PHOSPHAMIDON

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1.2.1) MOLECULAR FORMULA
1) C10-H19-Cl-N-O5-P

Available Forms Sources

1) Phosphamidon is an organophosphate compound. It is a clear to pale yellowish oily liquid which can be odorless or have a faint odor (EPA, 1985; Clayton & Clayton, 1982; Sax & Lewis, 1987; HSDB , 1993). It is miscible with water and with most organic solvents, except saturated hydrocarbons (HSDB , 1993). Technical preparations of phosphamidon may contain one to two percent of the much more potent cholinesterase inhibitor, gamma-chlorophosphamidon, as an impurity (HSDB , 1993; Clayton & Clayton, 1982).
2) The ACGIH has established a Biological Exposure Index (BEI) for organophosphate cholinesterase inhibitors. Refer to the BIOMONITORING section for more information.
3) 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 phosphamidon noted.

1) Phosphamidon is used as an acaricide and an insecticide on fruits, vegetables, sugar cane, nuts, and cotton (EPA, 1985; Clayton & Clayton, 1982; Sax & Lewis, 1987; Budavari, 1989; HSDB , 1993).

Overview

Life Support

Clinical Effects

0.2.1)

A) 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 phosphamidon, but could potentially occur in individual cases.
B) USES: Phosphamidon, an organophosphate compound, has been used as an acaricide and insecticide. Phosphamidon is no longer used in any registered pesticide products in the US, but may be available in other countries.
C) TOXICOLOGY: Organophosphates competitively inhibit pseudocholinesterase and acetylcholinesterase, preventing hydrolysis and inactivation of acetylcholine. Acetylcholine accumulates at nerve junctions, causing malfunction of the sympathetic, parasympathetic, and peripheral nervous systems and some of the CNS. Clinical signs of cholinergic excess develop.
D) EPIDEMIOLOGY: Exposure to organophosphates is common, but serious toxicity is unusual in the US. Common source of severe poisoning in developing countries.
E) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: MUSCARINIC EFFECTS: Can include bradycardia, salivation, lacrimation, diaphoresis, vomiting, diarrhea, urination, and miosis. NICOTINIC EFFECTS: Tachycardia, hypertension, mydriasis, and muscle cramps.
2) SEVERE POISONING: MUSCARINIC EFFECTS: Bronchorrhea, bronchospasm, and acute lung injury. NICOTINIC EFFECTS: Muscle fasciculations, weakness, and respiratory failure. CENTRAL EFFECTS: CNS depression, agitation, confusion, delirium, coma, and seizures. Hypotension, ventricular dysrhythmias, metabolic acidosis, pancreatitis, and hyperglycemia can also develop.
3) DELAYED EFFECTS: Intermediate syndrome is characterized by paralysis of respiratory, cranial motor, neck flexor, and proximal limb muscles 1 to 4 days after apparent recovery from cholinergic toxicity, and prior to the development of delayed peripheral neuropathy. Manifestations can include the inability to lift the neck or sit up, ophthalmoparesis, slow eye movements, facial weakness, difficulty swallowing, limb weakness (primarily proximal), areflexia, and respiratory paralysis. Recovery begins 5 to 15 days after onset. Distal sensory-motor polyneuropathy has been reported in one patient following exposure to phosphamidon/mevinphos. It may rarely develop 6 to 21 days following exposure. Characterized by burning or tingling followed by weakness beginning in the legs which then spreads proximally. In severe cases, it may result in spasticity or flaccidity. Recovery requires months and may not be complete.
4) CHILDREN: May have different predominant signs and symptoms than adults (more likely CNS depression, stupor, coma, flaccidity, dyspnea, and seizures). Children may also have fewer muscarinic and nicotinic signs of intoxication (ie, secretions, bradycardia, fasciculations and miosis) as compared to adults.
5) INHALATION EXPOSURE: Organophosphate vapors rapidly produce mucous membrane and upper airway irritation and bronchospasm, followed by systemic muscarinic, nicotinic and central effects if exposed to significant concentrations.

0.2.3)

A) Fever, bradycardia and hypotension, or tachycardia and hypertension may occur. Apnea and cyanosis were noted in a fatal case of phosphamidon ingestion.

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) Excessive lacrimation has occurred in cases of phosphamidon exposure. A sensation of burning in the eyes was described in a group of workers drenched or splashed with phosphamidon.

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. Apnea and cyanosis were noted in a fatal case of phosphamidon ingestion.
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.

1) Headache, dizziness, confusion, and restlessness have been reported in patients with phosphamidon poisoning.

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.

1) Nausea, vomiting, abdominal pain, and hypersalivation have been described in cases of phosphamidon poisoning.

B) Intussusception has been reported in a single pediatric organophosphate poisoning case.
C) Pancreatitis has occassionally been reported in acute organophosphate poisoning.

0.2.9)

A) Liver injury was seen in one fatal case of deliberate phosphamidon ingestion.

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, fatigability 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.

0.2.18)

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) Fetotoxicity has been observed in mouse studies at a dose of 5 to 10 mg/kg. Teratogenicity was not observed.

1) Changes in sperm morphology due to mutations have been reported in mouse studies.

0.2.21)

A) Phosphamidon has be designated an equivocal tumorigenic agent by RTECS criteria.

0.2.22)

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

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TOXICITY

1) A patient who is either asymptomatic or presents with mild clinical symptoms (i.e. normal vitals, pulse oximetry and an acetylcholinesterase greater than 80% of lower reference range), and remains stable for 12 hours can be discharged. Obtain appropriate psychiatric evaluation if an intentional exposure.

B) MANAGEMENT OF MODERATE TO SEVERE TOXICITY

1) Immediate assessment and evaluation. Airway management is likely to be necessary. Simple decontamination (i.e. skin and gastrointestinal, removal of contaminated clothes). Administer antidotes: atropine for muscarinic manifestations (e.g. salivation, diarrhea, bronchorrhea), pralidoxime for nicotinic manifestations (e.g. weakness, fasciculations). Treat seizures with benzodiazepines. Admit to intensive care with continuous monitoring, titration of antidotes, ventilation, and inotropes as needed. Consult a medical toxicologist and/or poison center.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal is contraindicated because of possible respiratory depression and seizures and risk of aspiration. Remove contaminated clothing, wash skin with soap and water. Universal precautions and nitrile gloves to protect personnel.
2) HOSPITAL: Activated charcoal for large ingestions. Consider nasogastric tube for aspiration of gastric contents, or gastric lavage for recent large ingestions, if patient is intubated or able to protect airway.
3) DERMAL: Remove contaminated clothing. Wash skin thoroughly with soap and water. Universal precautions and nitrile gloves to protect staff from contamination. Systemic toxicity can result from dermal exposure.
4) OCULAR: Copious eye irrigation.

D) AIRWAY MANAGEMENT

1) Immediately assess airway and respiratory function. Administer oxygen. Suction secretions. Endotracheal intubation may be necessary because of respiratory muscle weakness or bronchorrhea. Avoid succinylcholine for rapid sequence intubation as prolonged paralysis may result. Monitoring pulmonary function (FVC, FEV1, NIF) may help anticipate need for intubation.

