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
c) PRALIDOXIME

a) Incidence - Common. 50/61 patients (82 percent) in one study (Bardin et al, 1987).
b) In one study, miosis developed in 47 (84%) of 56 patients with organophosphate poisoning (Pazooki et al, 2011).
c) In a review of 16 cases of pediatric organophosphate poisoning, miosis was observed in 9 (56 percent) cases (Lifshitz et al, 1999).

a) In one study of OP intoxication patients (n=42) admitted to a nephrology ward, excessive salivation developed in 33.3% of patients (Lin et al, 2004).
b) Excessive salivation has been reported following the cutaneous absorption of organophosphate (Bjornsdottir & Smith, 1999).

a) CASE REPORT: A 3-year-old child with severe manifestations of polyneuropathy after chlorpyrifos ingestion developed bilateral vocal cord paralysis and stridor on the 11th day, which slowly resolved by discharge on day 52 (Aiuto et al, 1993).
b) CASE REPORT: A 2-year old boy with acute OP poisoning developed transient vocal cord paralysis with complete airway obstruction which resolved over 2 days (Thompson & Stocks, 1997).

a) Bradycardia and hypotension occur following moderate to severe poisoning (Karki et al, 2004; Kamijo et al, 1999; Ganendran, 1974; Bardin et al, 1987; Dive et al, 1994). Total peripheral vascular resistance may be low and cardiac output increased in patients with pre-existing vascular disease (Buckley et al, 1994).
b) INCIDENCE: Systolic blood pressure less than 90 mmHg occurred in 20 percent of patients in one study and in 12 percent in another study (Bardin et al, 1987; Saadeh et al, 1997).
c) 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).
d) In one study of OP intoxication patients (n=42) admitted to a nephrology ward, hypotension developed in 19% of patients (Lin et al, 2004).

a) HYPERTENSION occurred in 20 percent of patients in one study and in 10.5 percent of patients in another study (Karki et al, 2004; Wu et al, 2001; Koga et al, 1999; Saadeh et al, 1997; Agarwal, 1993).

a) Tachycardia and hypertension are also common (Aslan et al, 2011; Karki et al, 2004; Mattingly et al, 2001; Wang et al, 2000; Koga et al, 1999; Burgess & Audette, 1990; Bardin et al, 1987; Saadeh et al, 1997; Agarwal, 1993).
b) INCIDENCE: Heart rate greater than 100 beats/minute occurred in 49% of patients in one study (Bardin et al, 1987).
c) In a prospective study of 31 organophosphate poisoning cases, sinus tachycardia (heart rate greater than 100 beats/min) developed in 19 (61.2%) patients with organophosphate poisoning (Aslan et al, 2011).
d) PREVALENCE: In a study of 31 children (mean age 5.6 +/- 3.9 years) presenting with acute organophosphate poisoning, cardiovascular effects were the least common events reported. Of the events reported, tachyarrhythmias occurred in 35% (n=11) of patients (Levy-Khademi et al, 2007).

a) A heart rate of less than 60 beats/minute occurred in 21 percent of patients in one study (Aslan et al, 2011; Bardin et al, 1987). Bradycardia is relatively common (Karki et al, 2004; Mattingly et al, 2001; Wu et al, 2001; Kamijo et al, 1999; Nisse et al, 1998; Saadeh et al, 1997).
b) INCIDENCE: In a review of 16 pediatric patients with organophosphate poisoning, bradycardia occurred in 4 children (Lifshitz et al, 1999).
c) In one study, bradycardia developed in 48 (86%) of 56 patients with organophosphate poisoning (Pazooki et al, 2011).
d) MORTALITY PREDICTORS: In a retrospective study of 296 patients with organophosphate poisoning, bradycardia, age, glucose, lactate dehydrogenase level and acidosis were independent predictors of mortality (Gunduz et al, 2015).
e) In a prospective study of 31 organophosphate poisoning cases, sinus bradycardia (heart rate less than 60 beats/min) developed in 8 (25.8%) patients with organophosphate poisoning (Aslan et al, 2011).
f) PREVALENCE: In a study of 31 children (mean age 5.6 +/- 3.9 years) presenting with acute organophosphate poisoning, cardiovascular effects were the least common events reported. Bradyarrhythmias occurred in 1 patient, with tachyarrhythmias occurring in 35% (n=11) of patients (Levy-Khademi et al, 2007).
g) In one study of OP intoxication patients (n=42) admitted to a nephrology ward, bradycardia developed in 21.4% of patients (Lin et al, 2004).

a) Cardiac dysrhythmias and conduction defects have been reported in severely poisoned patients (Wren et al, 1981; Kiss & Fazekas, 1982; Chhabra & Sepaha, 1970; Agarwal, 1993).
b) Dysrhythmias and ECG abnormalities may include - sinus bradycardia or tachycardia, atrioventricular and/or intraventricular conduction delays, idioventricular rhythm, multiform premature ventricular extrasystoles, ventricular tachycardia or fibrillations, torsades de pointes, prolongation of the PR, QRS, and/or QT intervals, ST-T wave changes, and atrial fibrillation (Karki et al, 2004; Kamijo et al, 1999; Ludomirsky et al, 1982; Brill et al, 1984; Saadeh et al, 1997).
c) Cardiac complications and the late occurrence of sudden death may develop after initial clinical toxicity has abated (Roth et al, 1993).
d) CHLORPYRIFOS INGESTION: A 9-year-old boy inadvertently ingested chlorpyrifos, and initially developed tachycardia (150 beats per minute), atrioventricular dissociation, and marked QT interval prolongation, along with evidence of pulmonary edema. The patient clinically improved within 18 hours and was extubated after 24 hours. However, on day 5 the patient was readmitted to intensive care with tachypnea and hypoxia. Despite aggressive care including reintubation, the patient died on hospital day 10 of progressive hypoxia and acute respiratory distress syndrome (Nel et al, 2002).
e) PARATHION INGESTION: CASE REPORT: A woman who ingested approximately 250 mL of 47 percent parathion solution developed sinus tachycardia and dyspnea. Despite supportive care and treatment with atropine and pralidoxime, QT interval prolongation and pleomorphic ventricular tachycardia (torsade de points) appeared on the third hospital day; the patient died on the 14th hospital day in sepsis and multiorgan failure (Wang et al, 1998).
f) MALATHION INGESTION: CASE REPORT: Premature ventricular complexes, ventricular tachycardia and a prolonged Q-T interval (0.55 s) developed in a 65-yr-old woman 5 days after a suicide attempt, despite complete recovery from severe acute toxicity and the absence of measurable cholinesterase inhibitor in the plasma (Dive et al, 1994).

