atropine may be preferable in some circumstances (De Kort et al, 1988). Dosage should be individualized in each case, depending on dose of the organophosphate and response of the patient to atropine.

1) Inject atropine sulfate slowly intravenously. In cases where this is not possible, atropine can be injected subcutaneously or given endotracheally or intraosseously (Prete et al, 1987).
2) DOSE

a) ADULT - 2 to 5 milligrams slowly intravenously
b) CHILD - 0.05 milligram/kilogram slowly intravenously
c) Repeat doses may be administered every 10 to 30 minutes as needed to achieve and maintain full atropinization, indicated by complete clearing of rales and drying of pulmonary secretions.
d) Drying of excessive secretions is a preferable indicator of adequate atropinization rather than heart rate or pupil size; tachycardia and mydriasis can be nicotinic effects of severe organophosphate poisoning (Ganendran, 1974; Hirschberg & Lerman, 1984) Worrel, 1975).
e) In severe poisonings where atropinization may be required for a period of several days, continuous atropine infusion may be preferable. Initial undiluted atropine infusion rates of 0.02 to 0.08 milligram/kilogram/hour have been recommended (Du Toit et al, 1981). Infusion of atropine does not eliminate the need for an initial bolus dose if rapid atropinization is required (Heath, 1989).

c) PRECAUTIONS

1) Many parenteral atropine preparations contain benzyl alcohol or chlorobutanol as preservatives. High-dose therapy with these preparations may result in BENZYL ALCOHOL or CHLOROBUTANOL TOXICITY.
2) Preservative-free atropine preparations are available, and should be used if large doses are required.
3) The half-life of atropine is significantly longer in children under 2 years and adults over 60 (Kanto & Klotz, 1988); the rate of administration in these patients should be adjusted accordingly.
4) Effects of overdosing with atropine include fever, warm dry skin, inspiratory stridor, irritability, and dilated and unresponsive pupils (Meerstadt, 1982).

d) ATROPINIZATION

1) Atropinization must be maintained until all of the absorbed organophosphate has been metabolized. This may require administration of 2 to 2,000 milligrams of atropine over several hours to weeks. One case of parathion overdose required 19,590 milligrams of atropine over 24 days. In one 24 hour period, 2950 milligrams were administered (Golsousidis & Kokkas, 1985).
2) Atropine therapy may need to be prolonged in severe cases, because AChE activity may regenerate slowly.
3) Atropine therapy must be withdrawn slowly to prevent recurrence or rebounding of symptoms, often in the form of pulmonary edema. This is especially true of poisonings from lipophilic organophosphates such as fenthion. If atropine has been given for several days, it should be maintained for at least 24 hours after resolution of acute symptoms (Bardin et al, 1987).

e) AUTOMATIC INJECTORS

1) MARK I - This device (Survival Technology, Bethesda, Maryland) is currently used by the US Army (Friedl et al, 1989). The autoinjector delivers 2 milligrams atropine/0.7 milliliter and 600 milligrams pralidoxime chloride/2 milliliters into two separate intramuscular sites.
2) COMBOPEN MC - This autoinjector (Survival Technology, Bethesda, Maryland) delivers 2 milligrams atropine/0.7 milliliter and 600 milligrams pralidoxime chloride/2 milliliters through a single needle into the same intramuscular site (Friedl et al, 1989).
3) Friedl et al (1989) found the MARK I autoinjector was associated with significantly greater absorption of atropine in the first 30 minutes than the COMBOPEN MC autoinjector.

f) INHALED NEBULIZED ATROPINE

1) Atropine (2mg) administered in a hand held nebulizer was associated with improvement in bronchorrhea and respiratory distress in a case of malathion poisoning (Shockley, 1989).

D) IPRATROPIUM

1) Endotracheal ipratropium 0.5 mg every 6 hours was associated with improvement in rales in one case of organophosphate poisoning (Shemesh et al, 1988).

E) PRALIDOXIME

1) INDICATIONS

a) PRALIDOXIME/INDICATIONS

1) Severe organophosphate poisoning with nicotinic (muscle and diaphragmatic weakness, respiratory depression, fasciculations, muscle cramps, etc) and/or central (coma, seizures) manifestations should be treated with pralidoxime in addition to atropine(Prod Info PROTOPAM(R) Chloride injection, 2010).

b) PRALIDOXIME/CONTROVERSY

1) Human studies have not substantiated the benefit of oxime therapy in acute organophosphate poisoning (Eddleston et al, 2002; de Silva et al, 1992); however oxime dosing in these studies was not optimized and methodology was unclear. Most authors advocate the continued use of pralidoxime in the clinical setting of severe organophosphate poisoning (Singh et al, 2001; Singh et al, 1998).
2) It has been difficult to assess the value of pralidoxime in case studies because most of the patients have also received atropine therapy, or the pralidoxime was given late in the treatment or at a suboptimal dose (Peter et al, 2006; Rahimi et al, 2006).
3) More recent observational studies have indicated that acetylcholinesterase inhibited by various organophosphate (OP) pesticides varies in its responsiveness to oximes; diethyl OPs (eg, parathion, quinalphos) appear to be effectively reactivated by oximes, while dimethyl OPs (eg, monocrotophos or oxydemeton-methyl) appear to respond poorly. Profenofos, an OP that is AChE inhibited by a S-alkyl link, was also found to not reactivate at all to oximes (Eddleston et al, 2008).