E) ANTIDOTES

1) Atropine is used to antagonize muscarinic effects. Oximes (pralidoxime in the US, or obidoxime in some other countries) are used to reverse neuromuscular blockade. Use of oximes is usually indicated for patients with moderate to severe toxicity.

a) AUTOINJECTORS: PREHOSPITAL TREATMENT: DuoDote(R) (Meridian Medical Technologies, Columbia, MD) is a dual chambered device that delivers 2.1 mg atropine and 600 mg pralidoxime in a single needle for intramuscular use. It is intended for use in a civilian/community setting, and is administered by EMS personnel who have been trained to recognize and treat nerve agent or insecticide intoxication. ATNAA (Antidote Treatment Nerve Agent Autoinjector, Meridian Medical Technologies, Columbia, Maryland) is currently used by the US military and provides atropine injection and pralidoxime chloride injection in a single needle. Each self-contained unit dispenses 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL via intramuscular injection. The safety and efficacy of ATNAA or DuoDote(R) has not been established in children. These autoinjectors contain benzyl alcohol as a preservative. The AtroPen(R) autoinjector (atropine sulfate; Meridian Medical Technologies, Inc, Columbia, MD) delivers a dose of atropine in a self-contained unit. Since the AtroPen(R) comes in different strengths, certain dose units have been approved for use in children. If pralidoxime is required, pralidoxime prefilled autoinjector delivers 600 mg IM (adult dosing). The safety and efficacy of pralidoxime auto-injector for use in nerve agent poisoning have not been established in pediatric patients.
b) ATROPINE

1) Atropine is used to treat muscarinic effects (e.g. salivation, lacrimation, defecation, urination, bronchorrhea). ADULT: 1 to 3 mg IV; CHILD: 0.02 mg/kg IV. If inadequate response in 3 to 5 minutes, double the dose. Continue doubling the dose and administer it IV every 3 to 5 minutes as needed to dry pulmonary secretions. Once secretions are dried, maintain with an infusion of 10% to 20% of the loading dose every hour. Monitor frequently for evidence of cholinergic effects or atropine toxicity (e.g. delirium, hyperthermia, ileus) and titrate dose accordingly. Large doses (hundreds of milligrams) are sometimes required. Atropinization may be required for hours to days depending on severity.

c) PRALIDOXIME

1) 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. ADULT DOSE: 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). ALTERNATE ADULT DOSE: 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. Intravenous dosing is preferred; however, intramuscular administration may be considered. A continuous infusion of pralidoxime is generally preferred to intermittent bolus dosing to maintain a target concentration with less variation. CHILD DOSE: A loading dose of 20 to 40 mg/kg (maximum: 2 grams/dose) infused over 30 to 60 minutes in 0.9% sodium chloride. 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 DOSE: 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.

F) SEIZURES

1) IV benzodiazepines are indicated for seizures or agitation, diazepam 5 to 10 mg IV, lorazepam 2 to 4 mg IV; repeat as needed.

G) HYPOTENSIVE EPISODE

1) IV fluids, dopamine, norepinephrine.

H) BRONCHOSPASM

1) Inhaled ipratropium or glycopyrrolate may be useful in addition to intravenous atropine.

I) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with unintentional trivial exposures who are asymptomatic can be observed in the home or in the workplace.
2) OBSERVATION CRITERIA: Patients with deliberate or significant exposure and those who are symptomatic should be sent to a health care facility for evaluation, treatment and observation for 6 to 12 hours. Onset of toxicity is variable; most patients will develop symptoms within 6 hours. Patients that remain asymptomatic 12 hours after an ingestion or a dermal exposure are unlikely to develop severe toxicity. However, highly lipophilic agents (like fenthion) can produce initially subtle effects followed by progressive weakness including respiratory failure. Cholinesterase activity should be determined to confirm the degree of exposure.
3) ADMISSION CRITERIA: All intentional ingestions should be initially managed as a severe exposure. Determine cholinesterase activity to assess if a significant exposure occurred. Patients who develop signs or symptoms of cholinergic toxicity (e.g. muscarinic, nicotinic OR central) should be admitted to an intensive care setting.
4) CONSULT CRITERIA: Consult a medical toxicologist and/or poison center for assistance with any patient with moderate to severe cholinergic manifestations.

J) PITFALLS

1) Inadequate initial atropinization. Patients with severe toxicity require rapid administration of large doses, titrate to the endpoint or drying pulmonary secretions.
2) Monitor respiratory function closely, pulmonary function testing may provide early clues to the development of respiratory failure.
3) Some component of dermal exposure occurs with most significant overdoses, inadequate decontamination may worsen toxicity.
4) Patients should be monitored closely for 48 hours after discontinuation of atropine and pralidoxime for evidence of recurrent toxicity or intermediate syndrome.

K) TOXICOKINETICS

1) Well absorbed across the lung, mucous membranes (including gut), and skin; significant toxicity has been reported after all these routes of exposure.
2) Most patients who develop severe toxicity have signs and symptoms within 6 hours of exposure, onset of toxicity is rarely more than 12 hours after exposure. Highly lipophilic organophosphates (e.g. fenthion) may produce subtle early toxicity that can progress to severe weakness/respiratory failure over many hours.
3) Recurrence of toxicity after apparent improvement has been described.
4) Some organophosphates undergo "ageing", a process by which the bond of the organophosphate to acetylcholinesterase becomes stronger, and cannot be reversed readily by oximes. Early oxime administration may prevent aging and shorten clinical manifestations of toxicity.

L) PREDISPOSING CONDITIONS

1) Patients with chronic occupational exposure to organophosphates may have chronically depressed cholinesterase activity and may develop severe toxicity after smaller acute exposures.
2) Dermal absorption is enhanced in young children due to larger surface area to volume ratio and more permeable skin.

M) DIFFERENTIAL DIAGNOSIS

1) Gastroenteritis, food poisoning, asthma, myasthenic crisis, cholinergic excess from medications.

0.4.3)

A) Remove from exposure and administer oxygen if respiratory distress develops.
B) Inhaled ipratropium or glycopyrrolate may be useful in addition to intravenous atropine for bronchorrhea and bronchospasm. Inhaled beta agonists may be useful for bronchospasm unresponsive to anticholinergics.

0.4.4)

A) Irrigate exposed eyes with water or normal saline. Systemic toxicity is unlikely to develop from ocular exposure alone.

0.4.5)

A) OVERVIEW

1) Systemic effects can occur from dermal exposure to organophosphates. Remove contaminated clothing, wash skin thoroughly with soap and water. Use universal precautions and nitrile gloves to protect staff from contamination.
2) Monitor for the development of cholinergic toxicity and treat as in oral exposure.

0.4.6)

A) Monitor for the development of compartment syndrome, tissue necrosis, cellulitis, and thrombophlebitis in addition to systemic cholinergic toxicity (which may be prolonged) after subcutaneous, intramuscular or intravenous injection.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) Fever, bradycardia and hypotension, or tachycardia and hypertension may occur. Apnea and cyanosis were noted in a fatal case of phosphamidon ingestion.

3.3.2)

A) Apnea and cyanosis were noted in a fatal case of phosphamidon ingestion (HSDB , 1999).

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% 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% 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% 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%) 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).

1) Some individuals from a group of field workers exposed to phosphamidon and mevinphos complained of blurred vision for 18 weeks (Coye et al, 1987).

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) LACRIMATION - Excessive lacrimation has occurred in cases of phosphamidon exposure (HSDB , 1999).
F) BURNING SENSATION - A sensation of burning in the eyes was described in a group of workers drenched or splashed with phosphamidon (HSDB , 1999).
G) DECREASED VISUAL ACUITY - Fenthion has been reported to produce macular lesions in chronically exposed patients, some resulting in compromised vision (Misra et al, 1985).
H) 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% of patients in one study had excessive salivation (Bardin et al, 1987). Excessive salivation is a muscarinic sign.

1) Hypersalivation has been described in patients with phosphamidon poisoning (HSDB , 1999).

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% 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% of patients in one study (Bardin et al, 1987).

E) BRADYCARDIA

1) A heart rate of less than 60 beats/minute occurred in 21% 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% of patients in one study (Bardin et al, 1987). Hypoventilation occurred in 20% of patients in one study (Bardin et al, 1987).

B) ACUTE LUNG INJURY

1) Acute lung injury 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 preexisting 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% 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, 1984a).
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) APNEA

1) Apnea and cyanosis were noted in a fatal case of phosphamidon ingestion (HSDB , 1999).

Neurologic

3.7.1)

1) Headache, dizziness, confusion, and restlessness have been reported in patients with phosphamidon poisoning.

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).
2) Headache, dizziness, confusion, and restlessness have been reported in patients with phosphamidon poisoning (HSDB , 1999).

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%) 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% 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 unresponsive 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% 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, 1979b).
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% in this enzyme prior to changes in blood acetylcholinesterase, 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).

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).

Gastrointestinal

3.8.1)

A) Vomiting, hypersalivation, diarrhea, fecal incontinence and abdominal pain may occur.