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

a) LOW DOSE EXPOSURE: Conscious unrestrained rats given intravenous doses of PARAOXON (125 and 150 mcg/kg) developed cardiovascular effects (hypertension and bradycardia) even in the absence of major behavioral changes and respiratory depression (Bataillard et al, 1990). A combination of pralidoxime, diazepam, and atropine was effective against the cardiovascular effects of paraoxon.

a) Increased bronchial secretions, bronchospasm, chest tightness, heartburn, and dyspnea occur in severe and moderately severe poisonings (Hayes, 1965; Dive et al, 1994).
b) INCIDENCE: Rhonchi or crepitations occurred in 48% and hypoventilation in 20% of patients in one study (Bardin et al, 1987).
c) In one study, wheezing developed in 31 (55%) of 56 patients with organophosphate poisoning (Pazooki et al, 2011).
d) Dyspnea has been reported following systemic absorption of ophthalmic drops containing echothiophate iodide (Manoguerra et al, 1995).
e) In one study of OP intoxicated patients (n=42) admitted to a nephrology ward, bronchorrhea and dyspnea developed in 28.6% and 26.2% of patients, respectively (Lin et al, 2004).

a) Asthma may occur after the inhalation of nontoxic amounts of some organophosphates in sensitive patients with pre-existing asthma (Bryant, 1985).
b) Bronchospasm may also be a pharmacologic effect from the muscarinic activity of organophosphates (Lund & Monteagudo, 1986).
c) CASE REPORT: One patient developed persistently bronchospasm consistent with reactive airways dysfunction syndrome (RADS) after inhalation exposure to dichlorvos formulated in xylene (Deschamps et al, 1994).

a) Hyperventilation has been reported following the cutaneous absorption of organophosphates (Bjornsdottir & Smith, 1999).
b) A respiratory rate greater than 30/minute was reported in 39% of patients in one study (Bardin et al, 1987).

a) Acute lung injury (noncardiogenic pulmonary edema) is a manifestation of severe poisoning (Karki et al, 2004; Chhabra & Sepaha, 1970; Betrosian et al, 1995).
b) It was reported in 6 of 16 children (37%) with organophosphate poisoning (Lifshitz et al, 1999).
c) CASE REPORT: A 9-year-old boy inadvertently ingested chlorpyrifos, and initially developed a tachyarrhythmia, hypertension, and evidence of pulmonary edema, but was treated successfully and clinically improved. On day 5, the patient was readmitted to intensive care with tachypnea and hypoxia. Despite aggressive care including reintubation, the patient died on hospital day 10 of progressive hypoxia and acute respiratory distress syndrome. Histologic exam of the lungs showed extensive obliterative inflammatory and fibrosing processes, resulting in almost complete destruction of the lung parenchyma (Nel et al, 2002).
d) CASE REPORT: A 16-month-old girl developed acute lung injury (pulmonary edema) approximately 3 hours after the ingestion of a termite pesticide containing chlorpyrifos (Mattingly et al, 2001).

a) Acute respiratory insufficiency, due to any combination of CNS depression, respiratory paralysis, bronchospasm, ARDS, or increased bronchial secretions, is the main cause of death in acute organophosphate poisonings (Lin et al, 2004; Nair et al, 2001; Uzyurt et al, 1992; Tsao et al, 1990; Lerman & Gutman, 1988; Anon, 1984). In one study, respiratory failure occurred in 45% of patients (n=42) (Lin et al, 2004).
b) In a prospective study, all organophosphate (n=31) or carbamate (n=18) poisoning cases admitted to an ED during a 2-year period were evaluated. Bronchial hypersecretions-bronchorrhea and respiratory distress developed in 24 (77.4%) and 4 (12.9%) patients with organophosphate poisoning. All patients with muscarinic signs (n=22) and bradycardia (n=8) were treated with atropine (range, 5 to 32 mg) for 24 to 36 hours; 22 patients with organophosphate poisoning received pralidoxime. Respiratory failure, aspiration pneumonia, and septic shock developed in 8 (16.3%), 4 (8.2%), and 1 (2%) of patients, respectively. Overall, 10 patients in both groups died; 5 in the follow-up period, 3 from sudden cardiorespiratory arrest, and 2 from pneumonia complicated by adult respiratory distress (Aslan et al, 2011).
c) CASE REPORT: A patient had relatively minor symptoms for 48 hours before severe muscle fasciculations and respiratory compromise occurred (Sakamoto et al, 1984).
d) Respiratory failure may develop following organophosphate poisoning (Raikhlin-Eisenkraft et al, 2001; Hsieh et al, 2000; Kamijo et al, 1999; Nisse et al, 1998; Tsao et al, 1990; Burgess & Audette, 1990).
e) PREDISPOSING FACTORS include severity of poisoning, cardiovascular collapse and pneumonia (Tsao et al, 1990). Symptoms include an increase in respiratory rate. Insufficient management of respiratory failure was a common factor associated with death in one case series (Yamashita et al, 1997).
f) INCIDENCE: In a study of 76 patients with suicidal intent that used organophosphate insecticides, 10 patients required mechanical ventilation. Of those patients, the mortality rate was 50% (n=5). The causes of death were due to cardiopulmonary arrest, pneumonia and ARDS (Noshad et al, 2007). The authors noted that respiratory failure can be life threatening with a very high mortality rate. Patients should be carefully monitored and managed aggressively.
g) CASE SERIES: In one case series, patients with serum amylase levels above the normal range were more likely to develop respiratory failure necessitating ventilatory support than were patients with normal serum amylase levels (Lin et al, 2004; Matsumiya et al, 1996).
h) In an observational study of 65 consecutive patients with organophosphate poisoning, a QTc interval of 610 msec or more was 89.5% sensitive and 82.6% specific in predicting respiratory failure. A Glasgow Coma Score of 6 or less was 84.2% sensitive and 88.9% specific in predicting respiratory failure (Grmec et al, 2004).
i) Respiratory arrest has been reported following the cutaneous absorption of organophosphate (Bjornsdottir & Smith, 1999).
j) PERSISTENT CHOLINERGIC SYMPTOMS: A 23-year-old woman intentionally subcutaneously injected 3-4 mL of fenthion (82.5% w/w fenthion) into her antecubital fossa and developed compartment syndrome requiring urgent fasciotomy. The patient's hospital course was complicated by persistent symptoms of cholinergic crisis necessitating repeated doses of atropine and pralidoxime and mechanical ventilation. Respiratory status stabilized by hospital day 31 when the patient was successfully weaned from the ventilator (Bala et al, 2008).
k) 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 for survival among mechanically ventilated patients (Munidasa et al, 2004).
l) Another study reported that bradycardia, hypotension, fasciculation and coma were significant factors associated with respiratory failure; however, nausea, salivation, bronchorrhea and sweating did not significantly differ in the prediction of respiratory failure (Lin et al, 2004).