2) ADMINISTRATION

a) PRALIDOXIME/ADMINISTRATION

1) Pralidoxime is best administered as soon as possible after exposure; ideally, within 36 hours of exposure (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). However, patients presenting late (2 to 6 days after exposure) may still benefit (Borowitz, 1988; De Kort et al, 1988a; Namba et al, 1971; Amos & Hall, 1965) .
2) Some mechanisms which may account for pralidoxime efficacy with delayed administration include:

a) Poisoning with an agent such as parathion or quinalphos which produces "slow aging" of acetylcholinesterase (Eddleston et al, 2008).
b) Slow absorption of the organophosphate compound from the lower bowel or exposure to large amounts (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
c) Release of the organophosphate from fat stores (Borowitz, 1988).
d) Other actions of pralidoxime.

3) DOSE

a) PRALIDOXIME DOSE

1) ADULT: A loading dose of 30 mg/kg (maximum: 2 grams) over 30 minutes followed by a maintenance infusion of 8 to 10 mg/kg/hr (up to 650 mg/hr) (Howland, 2011). In vitro studies have recommended a target plasma concentration of close to 17 mcg/mL necessary for pralidoxime to be effective, which is higher than the previously suggested concentration of at least 4 mcg/mL (Howland, 2011; Eddleston et al, 2002). ALTERNATE ADULT: An alternate initial dose for adults is 1 to 2 grams diluted in 100 mL of 0.9% sodium chloride infused over 15 to 30 minutes. Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). In patients with serious cholinergic intoxication, a continuous infusion of 500 mg/hr should be considered. In patients with acute lung injury, a 5% solution may be administered by a slow IV injection over at least 5 minutes (Howland, 2006). Intravenous dosing is preferred; however, intramuscular administration may be considered using a 1-g vial of pralidoxime reconstituted with 3 mL of sterile water for injection or 0.9% sodium chloride for injection, producing a solution containing 300 mg/mL (Howland, 2011). An initial intramuscular pralidoxime dose of 1 gram or up to 2 grams in cases of very severe poisoning has also been recommended (Haddad, 1990; S Sweetman , 2002).
2) CHILD: A loading dose of 20 to 40 mg/kg (maximum: 2 grams/dose) infused over 30 to 60 minutes in 0.9% sodium chloride (Howland, 2006; Schexnayder et al, 1998). Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). ALTERNATE CHILD: An alternate loading dose of 25 to 50 mg/kg (up to a maximum dose of 2 g), followed via continuous infusion of 10 to 20 mg/kg/hr. In patients with serious cholinergic intoxication, a continuous infusion of 10 to 20 mg/kg/hr up to 500 mg/hr should be considered (Howland, 2006).
3) Presently, the ideal dose has NOT been established and dosing is likely based on several factors: type of OP agent (ie, diethyl OPs appear to respond more favorably to oximes, while dimethyl OPs seem to respond poorly) which may relate to a variation in the speed of ageing, time since exposure, body load, and pharmacogenetics (Eddleston et al, 2008)
4) CONTINUOUS INFUSION

a) A continuous infusion of pralidoxime is generally preferred to intermittent bolus dosing to maintain a target concentration with less variation (Howland, 2011; Eddleston et al, 2008; Roberts & Aaron, 2007; Gallagher et al, 1989; Thompson, 1987). In an open label, randomized study of moderately severe organophosphate poisoned patients treated with high dose continuous infusions required less atropine, were less likely to be intubated and had shorter duration of ventilatory support than patients treated with intermittent bolus doses. HIGH DOSE CONTINUOUS INFUSION: In this study, an initial 2 g bolus (pralidoxime chloride or iodide) was given, followed by 1 g over an hour every hour for 48 hours. Followed by 1 g every 4 hours until the patient could be weaned from mechanical ventilation. The response to therapy was beneficial in patients exposed to either a dimethyl or diethyl organophosphate pesticide (Pawar et al, 2006).
b) Infusion over a period of several days may be necessary and is generally well tolerated (Namba et al, 1971).

5) MAXIMUM DOSE

a) The maximum recommended dose for pralidoxime is 12 grams in 24 hours for adults (S Sweetman , 2002); based on WHO, this dose may be exceeded in severely poisoned adults (Tang et al, 2013).

6) DURATION OF INTRAVENOUS DOSING

a) Dosing should be continued for at least 24 hours after cholinergic manifestations have resolved (Howland, 2006). Prolonged administration may be necessary in severe cases, especially in the case of poisoning by lipophilic organophosphates (Wadia & Amin, 1988). Observe patients carefully for recurrent cholinergic manifestations after pralidoxime is discontinued.

4) ADVERSE EFFECTS

a) SUMMARY

1) Minimal toxicity when administered as directed; adverse effects may include: pain at injection site; transient elevations of CPK, SGOT, SGPT; dizziness, blurred vision, diplopia, drowsiness, nausea, tachycardia, hyperventilation, and muscular weakness (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). Rapid injection may produce laryngospasm, muscle rigidity and tachycardia (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).

b) MINIMAL TOXICITY

1) When administered as directed, pralidoxime has minimal toxicity (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). Up to 40.5 grams have been administered over seven days (26 grams in the first 54 hours) without ill effects (Namba et al, 1971).
2) One child developed delirium, visual hallucinations, tachycardia, mydriasis, and dry mucous membranes (Farrar et al, 1990). The authors were uncertain if these effects were related to 2-PAM or organophosphate poisoning per se.

c) NEUROMUSCULAR BLOCKADE

1) High doses have been reported to cause neuromuscular blockade, but this would not be expected to occur with recommended doses (Grob & Johns, 1958).

d) VISUAL DISTURBANCES

1) Oximes have produced visual disturbances (eg, blurred vision, diplopia) (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
2) Transient increases in intraocular pressure may occur (Ballantyne B, 1987).

e) ASYSTOLE

1) Pralidoxime administered intravenously at an infusion rate of 2 grams over 10 minutes was associated with asystole in a single reported case, which occurred about 2 minutes after initiation of the infusion (Scott, 1986). A cause and effect relationship was not established.