1) Nausea, vomiting, abdominal pain, and hypersalivation have been described in cases of phosphamidon poisoning.

B) Intussusception has been reported in a single pediatric organophosphate poisoning case.
C) Pancreatitis has occassionally been reported in acute organophosphate poisoning.

3.8.2)

A) GASTROENTERITIS

1) Nausea, vomiting, diarrhea, abdominal cramps and hypersalivation are common muscarinic signs of organophosphate poisoning. Vomiting and diarrhea occurred in 38% and 21% of patients, respectively, in one study (Bardin et al, 1987).
2) Nausea, vomiting, abdominal pain, and hypersalivation have been described in cases of phosphamidon poisoning (Coye et al, 1987; HSDB , 1999).

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).

Hepatic

3.9.1)

A) Liver injury was seen in one fatal case of deliberate phosphamidon ingestion.

3.9.2)

A) LIVER DAMAGE

1) Liver injury was seen in one fatal case of deliberate phosphamidon ingestion (HSDB , 1999).
2) Hepatotoxicity was observed in mice given 35 ppm of phosphamidon ad libitum in drinking water for 60 days and in rats exposed dermally to 3.98 mg/kg daily, 5 days per week, for 3 weeks (Bhatnager & Jain, 1986; Qadri et al, 1987).

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, 1979b).

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% of patients in one study (Bardin et al, 1987). Pallor is sometimes noted (Done, 1979b).

Musculoskeletal

3.15.1)

A) Muscle weakness, fatigability 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%) in one study (Bardin et al, 1987).

B) PARALYSIS

1) Muscle paralysis occasionally supervenes (Done, 1979b).
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)

A) Fetotoxicity has been observed in mouse studies at a dose of 5 to 10 mg/kg. Teratogenicity was not observed.

1) Changes in sperm morphology due to mutations have been reported in mouse studies.

3.20.2)

A) 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).

B) ANIMAL STUDIES

1) FETOTOXICITY

a) Phosphamidon was fetotoxic, but not teratogenic, in mice (Bhatnager & Soni, 1988; RTECS , 1997). When given phosphamidon at a level of 35 ppm in the diet for 30 days prior to conception, mice had fewer implants, increased resorptions, smaller litter size, and reduced fetal weight (Soni & Bhatnager, 1991).

2) LACK OF EFFECT

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

3.20.3)

A) HUMANS

1) CASE REPORTS

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) ANIMAL STUDIES

1) FETOTOXICITY

a) Fetotoxicity has been observed in mouse studies at a dose of 5 mg/kg (RTECS , 1997; Bhatnager & Soni, 1988). Teratogenicity was not observed (Bhatnager & Soni, 1988).

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 CAS13171-21-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) Phosphamidon has be designated an equivocal tumorigenic agent by RTECS criteria.

3.21.4)

A) CARCINOMA

1) Phosphamidon has be designated an equivocal tumorigenic agent by RTECS criteria, demonstrating vascular tumors and thyroid tumors in rat studies (RTECS , 1997).
2) However, phosphamidon was not carcinogenic in some mice studies; carcinogenicity studies in rats were inconclusive (HSDB , 1999; NCI, 1979).

Genotoxicity

1) Chromosomal aberrations have been seen in the circulating lymphocytes of workers chronically exposed to phosphamidon.

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs frequently. Institute continuous cardiac and pulse oximetry monitoring. Monitor for respiratory distress (i.e. bronchorrhea, bronchospasm) and for clinical evidence of cholinergic excess (i.e. salivation, vomiting, urination, defecation, miosis).
B) Determine plasma and/or red blood cell cholinesterase activities (plasma is generally more sensitive, but red cell correlates somewhat better with clinical signs and symptoms). Depression in excess of 50% of baseline is generally associated with cholinergic effects, in severe poisoning cholinesterase activity may be depressed by 90% of baseline. Correlation between cholinesterase levels and clinical effects in milder poisonings may be poor.
C) Obtain serial ECGs. Patients who develop a prolonged QTc interval or PVCs are more likely to develop respiratory insufficiency and have a worse prognosis.
D) Monitor electrolytes and serum lipase in patients with significant poisoning. Patients who have increased pancreatic enzyme concentrations are more likely to develop respiratory insufficiency and have a worse prognosis.
E) Monitor pulmonary function (i.e. forced vital capacity, expiratory volume in 1 second, negative inspiratory force) in symptomatic patients, may help anticipate need for intubation.

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% of the pre-exposure value (Milby, 1971).
2) Depressions in excess of 90% 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% 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 (Brown SS, 1989a; 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 (Brown SS, 1989a; 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% 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% 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% (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).

Radiographic Studies

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

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All intentional ingestions should be initially managed as a severe exposure. Patients that are asymptomatic, have only mild symptoms, or were unintentionally exposed do not usually require hospital admission. Determine cholinesterase activity to assess if a significant exposure occurred (Roberts & Aaron, 2007). Patients who develop signs or symptoms of cholinergic toxicity (muscarinic, nicotinic OR central) should be admitted to an intensive care setting.
B) Patients with a moderate to severe exposure that remain stable for 12 hours after receiving oxime can be transferred to a medical floor. If the patient remains stable 48 hours after discharge from intensive care they may be discharged to home with appropriate follow-up care (Roberts & Aaron, 2007).

6.3.1.2) HOME CRITERIA/ORAL

A) Patients with unintentional trivial exposures who are asymptomatic can be observed in the home or in the workplace (Roberts & Aaron, 2007).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist and/or poison control center for assistance with patients who have moderate to severe toxicity.

6.3.1.4) PATIENT TRANSFER/ORAL

A) If intensive care capabilities are not available or there are inadequate supplies of antidote (atropine, pralidoxime) at the initial treating facility, the patient should be transferred to a facility with intensive care capabilities and adequate antidote supplies (Roberts & Aaron, 2007).

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate or significant exposure and those who are symptomatic should be sent to a health care facility for evaluation, treatment and observation for 6 to 12 hours. Onset of toxicity is variable; most patients will develop symptoms within 6 hours. Patients that remain asymptomatic 12 hours after ingestion or a dermal exposure are unlikely to develop severe toxicity. However, highly lipophilic agents (like fenthion) can produce initially subtle effects followed by progressive weakness including respiratory failure. Cholinesterase activity should be determined to confirm the degree of exposure (Roberts & Aaron, 2007).
B) 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% (Midtling et al, 1985). This may take 3 to 4 months following severe poisoning.

Monitoring

Oral Exposure

6.5.1)

A) ORAL EXPOSURE

1) Prehospital gastrointestinal decontamination is NOT recommended because of the potential for early coma or seizures and aspiration.

B) DERMAL EXPOSURE

1) Remove contaminated clothing. Wash skin thoroughly with soap and water.

C) EYE EXPOSURE

1) Copious eye irrigation.

D) INHALATION EXPOSURE

1) Immediately assess airway and respiratory function. Administer oxygen.

E) PERSONNEL PROTECTION

1) Universal precautions should be followed by all individuals (i.e., first responders, emergency medical, and emergency department personnel) caring for the patient to avoid contamination. Nitrile gloves are suggested. Avoid direct contact with contaminated clothing, objects or body fluids.
2) Vomiting containing organophosphates should be placed in a closed impervious container for proper disposal.

F) 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, 1978a). The rate of hydrolysis depends on both the specific organophosphate compound involved and the increase in pH caused by the detoxicant used (EPA, 1978a; EPA, 1975a).

a) NOTE: Do NOT use a MIXTURE of BLEACH and ALKALI for DECONTAMINATING ACEPHATE or ACETYL ORGANOPHOSPHATE COMPOUNDS 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 JE, 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.

G) SMALL SPILL DECONTAMINATION

1) Three 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, 1978a).

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 firefighting 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; reabsorb scrubbing liquid and dispose as above; dispose of cleaning materials and contaminated clothing; wash gloves, overshoes and shovel with concentrated detergent. Call the National Pesticide Telecommunications Network for further assistance at 1-800-858-7378 or on the web at http://nptn.orst.edu.