a) Aspiration of preparations containing hydrocarbon solvents may cause potentially fatal lipoid pneumonitis (Lund & Monteagudo, 1986).

a) CASE REPORT: A 62-year-old man was found unconsciousness after ingesting an unknown quantity of O,O,-dimethyl O-4-nitro-m-toylphosphorothioate (MEP). He developed lung injury because of delayed (on the 31st day postingestion) massive hemoptysis complicated with aspiration of MEP. He experienced respiratory arrest as a result of airway obstruction due to an enormous blood clot. Because of massive hemorrhage from the airway, he was injected with several doses of a coagulant agent to the bronchus. However, surgical treatment was required to control the hemorrhage. Thoracotomy showed that the left upper lobe had firmly adhered to the pleurae and appeared red as a result of congestion due to massive hemoptysis. The large cavity had a blood clot in the segment. Inflammatory changes, massive congestion, edema of the interstitial tissue, and diffuse hemorrhage extending over a wide area were observed in microscopic examination (Ikegami et al, 2003).

a) Exposure to organophosphate vapors rapidly produces symptoms of mucous membrane and upper airway irritation and bronchospasm, followed by systemic symptoms if patients are exposed to significant concentrations (Daniels & LePard, 1991).

a) With prolonged exposure, systemic signs and symptoms can include muscarinic, nicotinic, and CNS effects (Daniels & LePard, 1991).

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

a) The earliest manifestations of poisoning are often referable to the central nervous system and include giddiness, uneasiness, restlessness, anxiety, agitation and tremulousness (Grob & Garlic, 1950).

a) Seizures may be an early symptom after significant exposure (Aslan et al, 2011; Joy, 1982). Children may be more susceptible to seizures than adults (Mattingly et al, 2001; Joy, 1982).
b) CASE REPORT: A 16-month-old girl experienced a generalized tonic clonic seizure 8 hours after the ingestion of a termite pesticide containing chlorpyrifos (Mattingly et al, 2001).
c) PREVALENCE: In a study of 31 children (mean age 5.6 +/- 3.9 years) presenting with acute organophosphate poisoning, CNS events were reported in 70.9% (n=22) of patients, and were frequently the presenting symptom(s), as compared to muscarinic or nicotinic effects. Seizures occurred in 38.7% (n=12) of patients (Levy-Khademi et al, 2007).
d) EEG changes similar to patterns present on interictal EEGs of temporal lobe epileptics have been described in cases of mild organophosphate poisoning (Brown, 1971).

a) SUMMARY: Muscle weakness and fasciculations are common in moderate to severe poisonings, particularly in children. Diaphragmatic weakness may necessitate intubation.
b) Muscle weakness, fatigability, and fasciculations commonly occur (Guven et al, 2004a; Raikhlin-Eisenkraft et al, 2001; Wu et al, 2001; Kamijo et al, 1999; Nisse et al, 1998; Burgess & Audette, 1990; Bardin et al, 1987; Dive et al, 1994; Kecik et al, 1993).
c) In one study of OP intoxication patients (n=42) admitted to a nephrology ward, fasciculation developed in 16.6% of patients (Lin et al, 2004).
d) In one case series, 33/61 patients (54 percent) developed muscle weakness (Bardin et al, 1987).
e) In a review of 16 cases of pediatric organophosphate poisoning, hypotonia was noted in all patients (Lifshitz et al, 1999).
f) MUSCLE PARALYSIS occasionally supervenes (Done, 1979).
g) RARE EFFECTS: DELAYED FASCICULATIONS: In one case, a patient had relatively minor symptoms for 48 hours before severe muscle fasciculations and respiratory compromise occurred (Sakamoto et al, 1984).

a) Initial central nervous system effects are commonly followed by headache, ataxia, drowsiness, dizziness, difficulty concentrating, mental confusion, and slurred speech (Wu et al, 2001; Wang et al, 2000; Bjornsdottir & Smith, 1999; Grob & Garlick, 1950). Blurred vision may be an early symptom (Milby, 1971).

a) Headache has been reported following organophosphate exposure (Dahlgren et al, 2004; Wu et al, 2001; Fischer & Eikmann, 1996; Grob & Garlick, 1950).

a) More than 50 percent of patients in one study had a decreased level of consciousness, manifested as confusion, difficulty sitting or standing, and stupor (Bardin et al, 1987).
b) In a review of 16 cases of pediatric organophosphate poisoning, all 16 children developed stupor and/or coma (Lifshitz et al, 1999).

a) Coma has been reported in patients with organophosphate poisoning (Dong et al, 2013; Kventsel et al, 2005; Kamijo et al, 1999; Hall & Baker, 1989; Grob & Garlick, 1950). In severe poisoning, coma supervenes, rarely followed by generalized seizures (Kamijo et al, 1999; Hall & Baker, 1989; Grob & Garlick, 1950). Deep tendon reflexes are weak or absent. It may be the presenting symptom in children (Levy-Khademi et al, 2007).
b) In a prospective observational study of 65 consecutive patients with organophosphate poisoning, a Glasgow Coma Score (GCS) of 6 or less was 84.2% sensitive and 88.9% predictive of the development of respiratory failure. A GCS of 6 was 70.2% sensitive and 87.3% predictive of in hospital mortality (Grmec et al, 2004).
c) PREVALENCE: In a study of 31 children (mean age 5.6 +/- 3.9 years) presenting with acute organophosphate poisoning, CNS events were reported in 70.9% (n=22) of patients, and were frequently the presenting symptom(s), as compared to muscarinic or nicotinic effects. Coma developed in 54.8% (n=17) of patients (Levy-Khademi et al, 2007).
d) CASE SERIES: In a review of 16 cases of pediatric organophosphate poisoning, all 16 children developed stupor and/or coma (Lifshitz et al, 1999).
e) CASE SERIES: In one study of OP intoxication patients (n=42) admitted to a nephrology ward, coma developed in 14.3% of patients (Lin et al, 2004).
f) CASE REPORT: Coma was reported in a case of acute hemorrhagic panesophagitis after organophosphorus poisoning (Koga et al, 1999).
g) CASE REPORT: After the ingestion of 25 g of ethyl parathion concentrate diluted in exylene, a 44-year-old woman fell into a non-reactive deep coma (Nisse et al, 1998).
h) CASE REPORT: A 2 1/2-year-old boy with a history of generalized seizure developed coma with frothing from the mouth, gasping respiration, pinpoint pupils and the characteristic smell of an organophosphate compound after accidentally ingesting an insecticide preparation kept in a "Pepsi" bottle. After treatment with pralidoxime, atropine and positive pressure ventilation, he made a full recovery (Nair et al, 2001).