f) WEAKNESS

1) Mild weakness, blurred vision, dizziness, headache, nausea, and tachycardia may occur if the rate of pralidoxime infusion exceeds 500 milligrams/minute (Jager & Stagg, 1958).

g) ATROPINE SIDE EFFECTS

1) Concomitant administration of pralidoxime may enhance the side effects of atropine administration (Hiraki et al, 1958). The signs of atropinization may occur earlier than anticipated when the agents are used together (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).

h) CARDIOVASCULAR

1) Transient dose-dependent increases in blood pressure have occurred in adults receiving 15 to 30 milligrams/kilogram of 2-PAM (Calesnick et al, 1967). Increases in systolic and diastolic blood pressure have been observed in healthy volunteers given parenteral doses of pralidoxime (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
2) Electrocardiographic changes and marked hypertension were observed at doses of 45 milligrams/kilogram (Calesnick et al, 1967).

5) PHARMACOKINETICS

a) HALF-LIFE: Pralidoxime is relatively short-acting with an estimated half-life of 75 minutes (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). One report found that the effective half-life of pralidoxime chloride was longer in poisoned individuals than in healthy volunteers. This was attributed to a reduced renal blood flow in the poisoned patients (Jovanovic, 1989).

6) AVAILABLE FORMS

a) VIALS

1) Each 20-mL vial contains 1 gram of pralidoxime chloride (Prod Info PROTOPAM(R) Chloride injection, 2010)

b) SELF-INJECTOR

1) Each auto-injector contains 600-mg of pralidoxime chloride in 2 mL of a sterile solution containing 20 mg/mL benzyl alcohol, 11.26 mg/mL glycine in water for injection (Prod Info PRALIDOXIME CHLORIDE intramuscular injection, 2003).

c) CONVERSION FROM AUTOINJECTOR TO IV SOLUTION

1) In one study, the conversion of intramuscular pralidoxime (from a MARK I Injector) to an IV solution resulted in a stable and sterile solution for up to 28 days. It is suggested that this conversion may be used in a mass casualty situation when additional IV doses of pralidoxime are needed. The following method may be used to transfer the syringe content: (Corvino et al, 2006).

a) Avoid a shattered glass incident by using a biological safety cabinet.
b) Double-glove and use a 30 mL empty sterile glass vial.
c) Sterilize the vial diaphragm with alcohol.
d) To vent the vial, insert a 1 1/2 inch 21 gauge IV needle bent to 90 degrees.
e) Obtain the pralidoxime syringe from the kit and place it over the top of the vial diaphragm.
f) Keep the syringe perpendicular to the vial and grasp the barrel of the syringe and press down firmly until the needle is deployed, and allow the syringe contents to enter into the vial.
g) Use 5 pralidoxime injectors for one vial, which will be 10 mL in each vial.
h) A 19 gauge 1.5 inch 5 micro filter needle is used with the 5 or 10 mL syringe to withdraw the pralidoxime solution from the 30 mL vial.
i) Each vial (10 mL) is used to prepare either 250 mL, 0.9% sodium chloride injection IV bag at 8 mg/mL OR 100 mL, 0.9% sodium chloride injection IV bag to yield a final pralidoxime concentration of 10 mg/mL; 3.33 mL should be added into a 100 mL bag and 6.66 mL should be added into a 250 mL bag.

d) OTHER SALTS

1) Pralidoxime mesylate (P2S) in the United Kingdom (UK License holder, Department of Health).
2) Pralidoxime methisulfate (Contrathion(R)) available in Greece (from IFET), Turkey (from Keymen), Brazil (from Sanofi-Aventis), Italy (from Sanofi-Aventis) and France (from SERB).

F) OBIDOXIME CHLORIDE

1) OBIDOXIME/INDICATIONS

a) Obidoxime dichloride, Toxogonin(R), may be a less toxic and more efficacious alternative to pralidoxime in poisonings from organophosphates containing a dimethoxy or diethoxy moiety.
b) Clinical experience with this compound is limited (Kassa, 2002; Willems, 1981; De Kort et al, 1988a; Barckow et al, 1969).
c) It is apparently favored over pralidoxime in clinical practice in Belgium, Israel, The Netherlands, Scandinavia, and Germany and is the only oxime available in Portugal. It is currently not available in the US, but may be available through Merck in some countries.

2) ADULT DOSE

a) INITIAL: Obidoxime may be given as an intravenous bolus of 250 milligrams and may be repeated once or twice at 2 hour intervals (Prod Info TOXOGONIN(R) IV injection, 2007). It is more effective if given early, and the manufacturer recommends that it not be administered more than after 6 hours following organophosphate intoxication (Prod Info TOXOGONIN(R) IV injection, 2007), however in clinical practice it is often used in patients presenting more than 6 hours after poisoning (Thiermann et al, 1997).
b) ALTERNATIVE DOSING: For the treatment of organophosphorous pesticide poisoning, administer 250 milligrams of obidoxime as an intravenous or intramuscular bolus, followed by a continuous intravenous infusion of 750 milligrams/day (Antonijevic & Stojiljkovic, 2007; Thiermann et al, 1997).
c) CONTINUOUS INFUSION: To achieve a 4 microgram/milliliter threshold plasma level of obidoxime for the treatment of nerve agent intoxication, the following loading and maintenance doses are suggested: LOADING DOSE: 0.8 milligram/kilogram. INFUSION RATE: 0.5 milligram/kilogram/hour (Kassa, 2002).

3) PEDIATRIC DOSE

a) Children may be given single doses of 4 to 8 milligrams/kilogram, followed by an intravenous infusion of 0.45 milligrams/kilogram/hour (Prod Info TOXOGONIN(R) IV injection, 2007; Antonijevic & Stojiljkovic, 2007; Thiermann et al, 1997) not to exceed 250 milligrams, usual adult dose, in older children (Prod Info Toxogonin(R), obidoxime chloride, 1989).