H) 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, 1978a).
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 firefighting 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; reabsorb scrubbing liquid and dispose as above; dispose of cleaning materials and contaminated clothing; wash gloves, overshoes and shovel with concentrated detergent.

3) FURTHER CONTACT INFORMATION

a) For further information contact the National Pesticide Telecommunications Network at 1-800-858-7378 or contact on the web at http://nptn.orst.edu.
b) Disposal of large quantities or contamination of large areas may be regulated by various governmental agencies and reporting may be required. For small pesticide spills or for further information call the pesticide manufacturer or the National Pesticide Information Center (NPIC) at 1-800-858-7378.
c) The National Response Center (NRC) is the federal point of contact for reporting of spills and can be reached at 1-800-424-8802. For those without 800 access, contact 202-267-2675.
d) CHEMTREC can provide technical and hazardous materials information and can be reached at 1-800-424-9300 in the US; or 703-527-3887 outside the US.

I) ANTIDOTES

1) SUMMARY: Atropine is used to antagonize muscarinic effects. Oximes (pralidoxime in the US, or obidoxime in some other countries) are used to reverse neuromuscular blockade. Use of oximes is usually indicated for patients with moderate to severe toxicity.
2) AUTOINJECTORS

a) INDICATION: Atropine-containing autoinjectors are used for the initial treatment of poisoning by organophosphate nerve agents and organophosphate or carbamate insecticides (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info ATROPEN(R) IM injection, 2005). Pralidoxime use following carbamate exposure may not be indicated.
b) NOTE: The safety and efficacy of MARK I kit (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.), ATNAA, or DuoDote(R) has not been established in children. All of these autoinjectors contain benzyl alcohol as a preservative (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002). Since the AtroPen(R) comes in different strengths, certain dose units have been approved for use in children (Prod Info ATROPEN(R) IM injection, 2005).
c) The AtroPen(R) autoinjector (atropine sulfate; Meridian Medical Technologies, Inc, Columbia, MD) delivers a dose of atropine in a self-contained unit. There are 4 AtroPen(R) strengths: AtroPen(R) 0.25 mg in 0.3 mL of solution (dispenses 0.21 mg of atropine base; equivalent to 0.25 mg of atropine sulfate), AtroPen(R) 0.5 mg in 0.7 mL of solution (dispenses 0.42 mg of atropine base; equivalent to 0.5 mg of atropine sulfate), Atropen(R) 1 mg in 0.7 mL of solution (dispenses 0.84 mg of atropine base; equivalent to 1 mg of atropine sulfate), and AtroPen(R) 2 mg in 0.7 mL of solution (dispenses 1.67 mg of atropine base; equivalent to 2 mg of atropine sulfate) (Prod Info ATROPEN(R) IM injection, 2005).

1) AtroPen(R): DOSE: ADULT AND CHILDREN OVER 10 YEARS OF AGE: Mild symptoms, in cases where exposure is known or suspected: Inject one 2 mg AtroPen(R) (green pen) into the outer thigh as soon as symptoms appear; pralidoxime chloride may also be required. Severe symptoms: Inject one 2 mg AtroPen(R) (green pen) into the outer thigh as soon as symptoms appear, administer 2 additional 2 mg AtroPen(R) doses in rapid succession 10 min after receiving the first dose; pralidoxime chloride and/or an anticonvulsant may also be required, patients should be closely monitored for at least 48 to 72 hr. PEDIATRIC: Mild symptoms, in cases where exposure is known or suspected: dose for infants less than 7 kg (generally less than 6 months of age) = 0.25 mg (yellow pen), dose for children 7 to 18 kg (generally 6 months to 4 years of age) = 0.5 mg (blue pen), dose for children 18 to 41 kg (generally 4 to 10 years of age) = 1 mg (dark red pen), dose for children over 41 kg = 2 mg (green pen): inject one AtroPen(R) into the outer thigh as soon as symptoms appear; pralidoxime chloride may also be required. Severe symptoms: Administer 2 additional AtroPen(R) doses (see above) in rapid succession 10 min after receiving the first dose; pralidoxime chloride and/or an anticonvulsant may also be required, patients should be closely monitored for at least 48 to 72 hr (Prod Info ATROPEN(R) IM injection, 2005).
2) If pralidoxime is required, pralidoxime prefilled autoinjector delivers 600 mg IM (adult dosing); may repeat every 15 minutes up to 3 injections if symptoms persist. The safety and efficacy of pralidoxime auto-injector for use in nerve agent poisoning have not been established in pediatric patients (Prod Info pralidoxime chloride intramuscular auto-imjector solution, 2003)

d) ATNAA (Antidote Treatment Nerve Agent Autoinjector, Meridian Medical Technologies, Columbia, Maryland) is currently used by the US military and provides atropine injection and pralidoxime chloride injection in a single needle. Each self-contained unit dispenses 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL via intramuscular injection (Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002).

1) ATNAA: DOSE: ADULT: One ATNAA into the lateral thigh muscle or buttocks. Wait 10 to 15 minutes for effect (Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002).

e) MARK I: This device (Meridian Medical Technologies, Columbia, Maryland) was used by the US military. (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.) Each kit contains two autoinjectors: an atropine and a pralidoxime autoinjector. The atropine autoinjector delivers 2.1 mg of atropine in 0.7 mL via intramuscular injection. The pralidoxime autoinjector delivers 600 mg pralidoxime chloride in 2 mL via intramuscular injection (Prod Info DUODOTE(TM) IM injection, 2006).
f) DuoDote(R) is a dual chambered device (Meridian Medical Technologies, Columbia, Maryland) that delivers 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL sequentially using a single needle for use in a civilian or community setting. It should be administered by Emergency Medical Services personnel who have been trained to recognize and treat nerve agent or insecticide intoxication (Prod Info DuoDote(R) intramuscular injection solution, 2011).
g) DuoDote(R): DOSE: ADULT: Two or more mild symptoms, initial dose, 1 injector (atropine 2.1 mg/pralidoxime chloride 600 mg) IM into the mid-lateral thigh, wait 10 to 15 minutes for effect; subsequent doses, if at any time severe symptoms develop, administer 2 additional injectors in rapid succession IM into the mid-lateral thigh and immediately seek definitive medical care; MAX 3 doses unless definitive medical care is available (Prod Info DuoDote(R) intramuscular injection solution, 2011).
h) Therapeutic plasma concentrations of pralidoxime exceeding 4 mcg/mL were achieved within 4 to 8 minutes after injection (Sidell & Groff, 1974).
i) DIAZEPAM Autoinjector (Meridian Medical Technologies): Contains 10 mg of diazepam in 2 mL for intramuscular injection for seizure control (Prod Info diazepam autoinjector IM injection solution, 2005).
j) These devices are designed for initial field treatment. Although autoinjector doses may be adequate for nerve agent exposures, ORGANOPHOSPHATE exposures may require additional atropine or pralidoxime doses in the hospital setting that exceed those in the available autoinjectors.
k) For medical questions concerning Meridian products, you can call 1-800-438-1985. For general product information, call 1-800-638-8093.

6.5.2)

A) ACTIVATED CHARCOAL

1) Activated charcoal may be considered for a large recent ingestion, if patient is intubated or able to protect airway.
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).

B) GASTRIC LAVAGE

1) Consider nasogastric tube for aspiration of gastric contents, or gastric lavage for recent large ingestions, if patient is intubated or able to protect airway.
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.

6.5.3)

A) AIRWAY MANAGEMENT

B) MONITORING OF PATIENT

1) Cardiac monitoring, pulse oximetry, obtain plasma and red cell cholinesterase levels. Monitor clinical exam for evidence of muscarinic (e.g., bronchospasm, bronchorrhea, salivation, lacrimation, defecation, urination, miosis), nicotinic (e.g., muscle weakness or fasciculations, respiratory insufficiency) or CNS (e.g., seizures, coma) manifestations of cholinergic toxicity. Monitor serial ECGs, serum electrolytes and lipase in symptomatic patients.

a) Prolonged QTc interval or presence of PVCs on ECG are associated with a higher risk of respiratory failure and a worse prognosis, as is an initial serum pancreatic isoamylase level greater than the normal range (Grmec et al, 2004; Chuang et al, 1996; Jang et al, 1995; Matsumiya et al, 1996).