a) Choreoathetosis, opisthotonos, torticollis, facial grimacing and tongue protrusion have been reported following organophosphate poisoning (Smith, 1977; Joubert et al, 1984; Joubert & Joubert, 1988; Moody & Terp, 1988).

a) INTERMEDIATE SYNDROME: SUMMARY: Type II neurological effects involve paralysis appearing from 12 hours to 7 days after exposure; this paralysis is unresponsive to atropine and may be due to persistent excess acetylcholine at nicotinic receptors (Aygun, 2004 ; Karki et al, 2004; Villamangca et al, 2000; Sudakin et al, 2000; Wadia et al, 1987; Hall & Baker, 1989; de Wilde et al, 1990; De Wilde et al, 1991; De Bleecker, 1995) De Bleecker et al, 1993).
b) Paralytic signs include inability to lift the neck or sit up, ophthalmoparesis, slow eye movements, facial weakness, difficulty swallowing, limb weakness (primarily proximal), areflexia, respiratory paralysis, and death (Senel et al, 2001; (Villamangca et al, 2000; Nisse et al, 1998; Good et al, 1993; Wadia et al, 1987).
c) 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).
d) CASE REPORT: A 55-year-old woman developed delayed neuropathy and quadriplegia after multiple sprayings of acephate in her office. Despite supportive care, her symptoms did not improve and she developed respiratory failure and died 2 years after presentation. A transverse myelitis in her spinal cord was observed during an autopsy (Beavers et al, 2014).
e) CASE REPORT/SERIES: Paralysis of the diaphragm occurred in a patient who ingested malathion. Full recovery required 9 months (Rivett & Potgieter, 1987). In one case series of patients with OP poisoning, 4/21 who developed the intermediate syndrome died of respiratory insufficiency, while 3 of 16 similar patients died in another case series (He et al, 1998; (Groszek et al, 1995).
f) Intermediate syndrome occurs unexpectedly, does not respond to atropine and pralidoxime, and has been described primarily after exposure to dimethyl compounds such as fenthion, chlorpyrifos, dimethoate, monocrotophos, diazinon (a diethyl compound), trichlorfon, malathion, sumithion, fenitrothion, ethyl parathion, and methyl parathion (Senel et al, 2001; (Mattingly et al, 2001; Sudakin et al, 2000; Nisse et al, 1998; Senanayake & Karalliedde, 1987; Hall & Baker, 1989) Karademir et al, 1991; (De Bleecker et al, 1992; De Bleecker et al, 1992a; Groszek et al, 1995).
g) CASE REPORT: Electrophysiologic studies in a patient who developed the intermediate syndrome after phosmet exposure revealed decremental responses of muscle action potentials to repetitive stimulation, reduced miniature endplate potential frequency and amplitude, and reduced acetylcholine sensitivity. Electron microscopy revealed degeneration and regeneration of the endplates (Good et al, 1993).
h) CASE SERIES: Ten patients from Sri Lanka developed profound proximal muscle and cranial nerve weakness 1 to 4 days after exposure to fenthion (4 cases), dimethoate, or monocrotophos (Senanayake & Karalliedde, 1987).
i) Some believe that early aggressive gastric decontamination, followed by atropinization and high-dose pralidoxime therapy (1 gram every 4 to 6 hours or 500 milligrams/hour as a continuous infusion in severe cases) may reduce the incidence of the intermediate syndrome (Haddad, 1992; Benson et al, 1992). Clinical trials will be necessary to confirm this hypothesis.
j) CASE REPORT: A 33-year-old woman who ingested an unknown amount of malathion in a suicide attempt developed intermediate syndrome despite continuous, prolonged administration of 2-PAM, at 400 mg/hour intravenously for 5 days (Sudakin et al, 1999).
k) CHLORPYRIFOS: A 17-year-old girl presented with altered mental status, miosis, salivation, and sweating 30 minutes after ingesting an unknown amount of chlorpyrifos 40%. Laboratory results revealed serum pseudocholinesterase activity concentration of 129 Units/L (reference range: 4260 to 11,250 Units/L). Despite supportive therapy, including IV atropine, and obidoxime chloride (250 mg at 6-hour intervals), she developed generalized edema, oliguria and hypertension on day 3. Her BUN increased to 65 mg/dL and serum creatinine to 2.6 mg/dL. Fractional excretion of sodium was high at 3.6%, indicating acute tubular necrosis. On day 7, her BUN increased to 233 mg/dL and serum creatinine increased to 6.4 mg/dL with a creatinine clearance of 9 mL/min. She was treated with continuous venovenous hemofiltration (CVVH) for about 40 hours and her BUN and serum creatinine concentrations gradually decreased. Her renal function gradually normalized about 12 days after the first sign of renal failure. Despite supportive care, she developed neurologic complications, including intermediate syndrome (facial, proximal limb, and respiratory muscles weakness), necessitating mechanical ventilation for 8 days. She later developed delayed polyneuropathy and spastic paraplegia. Despite spending 6 months at a rehabilitation center, she had spastic paraparesis a year and a half after chlorpyrifos intoxication (Cavari et al, 2013).

a) DELAYED POLYNEUROPATHY: SUMMARY: Improvement may be observed followed by the delayed development of a motor or sensory-motor peripheral neuropathy. The motor component is usually more pronounced than the sensory component (Moretto & Lotti, 1998).

a) SUMMARY: Sequelae may include subtle neuropsychological deficits and the extent of such chronic effects may not be correlated with the severity of signs and symptoms following acute exposure (Stephens et al, 1996). In one South African study, chronically exposed pesticide applicators reported more dizziness, drowsiness, and headaches and had higher scores on a neurological symptom questionnaire than did unexposed controls (London et al, 1998).
b) ORGANIC BRAIN SYNDROME: CASE REPORT: A 60-year-old farm worker with repeated exposures to organophosphates presented with persistent headaches, memory loss, confusion, and fatigue. Diagnostic evaluation was unremarkable except for neuropsychological testing which revealed impaired functioning (Rosenstock et al, 1990). Organic brain dysfunction has been reported in seven family members following an accidental exposure to diazinon through dermal absorption and inhalation over a two-day period (Dahlgren et al, 2004).
c) NEUROPSYCHOLOGICAL DEFICITS - CASE SERIES: A study of 36 occupational acute organophosphate poisonings examined neuropsychological tests 10 to 34 months after exposure. All had been treated with atropine.