4) DURATION:

a) More severely poisoned patients generally require a longer duration of infusion (Thiermann et al, 1997). If cholinergic signs or symptoms worsen or if cholinesterase concentrations decline after obidoxime is discontinued, therapy should be reinstituted.

5) ADVERSE EFFECTS

a) Mild, transient liver dysfunction has been noted with obidoxime use (Finkelstein et al, 1989).

G) ASOXIME CHLORIDE

1) HI-6 is an oxime being investigated for efficacy and safety in the treatment of organophosphate poisoning. HI-6 appeared to be effective against the diethoxy group of organophosphates, which age more slowly than the dimethoxy type (Kusic et al, 1991).
2) After administration of sustained-release tablets of HI-6 to volunteers, maximal concentration (8.8 micromol/L) was attained in 2.2 hours, elimination half-life was 1.9 hours, and 4.2 percent of the dose was excreted unchanged in the urine.

a) No undesirable effects were reported. This study suggests low oral bioavailability of HI-6 in man (Jovanovic et al, 1990).

3) ANIMALS - Ligtenstein & Moes (1991) found HI-6 acts peripherally in a rat model of organophosphate intoxication. Slight anticonvulsive action was noted when rats were pretreated with HI-6. Atropine had a synergistic effect with HI-6 when rats were pretreated with both atropine and HI-6.

a) The LD50 of the centrally acting organophosphate (methiodide derivative of S-diethylaminoethyl-O-cyclohexyl-methyl phosphonothioate) increased from 28.2 micrograms/kilogram with no treatment to 2 milligrams/kilogram with pretreatment with HI-6 (50 milligrams/kilogram), and 2.7 milligrams/kilogram with pretreatment with both atropine and HI-6. Pretreatment with atropine (37.5 milligrams/kilogram) alone did not change the LD50 of this centrally acting organophosphate.

H) HYPOTENSIVE EPISODE

1) SUMMARY

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

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

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) PULMONARY ASPIRATION

1) Many organophosphate compounds are found in solution with a variety of hydrocarbon-based solvents.
2) Aspiration pneumonitis may occur if these products are aspirated into the lungs.
3) Bronchopneumonia may develop as a complication of organophosphate-induced pulmonary edema.

K) MONITORING OF PATIENT

1) CARDIAC MONITORING - Monitor cardiac functions and electrocardiogram closely.

L) CONTRAINDICATED TREATMENT

1) Do NOT administer OILS, which enhance the absorption of organophosphates.

M) BRONCHOSPASM

1) Bronchospasm may occur after inhalation exposure to organophosphates, or as part of the pattern of pharmacological muscarinic effects.
2) Inhaled sympathomimetic bronchodilators or atropine may be effective in treating bronchospasm.
3) Theophylline, when used cautiously, is probably not contraindicated in treating organophosphate-induced bronchospasm.

N) DRUG INTERACTION

1) NEUROMUSCULAR BLOCKER

a) Do NOT administer SUCCINYLCHOLINE (SUXAMETHONIUM) or other cholinergic medications.
b) Prolonged neuromuscular blockade may result when succinylcholine is administered after organophosphate exposure (Perez-Guillermo et al, 1988; (Selden & Curry, 1987).

O) EXPERIMENTAL THERAPY

1) Calcium channel blockers and phenytoin, were effective in protecting mice from the lethal effects of diisopropylfluorophosphate (Dretchen et al, 1986).
2) Clonidine pretreatment protected against some of the CNS effects of soman in mice; clonidine and atropine acted synergistically to protect against lethal effects. Clonidine inhibits the release of acetylcholine and also prevents binding of ligands to muscarinic receptors in the cortex (Buccafusco & Aronstam, 1986).
3) Pretreatment with meptazinol (+/-) m-(1-methyl-3-ethyl-hexahydro -1H-azepin-3-yl) phenol hydrochloride, an opioid analgesic, was effective in protecting mice from the lethal effects of diisopropylfluorophosphate, but was ineffective when given afterward; it appeared to bind directly to acetylcholinesterase (Galli & Mazri, 1988).
4) PYRIDOSTIGMINE BROMIDE

a) PYRIDOSTIGMINE BROMIDE - reversibly inhibits peripheral acetylcholinesterase. PRETREATMENT with pyridostigmine bromide PRIOR to exposure to nerve agents protects a portion of acetylcholinesterase from nerve agent binding (Dunn & Sidell, 1989).
b) Pyridostigmine bromide use, combined with current antidote therapy, is reported to greatly reduce the potential lethality of exposure to GD (soman) (Dunn & Sidell, 1989; (Dirnhuber et al, 1979) Kluwe, 1987).
c) PRETREATMENT DOSE - 30 milligrams orally every 8 hours is to be taken in situations where there is a threat of nerve agent attack (Dunn & Sidell, 1989).
d) ADVERSE EFFECTS - In humans oral administration of 30 milligrams every 8 hours causes no interference with performance (US Army, 1987). Larger doses have been associated with toxic effects including interference with visual acuity and accommodation and intestinal disturbances (Dunn & Sidell, 1989).

5) GLYCOPYRROLATE - Glycopyrrolate, a quaternary ammonium compound, has been proposed for treatment of organophosphate poisoning because of its better control of secretions, less tachycardia, and fewer CNS effects.

a) Except for a trend to fewer respiratory tract infections among those treated with glycopyrrolate, no significant differences in outcome were noted when comparable groups of organophosphate poisoned patients were treated with either atropine or glycopyrrolate (Bardin & Van Eeden, 1990).
b) Tracey & Gallagher (1990) report using combination glycopyrrolate/atropine therapy to successfully treat two cases of acute organophosphorus poisoning.