2) OBSERVATION: Onset of clinical toxicity is variable, but most patients with a severe exposure become symptomatic within 6 hours. If a patient remains asymptomatic 12 hours after ingestion, severe toxicity is not anticipated. Exceptions can include highly lipophilic compounds (ie, fenthion) which initially produce only subtle cholinergic effects that can progress to muscle weakness and respiratory failure (Roberts & Aaron, 2007).
3) POOR PROGNOSTIC INDICATORS: Systolic blood pressure of less than 100 mmHg and fraction of inspired oxygen (FiO2) greater than 40%, to maintain a SpO2 of greater than 92% within the first 24 hours, are poor prognostic indicators among mechanically ventilated patients (Munidasa et al, 2004).
4) CHOLINESTERASES: Measure plasma pseudocholinesterase (ChE) or red cell acetylcholinesterase (AChE) activities. Specimens should be obtained prior to administration of pralidoxime when possible.
5) 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 (Brown SS, 1989). However, severe clinical toxicity is likely when the erythrocyte acetylcholinesterase activity is less than 20% of normal (Roberts & Aaron, 2007).

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) ANTIDOTE

1) GENERAL

a) There are three primary classes of antidotes: ATROPINE (muscarinic antagonist); OXIMES (pralidoxime in the US, or obidoxime in some other countries) to reverse neuromuscular blockade. Use of oximes is usually indicated for patients with moderate to severe toxicity. BENZODIAZEPINES are indicated for agitation and seizures.

2) PREHOSPITAL TREATMENT

a) AUTOINJECTORS

1) INDICATION: Atropine-containing autoinjectors are used for the initial treatment of poisoning by organophosphate nerve agents and organophosphate or carbamate insecticides (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info ATROPEN(R) IM injection, 2005). Pralidoxime use following carbamate exposure may not be indicated.
2) NOTE: The safety and efficacy of MARK I kit (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.), ATNAA, or DuoDote(R) has not been established in children. All of these autoinjectors contain benzyl alcohol as a preservative (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002). Since the AtroPen(R) comes in different strengths, certain dose units have been approved for use in children (Prod Info ATROPEN(R) IM injection, 2005).
3) The AtroPen(R) autoinjector (atropine sulfate; Meridian Medical Technologies, Inc, Columbia, MD) delivers a dose of atropine in a self-contained unit. There are 4 AtroPen(R) strengths: AtroPen(R) 0.25 mg in 0.3 mL of solution (dispenses 0.21 mg of atropine base; equivalent to 0.25 mg of atropine sulfate), AtroPen(R) 0.5 mg in 0.7 mL of solution (dispenses 0.42 mg of atropine base; equivalent to 0.5 mg of atropine sulfate), Atropen(R) 1 mg in 0.7 mL of solution (dispenses 0.84 mg of atropine base; equivalent to 1 mg of atropine sulfate), and AtroPen(R) 2 mg in 0.7 mL of solution (dispenses 1.67 mg of atropine base; equivalent to 2 mg of atropine sulfate) (Prod Info ATROPEN(R) IM injection, 2005).

a) AtroPen(R): DOSE: ADULT AND CHILDREN OVER 10 YEARS OF AGE: Mild symptoms, in cases where exposure is known or suspected: Inject one 2 mg AtroPen(R) (green pen) into the outer thigh as soon as symptoms appear; pralidoxime chloride may also be required. Severe symptoms: Inject one 2 mg AtroPen(R) (green pen) into the outer thigh as soon as symptoms appear, administer 2 additional 2 mg AtroPen(R) doses in rapid succession 10 min after receiving the first dose; pralidoxime chloride and/or an anticonvulsant may also be required, patients should be closely monitored for at least 48 to 72 hr. PEDIATRIC: Mild symptoms, in cases where exposure is known or suspected: dose for infants less than 7 kg (generally less than 6 months of age) = 0.25 mg (yellow pen), dose for children 7 to 18 kg (generally 6 months to 4 years of age) = 0.5 mg (blue pen), dose for children 18 to 41 kg (generally 4 to 10 years of age) = 1 mg (dark red pen), dose for children over 41 kg = 2 mg (green pen): inject one AtroPen(R) into the outer thigh as soon as symptoms appear; pralidoxime chloride may also be required. Severe symptoms: Administer 2 additional AtroPen(R) doses (see above) in rapid succession 10 min after receiving the first dose; pralidoxime chloride and/or an anticonvulsant may also be required, patients should be closely monitored for at least 48 to 72 hr (Prod Info ATROPEN(R) IM injection, 2005).
b) If pralidoxime is required, pralidoxime prefilled autoinjector delivers 600 mg IM (adult dosing); may repeat every 15 minutes up to 3 injections if symptoms persist. The safety and efficacy of pralidoxime auto-injector for use in nerve agent poisoning have not been established in pediatric patients (Prod Info pralidoxime chloride intramuscular auto-imjector solution, 2003)

4) ATNAA (Antidote Treatment Nerve Agent Autoinjector, Meridian Medical Technologies, Columbia, Maryland) is currently used by the US military and provides atropine injection and pralidoxime chloride injection in a single needle. Each self-contained unit dispenses 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL via intramuscular injection (Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002).

a) ATNAA: DOSE: ADULT: One ATNAA into the lateral thigh muscle or buttocks. Wait 10 to 15 minutes for effect (Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002).

5) MARK I: This device (Meridian Medical Technologies, Columbia, Maryland) was used by the US military. (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.) Each kit contains two autoinjectors: an atropine and a pralidoxime autoinjector. The atropine autoinjector delivers 2.1 mg of atropine in 0.7 mL via intramuscular injection. The pralidoxime autoinjector delivers 600 mg pralidoxime chloride in 2 mL via intramuscular injection (Prod Info DUODOTE(TM) IM injection, 2006).
6) DuoDote(R) is a dual chambered device (Meridian Medical Technologies, Columbia, Maryland) that delivers 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL sequentially using a single needle for use in a civilian or community setting. It should be administered by Emergency Medical Services personnel who have been trained to recognize and treat nerve agent or insecticide intoxication (Prod Info DuoDote(R) intramuscular injection solution, 2011).
7) DuoDote(R): DOSE: ADULT: Two or more mild symptoms, initial dose, 1 injector (atropine 2.1 mg/pralidoxime chloride 600 mg) IM into the mid-lateral thigh, wait 10 to 15 minutes for effect; subsequent doses, if at any time severe symptoms develop, administer 2 additional injectors in rapid succession IM into the mid-lateral thigh and immediately seek definitive medical care; MAX 3 doses unless definitive medical care is available (Prod Info DuoDote(R) intramuscular injection solution, 2011).
8) Therapeutic plasma concentrations of pralidoxime exceeding 4 mcg/mL were achieved within 4 to 8 minutes after injection (Sidell & Groff, 1974).
9) DIAZEPAM Autoinjector (Meridian Medical Technologies): Contains 10 mg of diazepam in 2 mL for intramuscular injection for seizure control (Prod Info diazepam autoinjector IM injection solution, 2005).
10) These devices are designed for initial field treatment. Although autoinjector doses may be adequate for nerve agent exposures, ORGANOPHOSPHATE exposures may require additional atropine or pralidoxime doses in the hospital setting that exceed those in the available autoinjectors.
11) For medical questions concerning Meridian products, you can call 1-800-438-1985. For general product information, call 1-800-638-8093.

D) ATROPINE

1) SUMMARY

a) Atropine is primarily effective for the treatment of muscarinic effects (e.g., bronchospasm, bronchorrhea, salivation, lacrimation, defecation, urination, miosis) of organophosphate poisoning, and will not reverse nicotinic effects (muscular weakness, diaphragmatic weakness, etc).