a) A nationwide population-based cohort study, evaluating the risk of dementia in patients with acute organophosphate and carbamate poisoning, identified 9616 exposed patients and compared them with 38,510 control patients. The incidence of dementia was 29.4 per 10,000 person-years in the exposed group as compared with 14.2 per 10,000 person-years in the control group, indicating a 1.98-fold increased risk of dementia compared with the control cohort. The risk of dementia was the highest during the first year of exposure, peaked among patients 50 to 64 years of age, and was independent of underlying diseases(Lin et al, 2015).

a) RARE EFFECTS: 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).

a) Transient bilateral recurrent laryngeal nerve paralysis resulting in paralysis of the true vocal cords has been reported as a delayed complication (25 to 35 days after acute exposure) in patients with significant organophosphate poisoning (de Silva et al, 1994).

a) CASE REPORT: A 56-year-old man with severe organophosphate poisoning developed typical but transient signs and symptoms of Parkinsonism from the 8th through the 61st days after exposure (Muller-Vahl et al, 1999).
b) In a case-control study of Parkinson's disease (PD) patients with a high prevalence of pesticide exposure, it was found that pesticide exposure has a modest effect increasing the incidence of PD in non-CYP2D6 poor metabolizers, and their effect is increased in poor metabolizers (approximately 2-fold). However, poor metabolizers are not at increased PD risk in the absence of pesticide exposure (Elbaz et al, 2004).

a) RARE EFFECTS: Patients poisoned with highly lipid soluble OPs such as fenthion have rarely developed extrapyramidal effects including dystonia, resting tremor, cog-wheel rigidity, and choreoathetosis. These effects began 4 to 40 days after acute OP poisoning and spontaneously resolved over 1 to 4 weeks in survivors (Hsieh et al, 2000; Senanayake & Sanmuganathan, 1995). A delayed extrapyramidal syndrome has also been reported following acute dichlorvos organophosphate poisoning (Brahmi et al, 2004).
b) CASE SERIES: After ingesting organophosphate compounds (one patient drank 10 mL of monocrotophos), two patients developed extrapyramidal signs (tremor, blepharoclonus, drooling, hyperreflexia, dysarthria, neck stiffness, cogwheel rigidity, pill-rolling tremor, and shuffling gait, asymmetrical facial and shoulder muscle spasm, chorea, trismus, blepharospasm and occasional facial grimacing). Both were treated with PAM and atropine. One patient developed respiratory failure several hours after the ingestion. It is believed that extrapyramidal signs resulted from the decreased ratio of dopaminergic to cholinergic activity within basal ganglia and substantia nigra (Hsieh et al, 2000).
c) CASE REPORT: 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 in a suicidal attempt. Since she was asymptomatic (plasma cholinesterase level 146 Units/L; normal 5300-12900 Units/L) for the first 12 hours, she was not treated with atropine. She responded immediately to intravenous scopolamine (0.5 mg) therapy. 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).
d) CASE REPORT: Following the ingestion of an insecticide, a 50-year-old woman developed signs and symptoms of parkinsonism (tremors, dysarthria, cogwheel rigidity, mask-like facies, and a positive Babinski signs, agitation) after a severe acute cholinergic phase (plasma cholinesterase level 161 Units/L) and before the development of the intermediate syndrome. Following supportive therapy, she recovered gradually and was discharged on day 27. No antiparkinson drugs were required (Tafur et al, 2005).
e) CASE REPORT: 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. This resulted in his complete recovery within 1 week (Shahar et al, 2005).

a) ELECTROPHYSIOLOGICAL CHANGES: Dimethoate, dichlorvos, and parathion-methyl given orally to rats at lethal doses caused changes in the mean amplitudes and frequency of EEG patterns as well as changes in the delta, theta, alpha, beta1a, beta2 and gamma EEG frequency bands. Nerve conduction velocities were decreased, absolute and relative refractory periods were increased, and amplitudes of the muscle action potentials were increased in the tail nerve (Nagymajtenyi et al, 1988).
b) When the same organophosphates were given at 1/50 the LD50, 5 times a week for 6 weeks, similar electrophysiological changes were seen IN THE ABSENCE OF OVERT CHOLINERGIC SIGNS OR CONSISTENT DEPRESSION OF PLASMA AND ERYTHROCYTE CHOLINESTERASE ACTIVITIES (Nagymajtenyi et al, 1988).
c) All of the three organophosphates used in this study produced changes in the peripheral nervous system, even though none of them is known to cause peripheral neuropathy (Nagymajtenyi et al, 1988).
d) These results suggest that subtle changes in the central and peripheral nervous system, which would not be detectable using standard clinical monitoring methods, may occur with prolonged exposure to organophosphates.

a) Nausea and vomiting are common muscarinic signs of poisoning (Dong et al, 2013; Aslan et al, 2011; Guven et al, 2004a; Dahlgren et al, 2004; Wu et al, 2001; Wang et al, 2000; Bardin et al, 1987; Richter et al, 1992).
b) In one study of OP intoxication patients (n=42) admitted to a nephrology ward, nausea and vomiting developed in 45.2% of patients (Lin et al, 2004).
c) Nausea and vomiting have been reported following the cutaneous absorption of organophosphates (Bjornsdottir & Smith, 1999).
d) PREVALENCE: In a study of 31 children (mean age 5.6 +/- 3.9 years) presenting with acute organophosphate poisoning, gastrointestinal events were commonly reported. Vomiting occurred in 51.6% (n=16) of patients with the symptoms reported as being mild. Excess salivation (54.8%) (n=17) was also frequently reported (Levy-Khademi et al, 2007).

a) In one study of organophosphate intoxication patients (n=42) admitted to a nephrology ward, abdominal pain developed in 23.8% of patients (Lin et al, 2004).
b) In a prospective study, all organophosphate (n=31) or carbamate (n=18) poisoning cases admitted to an ED during a 2-year period were evaluated. Abdominal pain developed in 32 (65.3%) patients (22 [70.9%] organophosphate cases and 10 [55.5%] carbamate cases). Twenty-two patients developed moderate to severe abdominal pain with serious muscarinic symptoms; all of these patients underwent abdominal ultrasonography. Abdominal free fluid was observed in 14 (63.6%) of these cases. Two patients (14.2%) had massive free fluid collection throughout the abdomen. One patient developed pancreatitis and peritonitis. Three of the 14 patients with abdominal free fluid were pregnant, gestational ages: 9, 15, and 28 weeks, respectively. Two of these women had intrauterine fetal demise (Aslan et al, 2011).