6) PANCURONIUM - Has been used in acutely poisoned, mechanically ventilated patients to decrease repetitive nerve discharges. However, clinical status in these patients remained unchanged (Besser et al, 1990).
7) PRETREATMENT

a) DIPHENHYDRAMINE - PRETREATING mice with more than 20 milligrams/kilogram diphenhydramine reduced organophosphate toxicity and increased survival (Mohammed et al, 1989).
b) PHYSOSTIGMINE/AZAPROPHEN - 100 micrograms/kilogram physostigmine and 5 milligrams/kilogram azaprophen proved protective to guinea pigs against Soman at a level 5 times the LD50 (Solana et al, 1990).

1) Rats pretreated with physostigmine showed decreased weight loss, cholinergic effects and lethality following exposure to Soman than did controls (Miller et al, 1993).

P) PATIENT CURRENTLY PREGNANT

1) Therapeutic choices DURING PREGNANCY depend upon specific circumstances such as stage of gestation, severity of poisoning, and clinical signs of mother and fetus. The mother must be treated adequately to treat the fetus (Haddad & Winchester, 1990).
2) DELIVERY - A severely poisoned patient with a late gestation viable fetus may be a candidate for emergency Caesarean section. The fetus may require intensive care after birth (Weis et al, 1983).
3) PRALIDOXIME CHLORIDE - Is recommended for use in the pregnant patient to counteract muscle weakness (Sosis et al, 1983).
4) GLYCOPYRROLATE - Unlike atropine, usually does not readily cross the placenta and would not directly treat fetal poisoning. However, the fetus may be best served by treating the mother to retain good respiratory function and fetal oxygenation (Haddad & Winchester, 1990).

Inhalation Exposure

6.7.1)

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

6.7.2)

A) IRRITATION SYMPTOM

1) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.

B) OBSERVATION REGIMES

1) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

C) SEIZURE

1) SUMMARY

2) DIAZEPAM

3) NO INTRAVENOUS ACCESS

4) LORAZEPAM

5) PHENOBARBITAL

6) OTHER AGENTS

D) MONITORING OF PATIENT

a) Plasma cholinesterase appears to be a more sensitive index of exposure, while erythrocyte acetylcholinesterase activity appears to better correlate with clinical effects (Muller & Hunt, 1980).

E) ATROPINE

a) Organophosphate-poisoned patients are generally tolerant to the toxic effects of atropine (dry mouth, rapid pulse, dilated pupils, etc). If these findings occur following a diagnostic atropine dose, the patient is probably not seriously poisoned.

1) DIAGNOSTIC DOSE - ADULT - 1 milligram intravenously or intramuscularly; CHILD - 0.25 milligram (about 0.01 milligram/kilogram) intravenously or intramuscularly.

3) THERAPEUTIC DOSE

a) Severely poisoned patients may require exceedingly large doses of atropine (up to 100 milligrams over a few hours or several grams over several days) to achieve adequate atropinization (ie, drying of secretions, especially pulmonary) (Golsousidis & Kokkas, 1985). Early and prompt atropinization is of paramount importance in severe poisoning.
b) Organophosphate manufacturers and some medical references grossly underestimate the amount of atropine that may be required in severe poisonings. Recent evidence suggests that low dosages of atropine may be preferable in some circumstances (De Kort et al, 1988). Dosage should be individualized in each case, depending on dose of the organophosphate and response of the patient to atropine.

1) Inject atropine sulfate slowly intravenously. In cases where this is not possible, atropine can be injected subcutaneously or given endotracheally or intraosseously (Prete et al, 1987).
2) DOSE

c) PRECAUTIONS

d) ATROPINIZATION

e) AUTOMATIC INJECTORS

f) INHALED NEBULIZED ATROPINE

1) Atropine (2mg) administered in a hand held nebulizer was associated with improvement in bronchorrhea and respiratory distress in a case of malathion poisoning (Shockley, 1989).

F) IPRATROPIUM

1) Endotracheal ipratropium 0.5 mg every 6 hours was associated with improvement in rales in one case of organophosphate poisoning (Shemesh et al, 1988).

G) PRALIDOXIME

1) INDICATIONS

a) PRALIDOXIME/INDICATIONS

b) PRALIDOXIME/CONTROVERSY

2) ADMINISTRATION

a) PRALIDOXIME/ADMINISTRATION

3) DOSE

a) PRALIDOXIME DOSE

5) MAXIMUM DOSE

a) The maximum recommended dose for pralidoxime is 12 grams in 24 hours for adults (S Sweetman , 2002); based on WHO, this dose may be exceeded in severely poisoned adults (Tang et al, 2013).

6) DURATION OF INTRAVENOUS DOSING

4) ADVERSE EFFECTS

a) SUMMARY

b) MINIMAL TOXICITY

c) NEUROMUSCULAR BLOCKADE

1) High doses have been reported to cause neuromuscular blockade, but this would not be expected to occur with recommended doses (Grob & Johns, 1958).

d) VISUAL DISTURBANCES

e) ASYSTOLE

f) WEAKNESS

1) Mild weakness, blurred vision, dizziness, headache, nausea, and tachycardia may occur if the rate of pralidoxime infusion exceeds 500 milligrams/minute (Jager & Stagg, 1958).

g) ATROPINE SIDE EFFECTS

h) CARDIOVASCULAR

5) PHARMACOKINETICS

6) AVAILABLE FORMS

a) VIALS

1) Each 20-mL vial contains 1 gram of pralidoxime chloride (Prod Info PROTOPAM(R) Chloride injection, 2010)

b) SELF-INJECTOR

c) CONVERSION FROM AUTOINJECTOR TO IV SOLUTION

d) OTHER SALTS

H) OBIDOXIME CHLORIDE

1) OBIDOXIME/INDICATIONS

2) ADULT DOSE

3) PEDIATRIC DOSE

4) DURATION:

5) ADVERSE EFFECTS

a) Mild, transient liver dysfunction has been noted with obidoxime use (Finkelstein et al, 1989).