2) DOSE

a) ADULT: 1 to 3 mg IV; CHILD: 0.02 mg/kg IV. If inadequate response in 3 to 5 minutes, double the dose. Continue doubling the dose and administering it IV every 3 to 5 minutes as needed to dry pulmonary secretions. Once secretions are dried, maintain with an infusion of 10% to 20% of the loading dose every hour. Monitor frequently for evidence of cholinergic effects or atropine toxicity (e.g., delirium, hyperthermia, ileus) and titrate dose accordingly. Large doses (hundreds of milligrams) are sometimes required. Atropinization may be required for hours to days depending on severity (Roberts & Aaron, 2007).

3) DURATION

a) Atropinization must be maintained until all of the absorbed organophosphate has been metabolized. This may require administration of 2 to 2000 mg of atropine over several hours to weeks. One case of parathion overdose required 19,590 mg of atropine over 24 days. In one 24 hour period, 2950 mg were administered (Golsousidis & Kokkas, 1985).
b) Atropine therapy may need to be prolonged in severe cases, because AChE activity may regenerate slowly.
c) 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).

4) ATROPINIZATION REGIMENS

a) COMPARISON STUDY: A prospective cohort study of patients with acute cholinesterase inhibitor pesticide poisoning (n=226) was conducted in Sri Lanka to determine the safety and efficacy of titrated atropine therapy (i.e., an initial bolus followed by an infusion until atropinization occurred) vs. ad hoc atropine therapy (i.e., intermittent boluses, an infusion or a combination of bolus and infusion as determined by the treating physician). At baseline, patients in the titrated group had signs of greater toxicity, which included higher doses of insecticide ingested, more clinical symptoms of anticholinesterase poisoning at presentation, and higher rates of dimethoate ingestions as compared to the ad hoc group with a higher proportion of chlorpyrifos ingestions. The total atropine dose in the titrated cohort (n=126) was 37.3 mg as compared to 65.4 mg in the ad hoc cohort (n=100). Likewise, the amount of atropine boluses (3.9 mg {1.2-19.2} vs. 15 mg {10-20}) and infusion rates (1.39 mg/hour {0.46-2.32} vs. 2.1 mg/hour {1.18-3.39}) were also significantly lower in the titrated dose regimen. Atropine toxicity was more likely to occur in the ad hoc regimen with more frequent episodes of agitated delirium (17% vs. 1%) and hallucinations (35% vs. 1%); sedation and physical restraint were also more frequently required. Overall, patients in the titrated dose cohort had a shorter length of stay, less atropine toxicity, and improved patient outcome. Mortality rates were similar in both groups following adjustment for the pesticide ingested (Perera et al, 2008).
b) One retrospective study of 34 patients evaluated atropine maintenance dosage required to treat muscarinic features of severe organophosphate poisoning. When red cell acetylcholinesterase activity (RBC-AChE) was between 10% to 30% of normal, an atropine dose of 0.005 mg/kg/hr was adequate. Higher doses of atropine up to 0.06 mg/kg/hr were required to treat cholinergic crisis only when RBC-AChE was completely inhibited (Thiermann et al, 2011).

E) 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).

F) 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, 1988; 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).

7) EFFICACY

a) One review article evaluated two randomized-controlled trials of 182 organophosphate-poisoned patients treated with pralidoxime. These studies reported that high-dose pralidoxime was associated with a worse outcome (an increased mortality rate, increased requirement for ventilation, and increased rate of Intermediate syndrome) and pralidoxime should not have a role in the routine management of patients with organophosphate poisoning. However, the effects of oximes on pneumonia, duration of ventilation, or significant persistent neurological injury were not obtained. These studies did not consider a number of issues important for outcome (baseline characteristics were not evenly balanced; lower oxime dose than recommended; substantial treatment delays; type of organophosphate was not taken into account), and the methodology was unclear. The authors of the review article concluded that the current evidence is insufficient to indicate whether oximes are harmful or beneficial in the management of organophosphate-poisoned patients (Buckley et al, 2005).
b) One review article evaluated 7 controlled trials (2 randomized controlled trials, 1 study with historical controls, 3 retrospective studies, a prospective trial of 3 groups) of oximes in human organophosphate poisoning. These trials used varying dosage schedules of pralidoxime or obidoxime, and examined the effects of oxime therapy on mortality rate, mechanical ventilation, incidence of intermediate syndrome, and need for intensive care therapy. Oxime therapy was not associated with a significant change in mortality (risk difference 0.09, 95% CI -0.08 to 0.27, p=0.31), ventilatory requirements (risk difference 0.16, 95% CI -0.07 to 0.38, p=0.17), or a reduction in the incidence of intermediate syndrome (risk difference 0.16, 95% CI -0.12 to 0.45, p = 0.26) ; however, it was associated with an increased need for intensive care therapy (risk difference 0.19, 95% CI 0.01 to 0.36, p=0.04). The authors concluded that oxime therapy was associated with either a null effect or possible harm (Peter et al, 2006).
c) One study used high doses of pralidoxime to evaluate the biochemical profile of butyrylcholinesterase (BuChE) reactivation in both treated and untreated cases of moderate and severe organophosphate poisonings. Mortality, ICU stay, and type I and II paralysis and its correlation to BuChE profile were also studied. Twenty-one cases (11 moderately severe [6 in placebo and 5 in treatment group] and 10 severe cases [5 in placebo and 5 in treatment group) were included. In both groups, the BuChE levels increased gradually over several days (6-7 days). The BuChE levels were not different in control and treatment groups. There was no correlation between BuChE levels and severity of poisoning, the incidence of Type I and II paralysis, complications, ICU stay, number of days ventilated or mortality (Cherian et al, 2005).

G) OBIDOXIME CHLORIDE

1) SUMMARY

a) At the time of this review, obidoxime chloride is not available in the United States.

2) 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, 1988; 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.

3) 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).

4) 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).

5) 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.

6) ADVERSE EFFECTS

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

7) A study of 63 patients with organophosphate poisoning found that high doses of obidoxime (8 mg/kg followed by 2 mg/kg/hour) were hepatotoxic compared to high dose pralidoxime (30 mg/kg followed by 8 mg/kg/hour). There were no fatalities in the group receiving pralidoxime while mortality was 50% in the obidoxime group (Balali-Mood & Shariat, 1998).

H) ASOXIME CHLORIDE

1) SUMMARY

a) Asoxime chloride is currently not available in the United States.
b) HI-6 is an oxime that was developed to treat organophosphate poisoning, and appears to be effective against the diethoxy group of organophosphates, which age more slowly than the dimethoxy portion (Kusic et al, 1991). It has been used increasingly in auto-injectors because it has been found to be a more effective reactivator of acetylcholinesterase inhibited by nerve agents compared with pralidoxime and obidoxime (Roberts & Aaron, 2007)

I) BENZODIAZEPINE

1) SUMMARY

a) Administer benzodiazepines to patients with severe poisoning or seizures.

2) DOSE

a) Starting doses for agitation or seizures are: 5 to 10 mg diazepam IV (0.05 to 0.3 mg/kg/dose); 2 to 4 mg lorazepam IV (0.05 to 0.1 mg/kg/dose); or 5 to 10 mg midazolam IV (0.15 to 0.2 mg/kg/dose) (Roberts & Aaron, 2007).

3) ANIMAL DATA

a) In animal models of organophosphate nerve agent poisoning, administration of diazepam along with oximes increased survival and decreased the incidence of seizures and neuropathy (Kusic et al, 1991; Lotti, 1991; Murphy et al, 1993). Diazepam may also decrease cerebral damage induced by organophosphate related seizures (McDonough et al, 1989; Sidell & Borak, 1992).

J) 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, 2010; 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).

K) 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).

L) CONDUCTION DISORDER OF THE HEART

1) Three phases of cardiac toxicity have been observed following OP poisoning (Bar-Meir et al, 2007):

1) Initial Phase: Hypertension and sinus tachycardia are present due to nicotinic effects.
2) Prolonged Phase: Sinus bradycardia and hypotension secondary to extreme parasympathetic overflow along with ST-T segment changes and AV conduction disturbances; alterations are based on the severity of the intoxication
3) Final Phase: QT prolongation, torsades de pointes, and sudden cardiac death can occur. This phase can begin within a few hours to 1 to 15 days after exposure. Signs of clinical intoxication may have resolved. The occurrence of late arrhythmias is poor clinical indicator, even if initial clinical treatment was adequate.