a) Fecal incontinence may occur in severe poisoning (Koga et al, 1999; Kecik et al, 1993; Burgess & Audette, 1990; Hayes, 1965).

a) Diarrhea and abdominal cramps are common muscarinic signs (Aslan et al, 2011; Wu et al, 2001; Bjornsdottir & Smith, 1999; Lifshitz et al, 1999; Bardin et al, 1987).
b) INCIDENCE: Diarrhea occurred in 21 percent of patients in one study (Bardin et al, 1987).
c) In one study, diarrhea developed in 34 (61%) of 56 patients with organophosphate poisoning (Pazooki et al, 2011).
d) In a review of 16 pediatric patients with organophosphate poisoning, 9 children (30 percent) had diarrhea (Lifshitz et al, 1999).

a) Both painless elevation of serum amylase/lipase and frank clinical pancreatitis have been reported (Aslan et al, 2011; Singh et al, 2007; Harputluoglu et al, 2003; Panieri et al, 1997; Hsiao et al, 1996; Lankisch et al, 1990).
b) INCIDENCE: In a retrospective study of 79 patients (n=61 with suicidal intent), mild elevation in serum amylase (greater than 200 SU/dL) was reported in 37 (46.95%) patients. Most patients had normal serum amylase levels within a few days of admission. There was also no significant correlation between severity of poisoning and degree of hyperamylasemia. Although elevated serum amylase was relatively common; acute pancreatitis was rare (Singh et al, 2007).
c) NECROTIZING PANCREATITIS: Severe necrotizing pancreatitis with retroperitoneal sepsis has been reported in two OP poisoned patients (Panieri et al, 1997). In another case, a 23-year-old man intentionally ingested an unknown amount of dichlorovos and developed evidence of acute pancreatitis with patchy necrosis of the pancreatic body and tail within 6 hours of exposure. A distal spleen and vessel preserving pancreatectomy was performed about 36 hours after exposure; the patient progressed well with discharge to psychiatric care 12 days later. Pathological exam confirmed necrotizing pancreatitis (Roeyen et al, 2008).
d) PREVALENCE - In a study of 31 children (mean age 5.6 +/- 3.9 years) presenting with acute organophosphate poisoning, pancreatitis (based on serum amylase concentrations) developed in 18.5% (n=5) of patients (Levy-Khademi et al, 2007).
e) HYPERAMYLASEMIA: Hyperamylasemia (serum amylase greater than or equal to 360 International units/L) was found in 121/159 patients (76%) with acute organophosphate poisoning (Lee et al, 1998). Hyperamylasemia is not synonymous with OP-induced pancreatitis (Lee et al, 1998).
f) CASE SERIES: Acute pancreatitis, as assessed by elevated amylase and trypsin levels, was found in 5 of 17 consecutive children admitted for symptomatic organophosphate or carbamate poisoning.

a) CASE REPORT: A 67-year-old man became comatose after ingesting an unknown amount of an organophosphate insecticide containing parathion. Bilateral facial swelling in the pre-auricular area was observed one day after admission, with an elevated serum amylase (6725 international units/L) and a normal serum lipase. The patient died on hospital day 2, after the development of ventricular fibrillation. Postmortem evaluation of the parotid glands revealed sialolithiasis, edema of the interstitial tissue, and infiltration in the periglandular region. Pathologic examination of the pancreas was normal (Gokel et al, 2002). The authors suggested that parathion toxicity produced acute parotitis, and the mechanism was thought to be due to ductal hypertension and stimulation of exocrine secretion from the parotid glands by organophosphate-induced cholinergic stimulation.

a) RARE EFFECTS: INTUSSUSCEPTION: A single case of intussusception has been reported following ingestion of an unspecified organophosphate by a 14-month-old child (Crispen et al, 1985).
b) CASE REPORT: One adult patient with severe organophosphate poisoning requiring an atropine continuous infusion for five weeks developed paralytic ileus on the 35th hospital day, probably as a complication of atropine therapy (Beards et al, 1994).

a) CASE REPORT: A 64-year-old man with a history of a partial gastrectomy for a duodenal ulcer, developed acute hemorrhagic panesophagitis after accidentally ingesting a small amount of organophosphorus insecticide (fenitrothion and malathion). Upper endoscopy revealed circumferential hyperemia, hemorrhage, and marked edema throughout the esophagus. Although the esophagogastric junction was not severely inflamed, the remnant stomach was inflamed with hemorrhagic erosions, especially at the gastroduodenal anastomosis (Koga et al, 1999).

a) CASE REPORT: A 30-year-old man presented with abdominal pain, vomiting, excessive salivation, and choking sensation after using a pesticide containing methyl parathion to spray his apple orchard on 2 consecutive days for about 4 hours daily. He received atropine injection, IV fluids, and other symptomatic therapy. Laboratory results revealed hepatitis with acute kidney injury (serum creatinine: 2.9 mg/dL on day 6 and 3 mg/dL on day 8), and depressed plasma cholinesterase levels. Following further supportive care, his condition resolved on follow-up (Vikrant, 2015).

a) Involuntary urination occurs in more severe poisonings. Urinary frequency and urinary incontinence may be evident (Aslan et al, 2011; Wu et al, 2001; Koga et al, 1999; Burgess & Audette, 1990; Done, 1979).
b) Urinary frequency with incontinence has been reported following the cutaneous absorption of organophosphate (Bjornsdottir & Smith, 1999).
c) In a prospective study of 31 organophosphate poisoning cases, urinary incontinence developed in 9 (29%) patients with organophosphate poisoning (Aslan et al, 2011).

a) RARE EFFECT: IMMUNE-COMPLEX NEPHROPATHY: Immune-complex nephropathy with proteinuria may have occurred in one case of malathion poisoning (Albright et al, 1983).
b) Another patient with malathion poisoning developed transient, mild renal insufficiency and proteinuria (Dive et al, 1994).

a) RARE EFFECT: AMORPHOUS CRYSTALLURIA : 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).

a) CASE REPORT: One patient who subsequently died following ingestion of dimethoate developed acute tubular necrosis (Betrosian et al, 1995).