I) ASOXIME CHLORIDE

a) No undesirable effects were reported. This study suggests low oral bioavailability of HI-6 in man (Jovanovic et al, 1990).

J) ACUTE LUNG INJURY

K) PULMONARY ASPIRATION

L) MONITORING OF PATIENT

1) CARDIAC MONITORING - Monitor cardiac functions and electrocardiogram closely.

M) CONTRAINDICATED TREATMENT

1) Do NOT administer OILS, which enhance the absorption of organophosphates.

N) BRONCHOSPASM

O) DRUG INTERACTION

1) NEUROMUSCULAR BLOCKER

P) EXPERIMENTAL THERAPY

a) DIPHENHYDRAMINE - Pretreating mice with more than 20 milligrams/kilogram diphenhydramine reduced organophosphate toxicity and increased survival (Mohammed et al, 1989).
b) PHYSOSTIGMINE/AZAPROPHEN - 100 micrograms/kilogram physostigmine and 5 milligrams/kilogram azaprophen proved protective to guinea pigs against Soman at a level 5 times the LD50 (Solana et al, 1990).

1) Rats pretreated with physostigmine showed decreased weight loss, cholinergic effects and lethality following exposure to Soman than did controls (Miller et al, 1993).

Q) PATIENT CURRENTLY PREGNANT

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

Eye Exposure

6.8.1)

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

6.8.2)

A) OCULAR ABSORPTION

1) Organophosphates can be absorbed and cause systemic poisoning by the ocular route (Kopel, 1962; (PDR, 1989).
2) Carefully observe patients with eye exposure for the development of systemic toxicity.

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

Dermal Exposure

6.9.1)

A) PERSONNEL PROTECTION

1) First responders, emergency medical, and emergency department personnel should take proper precautions (wear rubber gowns, rubber aprons, rubber gloves, etc) when treating patients with organophosphate poisoning to avoid contamination. Emesis containing organophosphates should be placed in closed impervious containers for proper disposal.

B) MULTIPLE WASHES

1) Remove contaminated clothing. Wash the skin, including the hair, beneath the nails, groin, and umbilical area, three times.
2) It has been shown using radiolabeled parathion that a single hand washing with soap and water will remove 80 to 92 percent of parathion if done immediately while removing only 50 to 70 percent if washing is delayed. Following this with decontamination with 95 percent ethanol will leave only a 5 to 10 percent residue. The author suggests that vigorous soap washing, followed by ethanol, and then again by soap washing is the best means of decontamination (Fredrikkson, 1961). Tincture of green soap contains 30 percent ethanol and thus has been recommended for organophosphate decontamination.

C) LEATHER

1) Leather absorbs organophosphates and is extremely difficult to decontaminate. Rescuers should not wear leather items that are not completely covered by rubber or impervious plastic. Contaminated leather items may need to be disposed of by incineration.

D) CLOTHING

1) Parathion spilled onto clothing may not be completely removed by laundering (Clifford & Nies, 1989). Dispose of contaminated clothing of in accordance with state and federal regulations for disposal of hazardous waste material.

E) DECONTAMINATION OF SPILLS/SUMMARY

1) A variety of methods have been described for organophosphate spill decontamination, most of which depend on changing the pH to promote hydrolysis to inactive phosphate diester compounds (EPA, 1978). The rate of hydrolysis depends on both the specific organophosphate compound involved and the increase in pH caused by the detoxicant used (EPA, 1978) EPA, 1975).

a) NOTE - Do NOT use a MIXTURE of BLEACH and ALKALI for DECONTAMINATING ACEPHATE ORGANOPHOSPHATES such as ORTHENE(R). This can cause release of toxic acetyl chloride, acetylene, and phosgene gas. Spills of acephate organophosphates should be decontaminated by absorption and scrubbing with concentrated detergent (Ford, 1989).

2) Treatment of the spilled material with alkaline substances such as sodium carbonate (soda ash), sodium bicarbonate (baking soda), calcium hydroxide (slaked or hydrated lime), calcium hydroxide (lime or lime water, when in dilute solutions), and calcium carbonate (limestone) may be used for detoxification (EPA, 1975a).
3) Chlorine-active compounds such as sodium hypochlorite (household bleach) or calcium hypochlorite (bleaching powder, chlorinated lime) may also be used to detoxify organophosphate spills (EPA, 1975a).

a) In some instances, a combination of an alkaline substance with a chlorine-active compound may be used (Pesticide User's Guide, 1976).

4) While ammonia compounds have also been suggested as alternate detoxicants for organophosphate spills, UNDER NO CIRCUMSTANCES SHOULD AMMONIA EVER BE COMBINED WITH A CHLORINE-ACTIVE COMPOUND (BLEACH) AS HIGHLY IRRITATING CHLORAMINE GAS MAY BE EVOLVED.