M) TORSADES DE POINTES

1) QT prolongation may develop with severe OP poisoning. In one study, patients with a QTc greater than 0.58 s were at high-risk for a fatal dysrhythmia and patients with a QTc of greater than 0.60 s developed potentially fatal dysrhythmias. In most cases, torsades de pointes occurred with QTc values of more than 0.50 s (Bar-Meir et al, 2007).
2) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

3) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

4) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

5) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

6) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

7) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

8) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

N) 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).

O) BRONCHOSPASM

1) SUMMARY

a) Bronchospasm may occur after inhalation exposure to organophosphates, or as part of the pattern of pharmacological muscarinic effects after systemic absorption.
b) Inhaled nebulized sympathomimetic bronchodilators and anticholinergics (eg, atropine, glycopyrrolate, ipratropium) may be effective in treating bronchospasm.

2) GLYCOPYRROLATE

a) Glycopyrrolate, a quaternary ammonium compound, has been used in the treatment of organophosphate poisoning because of its better control of secretions, less tachycardia, and fewer CNS effects.

1) DOSE (INHALATION): Racemic glycopyrrolate by inhalation is a long acting anticholinergic bronchodilator. It has been found to have a prolonged bronchodilator response and protection against bronchospasm in patients with asthma (Hansel et al, 2005). In one study, metered-dose glycopyrrolate aerosol in doses of 240, 480 and 960 micrograms, produced significant improvement in airway obstruction for 20 adult asthmatic patients for up to 12 hours. The 480 microgram dose appeared to produce the maximal bronchodilation without significant side effects (Schroeckenstein et al, 1988).
2) DOSE (INFUSION): In one small study, 7.5 mg of glycopyrrolate was added to 200 mL saline and titrated until mucous membranes were dry and secretions were minimal, heart rate was greater than 60 beat/minute with an absence of fasciculations. 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). Glycopyrrolate may be given intramuscularly or intravenously, without dilution (Prod Info ROBINUL(R) injection, 2006).
3) A combination of glycopyrrolate/atropine therapy has been used successfully to treat two cases of acute organophosphorus poisoning (Tracey & Gallagher, 1990).

3) INHALED NEBULIZED IPRATROPIUM

a) IPRATROPIUM BROMIDE, an anticholinergic (parasympatholytic) bronchodilator agent, which is a quaternary ammonium compound chemically related to atropine. Each 3 mL vial contains 3.0 mg (0.1%) of albuterol sulfate (equivalent to 2.5 mg (0.083%) of albuterol base) and 0.5 mg (0.017%) of ipratropium bromide in an isotonic, sterile, aqueous solution containing sodium chloride. Usual dose: one 3 mL vial administered 4 times a day via nebulization with up to 2 additional 3 mL doses as necessary (Prod Info DUONEB(R) inhalation solution, 2005).

P) 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.

Q) 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).

R) EXPERIMENTAL THERAPY

1) ALKALINIZATION

a) SODIUM BICARBONATE: In one study, constant infusion of high doses of sodium bicarbonate (5 to 6 mEq/kg in 1 hour followed by 5 to 6 mEq/kg every 20 to 24 hours until recovery/death) appeared to be effective in patients (n=27) with acute organophosphate pesticide poisoning. Although no significant differences on the atropine doses required on admission and during the first 24 hours between the groups was noted, the total atropine used in the test group was significantly (p=0.048) lower than in the control group (n=26; 93.4 +/- 59.1 mg and 129.5 +/- 61 mg, respectively). In addition, the mean hospitalization period was significantly (p=0.037) lower in the test group than in the controls (4.33 +/- 1.99 and 5.59 +/- 1.97 days, respectively). No statistically significant differences on AchE activity was observed during treatment between the groups (Balali-Mood et al, 2005).

1) One review article evaluated 5 studies to determine the efficacy of alkalinization (eg; sodium bicarbonate) for the treatment of organophosphate poisoning. Because of the poor quality of these studies (eg; uncontrolled; randomized but poorly concealed; marked heterogeneity between subjects and treatment), the authors determined that there is insufficient evidence to support the routine use of plasma alkalinization for the treatment of organophosphate poisoning (Roberts & Buckley, 2005).
2) Although the exact mechanism of action of alkalinization (including sodium bicarbonate) in the treatment of organophosphate poisoning is unknown, the following mechanisms have been proposed, based on in vitro, animal and human studies (Roberts & Buckley, 2005):

1) Enhanced pesticide clearance from the body through non-enzymatic and/or enzymatic hydrolysis
2) Volume expansion with improved tissue perfusion
3) Improved efficacy of oximes
4) Direct effect on neuromuscular function
5) Bicarbonate-induced release of lactate into the circulation

2) MAGNESIUM SULFATE

a) One single center, single-blind prospective control trial evaluated the use of magnesium sulfate in the management of patients (n=45) with organophosphate poisoning. Eleven of 45 patients were given magnesium sulfate (4 grams/day IV continued for only the first 24 hours after admission) in a systematic sampling (every fourth eligible patient). Although there was no significant difference between the two groups in terms of daily oxime or atropine requirements, the magnesium-treated group had a significantly lower mortality rate (0% vs 14.7% in control group) and duration of hospitalization (2.9 days vs 5 days in control group) compared to those who had not received magnesium sulfate (P<0.01). The authors suggested that magnesium sulfate inhibits acetylcholine release from motor nerve terminals and can antagonize the effects of organophosphates. In addition, it was proposed that intravenous use of magnesium sulfate can control premature ventricular contractions and it can counteract the direct toxic inhibitory action of organophosphate on sodium potassium AT-Pase (Pajoumand et al, 2004).

3) FRESH FROZEN PLASMA

a) In a prospective study of 33 patients with organophosphate poisoning, 20 patients received atropine and pralidoxime, 11 received atropine, pralidoxime and fresh frozen plasma (FFP) (2 of these had already developed intermediate syndrome before receiving FFP) , 1 received only atropine and one received atropine and FFP. Although approximately 29% of patients receiving pralidoxime without FFP developed intermediate syndrome, none of the patients receiving FFP developed intermediate syndrome after FFP was initiated. The mortality rates in the pralidoxime group and FFP/atropine/pralidoxime group were 14.3% and 0%, respectively. BuChE concentration in FFP was 4069.5 +/- 565.1 International Units/L. An increase in BuChE activity of approximately 461.7 +/- 142.1 International Units/L was observed for every two bags of fresh frozen plasma administered (Guven et al, 2004).
b) In a randomized clinical trial, 56 patients with organophosphate (OP) poisoning were randomly assigned to either receive fresh frozen plasma (FFP) (4 packs as stat dose at the start of therapy) or control group. All patients also received atropine (max stat dose: 25 mg; mean and median doses, 927 +/- 3016 mg and 77 mg; range, 26 to 244 mg, respectively) and patients with moderate to severe poisoning received pralidoxime (3 mg/kg/hr; mean and median doses, 7093 +/- 7539 mg and 4000 mg; range, 2000 to 11500 mg, respectively). It was determined that the use of FFP had no significant effect on atropine and pralidoxime doses, hospitalization length, and the mortality of OP poisoned patients (Pazooki et al, 2011).

4) EXTRACORPOREAL PERFUSION

a) Extracorporeal cardiopulmonary support, including intraaortic balloon pumping and percutaneous cardiopulmonary support, were used to treat a 50-year-old woman with respiratory arrest, refractory circulatory collapse, coma, and severe hypothermia, after ingesting 100 mL of an insecticide containing 35% fenitrothion and 15% malathion. The patient gradually improved following hemodynamic support and active rewarming. Nineteen hours after admission the patient was alert with evidence of severe muscle weakness. Intubation was required for more than 23 days. The patient was transferred on day 67 for further treatment for depression (Kamijo et al, 1999).