a) CHLORPYRIFOS: A 17-year-old girl presented with altered mental status, miosis, salivation, and sweating 30 minutes after ingesting an unknown amount of chlorpyrifos 40%. Laboratory results revealed serum pseudocholinesterase activity concentration of 129 Units/L (reference range: 4260 to 11,250 Units/L). Despite supportive therapy, including IV atropine, and obidoxime chloride (250 mg at 6-hour intervals), she developed generalized edema, oliguria and hypertension on day 3. Her BUN increased to 65 mg/dL and serum creatinine to 2.6 mg/dL. Fractional excretion of sodium was high at 3.6%, indicating acute tubular necrosis. On day 7, her BUN increased to 233 mg/dL and serum creatinine increased to 6.4 mg/dL with a creatinine clearance of 9 mL/min. She was treated with continuous venovenous hemofiltration (CVVH) for about 40 hours and her BUN and serum creatinine concentrations gradually decreased. Her renal function gradually normalized about 12 days after the first sign of renal failure. Despite supportive care, she developed neurologic complications, including intermediate syndrome (facial, proximal limb, and respiratory muscles weakness), necessitating mechanical ventilation for 8 days. She later developed delayed polyneuropathy and spastic paraplegia. Despite spending 6 months at a rehabilitation center, she had spastic paraparesis a year and a half after chlorpyrifos intoxication (Cavari et al, 2013).

a) CASE REPORT: A 30-year-old man presented with abdominal pain, vomiting, excessive salivation, and choking sensation after using a pesticide containing methyl parathion to spray his apple orchard on 2 consecutive days for about 4 hours daily. He received atropine injection, IV fluids, and other symptomatic therapy. Laboratory results revealed hepatitis with acute kidney injury (serum creatinine: 2.9 mg/dL on day 6 and 3 mg/dL on day 8), and depressed plasma cholinesterase levels. Following further supportive care, his condition resolved on follow-up (Vikrant, 2015).

a) Metabolic acidosis may occur following severe organophosphate poisoning (Hui, 1983; Meller et al, 1981; Moore & James, 1981). Lactic acidosis usually occurs secondary to shock or seizures.
b) MORTALITY PREDICTORS: In a retrospective study of 296 patients with organophosphate poisoning, bradycardia, age, glucose, lactate dehydrogenase level and acidosis were independent predictors of mortality (Gunduz et al, 2015).
c) CASE SERIES: In a 9 year retrospective study of 82 consecutive patients with acute organophosphate poisoning, arterial blood gas was measured prior to hospitalization to assess potential patterns of outcome based on early acid-base status. The findings indicated that a declining pH value (pH < 7.2 vs >/= 7.2; odds ration 10.1; 95% CI , 2.37-42.5; P = .002) and increasing age (> 50 years) were significant independent predictors of death. The type of acidosis also influenced outcome, with the highest mortality rate reported among patients with a mixed respiratory and metabolic acidosis (80%, 8/10). Mortality rates were also higher among patients with respiratory acidosis (50%, 4/8) as compared to patients with metabolic acidosis (25%, 8/32). The underlying cause of death was cardiovascular failure in patients with metabolic acidosis, and respiratory and cardiovascular failure in patients with respiratory acidosis. The authors suggest that acid-base interpretation is a relatively easy method to assess possible patient outcome following acute poisoning (Liu et al, 2008).
d) CASE REPORT: A 17-year-old girl became unconscious within 5 minutes of ingesting dichlorvos (unknown amount). On presentation, she was drowsy, gasping and cyanosed, and had generalized hypotonia, miosis, and downgoing plantars. She had a heart rate of 130 beats/min and blood pressure of 100/60 mmHg. At this time she was treated with supportive care, including atropine (2 mg IV, repeated every 10 minutes until complete atropinization) and pralidoxime (2 g IV bolus and continued as 8 mg/kg/hr IV infusion). A diffuse cerebral edema with compression of all the ventricles, basal cisternae and sulci was observed during an emergency non-contrast computed tomography of the head and she was treated with mannitol and dexamethasone. Laboratory results on day 1 revealed metabolic acidosis (pH 7.263; pCO2 24.3 mmHg; SO2 99.7%; HCO3 10.7 mEq/L). Despite supportive therapy and sodium bicarbonate treatment, her condition rapidly deteriorated and she developed hypotension (systolic BP 60 mm Hg) which gradually was not recordable. She died after unsuccessful cardiopulmonary resuscitation (Krishnamurthy et al, 2013).

a) 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; Murray et al, 1994).

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

a) Leukocytosis has been reported in patients after exposure to methamidophos-contaminated vegetables (Wu et al, 2001).

a) Profuse sweating may occur as one of the muscarinic signs of organophosphate poisoning (Aslan et al, 2011; Wu et al, 2001; Wang et al, 2000; Koga et al, 1999; Bjornsdottir & Smith, 1999; Bardin et al, 1987; Ganendran, 1974). Pallor is sometimes noted (Done, 1979).
b) In one study, sweating developed in 53 (95%) of 56 patients with organophosphate poisoning (Pazooki et al, 2011).
c) In a prospective study of 31 organophosphate poisoning cases, sweating developed in 25 (80.6%) patients with organophosphate poisoning (Aslan et al, 2011).
d) In one study of OP intoxication patients (n=42) admitted to a nephrology ward, increased sweating developed in 19% of patients (Lin et al, 2004).

a) SENSITIZATION: Dermal sensitization to malathion has been reported following skin exposure (Milby et al, 1964).

a) Urticaria, angioedema, and nonspecific skin rash have been reported following exposure to malathion (Schanker et al, 1992).

a) A burning sensation of the skin has been reported following overspray exposure to malathion (Dahlgren et al, 2004); O'Malley, 1992).

a) Organophosphates can be systemically absorbed through intact skin (Guloglu et al, 2004; Bjornsdottir & Smith, 1999; Wester et al, 1993).

a) Cellulitis and thrombophlebitis of the extremities have been reported following the intravenous or intramuscular misuse of organophosphates (Guloglu et al, 2004).
b) CASE REPORT: An 18-year-old woman developed cellulitis and abscess after the subcutaneous injection of chlorpyrifos to her left arm (Malla et al, 2013).
c) CASE REPORT: A 22-year-old woman developed vesicles and cellulitis after injecting her left arm proximal region with Entox insecticide aerosol, containing dichlorvos (Guloglu et al, 2004).

a) Cellulitis and thrombophlebitis of the extremities have been reported following the intravenous or intramuscular misuse of organophosphates (Guloglu et al, 2004).