F) SMALL SPILL DECONTAMINATION

1) 3 cups of Arm & Hammer washing soda (sodium carbonate) or Arm & Hammer baking soda (sodium bicarbonate) may be combined with one-half cup of household bleach and added to a plastic bucket of water. The washing soda is more alkaline and may be more efficacious, if available. Wear rubber gloves, and use a respirator certified effective against toxic vapors. Several washes may be required for decontamination (EPA, 1978).

a) Spilled liquid may first be adsorbed with soil, sweeping compound, sawdust, or dry sand and then both the adsorbed material and the floor decontaminated with one of the above solutions (EPA, 1975a).
b) NOTE - Do NOT use a COMBINATION of BLEACH and ALKALI to DECONTAMINATE ACEPHATE or ACETYL ORGANOPHOSPHATE COMPOUNDS such as ORTHENE(R). Spills involving acephate organophosphates should be decontaminated by the following procedure - Isolate and ventilate the area; keep sources of fire away; wear rubber or neoprene gloves and overshoes; get fire-fighting equipment ready; contain any liquid spill around the edge and absorb with Zorb-All(R) or similar material; dispose of absorbed or dry material in disposable containers; scrub the spilled area with concentrated detergent such as TIDE(R), ALL(R) or similar product; re-absorb scrubbing liquid and dispose as above; dispose of cleaning materials and contaminated clothing; wash gloves, overshoes and shovel with concentrated detergent. CALL the 24-HOUR EMERGENCY NUMBER (415) 233-3737 for further information on handling spills of acephate products (Ortho, 1989).

G) LARGE SPILL DECONTAMINATION

1) Sprinkle or spray the area with a mixture of one gallon of sodium hypochlorite (bleach) mixed with one gallon of water. Then spread calcium hydroxide (hydrated or slaked lime) liberally over the area and allow to stand for at least one hour (Pesticide User's Guide, 1976). Wear rubber gloves, and use a respirator certified effective against toxic vapors. Several washes may be required for decontamination (EPA, 1978).
2) Other decontamination methods may be recommended by manufacturers of specific agents. Check containers, labels, or product literature for possible instructions regarding spill decontamination.

a) NOTE - Do NOT USE a COMBINATION of BLEACH and ALKALI to DECONTAMINATE ACEPHATE or ACETYL ORGANOPHOSPHATE COMPOUNDS such as ORTHENE(R). Spills involving acephate organophosphates should be decontaminated by the following procedure - Isolate and ventilate the area; keep sources of fire away; wear rubber or neoprene gloves and overshoes; get fire-fighting equipment ready; contain any liquid spill around the edge and absorb with Zorb-All(R) or similar material; dispose of absorbed or dry material in disposable containers; scrub the spilled area with concentrated detergent such as TIDE(R), ALL(R) or similar product; re-absorb scrubbing liquid and dispose as above; dispose of cleaning materials and contaminated clothing; wash gloves, overshoes and shovel with concentrated detergent. CALL the 24-HOUR EMERGENCY NUMBER (415) 233-3737 for further information on handling spills of acephate products (Ortho, 1989).

3) Disposal of large quantities or contamination of large areas may be regulated by various governmental agencies and reporting may be required.

6.9.2)

A) OBSERVATION REGIMES

1) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

B) DERMATITIS

1) Some organophosphates can cause a dermal irritation or allergic contact dermatitis. This should be treated symptomatically.
2) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

C) SEIZURE

1) SUMMARY

2) DIAZEPAM

3) NO INTRAVENOUS ACCESS

4) LORAZEPAM

5) PHENOBARBITAL

6) OTHER AGENTS

D) MONITORING OF PATIENT

a) Plasma cholinesterase appears to be a more sensitive index of exposure, while erythrocyte acetylcholinesterase activity appears to better correlate with clinical effects (Muller & Hunt, 1980).

E) ATROPINE

a) Organophosphate-poisoned patients are generally tolerant to the toxic effects of atropine (dry mouth, rapid pulse, dilated pupils, etc). If these findings occur following a diagnostic atropine dose, the patient is probably not seriously poisoned.

1) DIAGNOSTIC DOSE - ADULT - 1 milligram intravenously or intramuscularly; CHILD - 0.25 milligram (about 0.01 milligram/kilogram) intravenously or intramuscularly.

3) THERAPEUTIC DOSE

1) Inject atropine sulfate slowly intravenously. In cases where this is not possible, atropine can be injected subcutaneously or given endotracheally or intraosseously (Prete et al, 1987).
2) DOSES

c) PRECAUTIONS

d) ATROPINIZATION

e) AUTOMATIC INJECTORS

f) INHALED NEBULIZED ATROPINE

1) Atropine (2mg) administered in a hand held nebulizer was associated with improvement in bronchorrhea and respiratory distress in a case of malathion poisoning (Shockley, 1989).

F) IPRATROPIUM

1) Endotracheal ipratropium 0.5 mg every 6 hours was associated with improvement in rales in one case of organophosphate poisoning (Shemesh et al, 1988).

G) PRALIDOXIME

1) INDICATIONS

a) PRALIDOXIME/INDICATIONS

b) PRALIDOXIME/CONTROVERSY

2) ADMINISTRATION

a) PRALIDOXIME/ADMINISTRATION

3) DOSE

a) PRALIDOXIME DOSE

5) MAXIMUM DOSE

a) The maximum recommended dose for pralidoxime is 12 grams in 24 hours for adults (S Sweetman , 2002); based on WHO, this dose may be exceeded in severely poisoned adults (Tang et al, 2013).