S) EXTRAPYRAMIDAL SIGN

1) SCOPOLAMINE: A 17-year-old girl developed extrapyramidal signs (cogwheel rigidity of the extremities, bradykinesia, bradyarthria, mask face, drooling), and coma within 36 hours of ingesting 150 mL of chlorpyrifos. She had not been treated with atropine because of lack of initial cholinergic manifestations. She responded immediately to intravenous scopolamine (0.5 mg). In addition, she received obidoxime 250 mg intravenously and then both drugs were repeated after 6 hours. She was discharged 4 days later without further sequelae (Kventsel et al, 2005).
2) AMANTADINE: Five days after ingesting a raw eggplant sprayed with dimethoate (Rogor), a 14-year-old boy developed overt extrapyramidal parkinsonism (a resting tremor, expressionless face, lack of blinking along with marked cogwheel rigidity and a stooped, slow gait, agitation) after recovering from the acute cholinergic crisis. He was treated with 100 mg of amantadine three times daily with complete recovery within 1 week. He continued to receive 100 mg of amantadine twice daily for 3 additional months (Shahar et al, 2005).
3) One study reported 27 patients with basal ganglia impairment after acute organophosphate insecticide poisoning. Twenty-one patients recovered; half of them were treated with various medications (eg; trihexyphenidyl, benzehexol, bromocriptine, biperidine, diphenhydramine, levodopa/carbidopa, and haloperidol). Four patients had persistent parkinsonism (Shahar et al, 2005).

Inhalation Exposure

6.7.2)

A) BRONCHOSPASM

1) Bronchospasm may occur after inhalation exposure to organophosphates, or as part of the pattern of pharmacological muscarinic effects. Inhaled sympathomimetic bronchodilators or atropine may be effective in treating bronchospasm.

B) SUPPORT

1) See ORAL exposure for further information on therapy.

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

Eye Exposure

6.8.2)

A) SUPPORT

1) Systemic toxicity is unlikely following ocular exposure only. However, see ORAL exposure if there is clinical evidence of systemic absorption.

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

Dermal Exposure

6.9.2)

A) SUPPORT

1) See ORAL exposure for further information on therapy.

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

Enhanced Elimination

1) Hemoperfusion, hemodialysis, and exchange transfusion have not been shown to affect outcome or duration of toxicity in controlled trials of organophosphate poisoning.

1) Exchange transfusions and/or hemoperfusion with activated carbon have been effective in lowering plasma concentrations of parathion, but it is not clear that these procedures affect outcome or speed of recovery (Windler et al, 1983; de Monchy et al, 1979).

1) CASE REPORT: After accidental dermal exposure to fenitrothion, a 62-year-old man developed nausea and vomiting, miosis, excess salivation, fasciculation and aspiration pneumonia. His conditions deteriorated during atropine and pralidoxime (PAM) therapies. On day 5, he developed sepsis and plasmapheresis was performed. Plasma cholinesterase was decreased initially and continued to decline even with high doses of atropine and PAM; however, it normalized after plasma exchange. He was discharged from the ICU without further sequelae (Guven et al, 2004a).

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).
2) In a retrospective study, use of hemoperfusion in patients with severe organophosphate poisoning appeared to be associated with a more rapid rise in plasma acetylcholinesterase concentrations, although this did not correlate with more rapid resolution of cholinergic manifestations or improved outcome (Altintop et al, 2005).
3) Several in vitro studies have shown acceptable clearances of parathion with hemoperfusion. Burgess & Audette (1990) reported that charcoal hemoperfusion is an efficient means to improve clearance of malathion on a short-term basis (the first 30 minutes); however, its effectiveness is limited by the short duration of effective removal (120 minutes), afforded by the column and the wide distribution of malathion in the body. Over a prolonged time in severe, acute malathion poisoning, the authors recommended that the column should be changed when it becomes saturated with the pesticide (Burgess & Audette, 1990).
4) Recurrence of toxicity after apparent improvement has been described after hemoperfusion for fenitrothion poisoning (Yoshida et al, 1987).

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% of total absorbed poison (Martinez-Chuecos et al, 1992).
2) In a study of 108 patients with dichlorvos poisoning, treatment with charcoal hemoperfusion in addition to standard care (atropine, pralidoxime) was associated with a reduced cumulative dose of atropine, reduced need for mechanical ventilation, lower mortality rate, decreased duration of coma and altered mental status, and shorter ICU stay. Hemoperfusion also improved serum ChE activity and reduced dichlorvos concentration (Peng et al, 2004).
3) 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) Phosphamidon is extremely toxic; the probable oral lethal dose for humans is 5 to 50 mg/kg, or between 7 drops and 1 teaspoonful for a 150 pound person (Gosselin et al, 1984; HSDB , 1999).
2) Deliberate ingestion of phosphamidon resulted in death in an 18-year-old female.

Maximum Tolerated Exposure

1) Dogs fed 5 mg/kg of phosphamidon daily for 90 days had no observable adverse effects. Rats fed up to 10 mg/kg of phosphamidon daily for 90 days did not have observable effects except for slower weight gain; weight gain was normal at daily doses of 2.5 mg/kg and lower.

a) Rats, guinea pigs, and dogs did not develop any marked toxic effects when exposed to air concentrations of phosphamidon at 0.125 mg/Liter 6 hours daily, 5 days per week, for 90 days.
b) In rats, dermal exposure to 3.98 mg/kg of phosphamidon daily, 5 days a week for 3 weeks, resulted in hypersalivation and frothing, as well as histopathic alterations of the skin, kidneys, lungs, and blood chemistry abnormalities.
c) Hepatotoxicity was observed in mice given 35 ppm of phosphamidon ad libitum in drinking water for 60 days.

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: HSDB, 2003; Lewis, 2000; RTECS, 2003. All values are from RTECS, 2003 unless otherwise indicated

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 5800 mcg/kg

2) LD50- (ORAL)MOUSE:

a) 6 mg/kg
b) 13 mg/kg (HSDB, 2003)

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 13,200 mcg/kg -- fasciculations; lacrimation; dyspnea
b) 26 mg/kg (HSDB, 2003)

4) LD50- (INTRAPERITONEAL)RAT:

a) 8700 mcg/kg

5) LD50- (INTRATRACHEAL)RAT:

a) 17 mg/kg

6) LD50- (ORAL)RAT:

a) 8 mg/kg
b) 17.4 mg/kg (HSDB, 2003)

7) LD50- (SKIN)RAT:

a) 125 mg/kg
b) 374 mg/kg (HSDB, 2003)

8) LD50- (SUBCUTANEOUS)RAT:

a) 15 mg/kg

Pharmacology Toxicology

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

178)

179)

180)

181)

182)

183)

184)

185)

186)

187)

188)

189)

190)

191)

192)

193)

194)

195)

196)

197)

198)

199)

200)

201)

202)

203)

204)

205)

206)

207)

208)

209)

210)

211)

212)

213)

214)

215)

216)

217)

218)

219)

220)

221)

222)

223)

224)

225)

226)

227)

228)

229)

230)

231)

232)

233)

234)

235)

236)

237)

238)

239)

240)

241)

242)

243)

244)

245)

246)

247)

248)

249)

250)

251)

252)

253)

254)

255)

256)

257)

258)

259)

260)

261)

262)

263)

264)

265)

266)

267)

268)

269)

270)

271)

272)

273)

274)

275)

276)

277)

278)

279)

280)

281)

282)

283)

284)

285)

286)

287)

288)

289)

290)

291)

292)

293)

294)

295)

296)

297)

298)

299)

300)

301)

302)

303)

304)

305)

306)

307)

308)

309)

310)

311)

312)

313)

314)

315)

316)

317)

318)

319)

320)

321)

322)

323)

324)

325)

326)

327)

328)

329)

330)

331)

332)

333)

334)

335)

336)

337)

338)

339)

340)

341)

342)

343)

344)

345)

346)

347)

348)

349)

350)

351)

352)

353)

354)

355)

356)

357)

358)

359)

360)

361)

362)

363)

364)

365)

366)

367)

368)

369)

370)

371)

372)

373)

374)

375)

376)

377)

378)

379)

380)

381)

382)

383)

384)

385)

386)

387)

388)

389)

390)

391)

FeedBack

PHOSPHAMIDON

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

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Workplace Standards

Toxicity Information

Physical Characteristics

Molecular Weight

General Bibliography