6) DURATION OF INTRAVENOUS DOSING

4) ADVERSE EFFECTS

a) SUMMARY

b) MINIMAL TOXICITY

c) NEUROMUSCULAR BLOCKADE

1) High doses have been reported to cause neuromuscular blockade, but this would not be expected to occur with recommended doses (Grob & Johns, 1958).

d) VISUAL DISTURBANCES

e) ASYSTOLE

f) WEAKNESS

1) Mild weakness, blurred vision, dizziness, headache, nausea, and tachycardia may occur if the rate of pralidoxime infusion exceeds 500 milligrams/minute (Jager & Stagg, 1958).

g) ATROPINE SIDE EFFECTS

h) CARDIOVASCULAR

5) PHARMACOKINETICS

6) AVAILABLE FORMS

a) VIALS

1) Each 20-mL vial contains 1 gram of pralidoxime chloride (Prod Info PROTOPAM(R) Chloride injection, 2010)

b) SELF-INJECTOR

c) CONVERSION FROM AUTOINJECTOR TO IV SOLUTION

d) OTHER SALTS

H) OBIDOXIME CHLORIDE

1) OBIDOXIME/INDICATIONS

2) ADULT DOSE

3) PEDIATRIC DOSE

4) DURATION:

5) ADVERSE EFFECTS

a) Mild, transient liver dysfunction has been noted with obidoxime use (Finkelstein et al, 1989).

I) ASOXIME CHLORIDE

a) No undesirable effects were reported. This study suggests low oral bioavailability of HI-6 in man (Jovanovic et al, 1990).

J) ACUTE LUNG INJURY

K) PULMONARY ASPIRATION

L) MONITORING OF PATIENT

1) CARDIAC MONITORING - Monitor cardiac functions and electrocardiogram closely.

M) CONTRAINDICATED TREATMENT

1) Do NOT administer OILS, which enhance the absorption of organophosphates.

N) BRONCHOSPASM

O) DRUG INTERACTION

1) NEUROMUSCULAR BLOCKER

P) EXPERIMENTAL THERAPY

a) Pyridostigmine bromide reversibly inhibits peripheral acetylcholinesterase. PRETREATMENT with pyridostigmine bromide PRIOR to exposure to nerve agents protects a portion of acetylcholinesterase from nerve agent binding (Dunn & Sidell, 1989).
b) Pyridostigmine bromide use, combined with current antidote therapy, is reported to greatly reduce the potential lethality of exposure to GD (soman) (Dunn & Sidell, 1989; (Dirnhuber et al, 1979) Kluwe, 1987).
c) PRETREATMENT DOSE - 30 milligrams orally every 8 hours is to be taken in situations where there is a threat of nerve agent attack (Dunn & Sidell, 1989).
d) ADVERSE EFFECTS - In humans oral administration of 30 milligrams every 8 hours causes no interference with performance (US Army, 1987). Larger doses have been associated with toxic effects including interference with visual acuity and accommodation and intestinal disturbances (Dunn & Sidell, 1989).

1) Rats pretreated with physostigmine showed decreased weight loss, cholinergic effects and lethality following exposure to Soman than did controls (Miller et al, 1993).

Q) PATIENT CURRENTLY PREGNANT

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

Enhanced Elimination

1) Exchange transfusions and/or hemoperfusion with activated carbon have been effective in lowering plasma concentrations of parathion and may be necessary in severe poisonings (Windler et al, 1983) de Monchy et al, 1979).

1) Hemoperfusion with coated activated charcoal or amberlite XAD-4 has been effective in clearing parathion, Demeton-S-methyl sulfoxide and dimethioate from human blood. Hemodialysis was less effective (Okonek et al, 1979).

1) Charcoal hemoperfusion was effective in lowering blood levels of malathion in a poisoned patient (Burgess & Audette, 1990).

1) Hemoperfusion was NOT successful in removing clinically relevant amounts of organophosphates in one study of 42 patients. The amount removed was less than 0.1 percent of total absorbed poison (Martinez-Chuecos et al, 1992).
2) EXTRACORPOREAL CARBOHEMOPERFUSION (ECHP) - Prehospital use of an activated charcoal intravenous bypass, in the ambulance or at home, was used in 16 patients with ingestion of "lethal" amounts of carbophos. All patients survived and required less atropine and artificial ventilation than a comparison group treated without ECHP. Eight of 30 patients in the control group died within 2 hours after admission (Afanasiev et al, 1992).

Abstracts

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) The minimum lethal human dose to this agent has not been delineated.
2) The actual lethal dose of an organophosphate can vary widely and depends strongly on the route and rate of exposure and on the aggressiveness of the treatment used.

Maximum Tolerated Exposure

1) A worker developed mild anticholinesterase poisoning symptoms and contact dermatitis following skin contact with a 0.00025 percent formothion solution (HSDB , 2000).
2) Three workers at a pesticide-formulating plant developed symptoms of organophosphate poisoning associated with each worker wearing a uniform that was contaminated with 76 percent parathion and then laundered. The uniform had been laundered three times before the third worker wore it and he still developed nausea, vomiting, and red cell cholinesterase activity of 75 percent of normal (Clifford & Nies, 1989).

1) Note that CHILDREN MAY EXHIBIT DIFFERENT PREDOMINANT SIGNS of organophosphate poisoning from adults. In a study on 25 children poisoned by organophosphate or carbamate compounds, the major symptoms in most of them were CNS depression, stupor, flaccidity, dyspnea, and coma.
2) Other classical signs of organophosphate poisoning, such as miosis, fasciculations, bradycardia, excessive salivation and lacrimation, and gastrointestinal symptoms, were infrequent (Sofer et al, 1989).
3) Children tend to be more sensitive to organophosphates than adults (Zwiener & Ginsburg, 1988).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
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
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) References: RTECS, 2000

1) LD50- (ORAL)MOUSE:

a) 83300 mcg/kg

2) LD50- (SKIN)MOUSE:

a) 400 mg/kg

3) LD50- (ORAL)RAT:

a) 250 mg/kg
b) 365-500 mg/kg (HSDB, 2000)

4) LD50- (SKIN)RAT:

a) 353 mg/kg

Pharmacology Toxicology

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

References

General Bibliography

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FORMOTHION

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

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Enhanced Elimination

Summary

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Workplace Standards

Toxicity Information

Physical Characteristics

Ph

Molecular Weight

General Bibliography