a) BULLOUS CONTACT DERMATITIS: A 28-year-old woman presented with vomiting and lost consciousness after exposure to organophosphorus pesticides. Laboratory results revealed organophosphorus concentrations of 332 ng/mL in blood and 490 ng/mL in urine, and a cholinesterase activity of 251 Units/L. Despite supportive care, including gastric lavage and atropine therapy, she developed redness, blisters (some bursting), and second-degree burn-like lesions on the skin of her neck, shoulders, and axillae 2 days later. At this time, the cholinesterase activity was 623 Units/L. Following treatment with atropine, repeated cleaning of the lesions with iodophor solution, covering of the blisters with moisturizing gel Urgotul(R), and changing of the wound exudation, the lesions completely healed after 11 days. The cholinesterase activity gradually increased to 3926 Units/L. On the follow-up visit 3 months later, she did not have any symptoms (Dong et al, 2013).

a) A 76-year-old woman using echothiophate iodide ophthalmic drops developed progressive neck and extremity weakness in addition to dyspnea. An initial diagnosis of myasthenia gravis was made; however, symptoms spontaneously resolved following discontinuation of the medication (Manoguerra et al, 1995).
b) Organophosphate compounds cause skeletal muscle weakness by 3 different mechanisms (Karalliedde & Henry, 1993):

a) CASE REPORT: A 43-year-old psychiatric patient developed rhabdomyolysis (creatine phosphokinase (CPK) 47,762 International units/L) after ingesting approximately 100 mL of fenitrothion emulsion (50%) in a suicide attempt. Because of the early diagnosis, she recovered from the acute cholinergic crisis and was protected against acute renal failure (Futagami et al, 2001).

a) A study of 24 agricultural workers revealed significantly lower cancellous bone area and bone formation at cellular and tissue level in workers with long-term exposure to organophosphates compared with healthy age-matched controls (Compston et al, 1999).

a) CASE REPORT: A 23-year-old woman intentionally subcutaneously injected 3-4 mL of fenthion (82.5% w/w fenthion) into her antecubital fossa and developed massive swelling, cellulitis and compartment syndrome requiring urgent fasciotomy. The patient's hospital course was complicated by persistent symptoms of cholinergic crisis necessitating repeated doses of atropine and pralidoxime and ongoing mechanical ventilation. Respiratory status stabilized by hospital day 31 when the patient was successfully weaned from the ventilator (Bala et al, 2008).

a) Hyperglycemia and glycosuria (with or without ketosis) are present in severe poisoning (Wu et al, 2001; Namba, 1972).
b) INCIDENCE: Hyperglycemia has been reported in about 22 percent of children with organophosphate or carbamate poisoning (Zwiener & Ginsburg, 1988), and may be the result of acute pancreatitis (Weizman & Sofer, 1992).
c) PROGNOSTIC INDICATOR: A retrospective, observational, case series of 184 non-diabetic patients with a history of organophosphate poisoning revealed that the risk of case fatality is increased as the glucose levels are increased to more than 200 mg/dL (11.11 mmol/L). However, the association between the glucose concentration and case fatality may differ by the type of organophosphate agent ingested. In this study, 4 groups of patients were monitored: group 1 (glucose level: less than 140 mg/dL; n=63); group 2 (glucose level: 140 to 200 mg/dL; n=58); group 3 (glucose level: 200 to 300 mg/dL; n=41); group 4 (glucose level: 300 mg/dL or greater; n=22). Dichlorvos (n=33), fenitrothion (n=25), and ethyl p-nitrophenol thio-benzene phosphonate (EPN; n=24) were the most commonly ingested organophosphates. Fatality occurred in 8.7% of the patients. Compared with the non-survivors (n=16), survivors (n=168) were significantly younger (58 +/- 16.5 years vs 71.8 +/- 11.9 years), had a higher initial GCS score, a lower International Program on Chemical Safety Poison Severity Score (IPCS PSS), and a lower glucose concentration at presentation (181.9 +/- 90.6 vs 267.6 +/- 101) (Moon et al, 2016).

a) In one prospective study, thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (PRG), adrenocorticotropic hormone (ACTH), cortisol, and testosterone (TST) levels of patients (n=44) with organophosphate poisoning were analyzed before and after treatment with atropine and pralidoxime. ACTH, cortisol, PRL, FT3, FT4, FSH, and PRG levels were significantly lower after treatment than before treatment (P<0.05). FT4 levels increased after treatment (P<0.05). TSH, LH and TST levels were lower after treatment, but did not reach statistical significance. On admission, sick euthyroid syndrome was identified in 6 patients; 11 euthyroid patients developed sick euthyroid syndrome following treatment. The authors concluded that these changes in hormone levels may be attributed to the effects of acetylcholine, the direct effect of organophosphates, or the effects of stress, possibly associated with the ingestion of the poison (Satar et al, 2004).

a) Delayed menarche has been reported in a child following an accidental dermal and inhalation exposures to diazinon over a two-day period. Causality cannot be assessed in this case (Dahlgren et al, 2004).

a) SENSITIZATION: Dermal sensitization to malathion has been reported following skin exposure (Milby et al, 1964).

a) Urticaria, angioedema, and nonspecific skin rash have been reported following exposure to malathion (Schanker et al, 1992).

a) Abnormalities included Down syndrome (4 births), ventricular septal defect and pulmonary atresia, congenital inguinal hernia, stenosis of the left bronchus, anal atresia, choanal atresia, cleft lip, and Robin sequence.

a) 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).
b) 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 an increased prevalence of this birth defect with exposure to any single pesticide group (Gordon & Shy, 1981).

a) References: (Budreau & Singh, 1973; Gofmekler & Khuriev, 1971; Tanimura et al, 1967; Fish, 1966; Robens, 1969; Machin & McBride, 1989; Dzierzawski & Minta, 1979).

a) The IARC classification is based on inadequate evidence of carcinogenicity in humans, but sufficient evidence in animals (Guyton et al, 2015).

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.
b) Symptomatic patients usually have depression of blood cholinesterase activities in excess of 50 percent of the pre-exposure value (Milby, 1971). Depressions in excess of 90 percent may occur in severe poisonings (Klemmer et al, 1978).
c) 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, 1986; Coye et al, 1987). In these patients, AChE decreased by as much as 50 percent but was still within the normal range.
d) The correlation between plasma cholinesterase levels and onset or extent of clinical effects may be poor (Nouira et al, 1994), especially if assays are done in different laboratories. Comparison with pre-exposure values may be helpful.
e) Serum cholinesterase levels measured at the beginning and after the end of a workday may indicate potential overexposure in agricultural workers (Lopez-Carillo & Lopez-Cervantes, 1993).
f) While serum cholinesterase levels were lower in a group of chronically exposed workers than in unexposed controls, there was no correlation with clinical symptoms of organophosphate overexposure (Peedicayil et al, 1991).
g) In one case series, 75 percent of patients with severely depressed serum cholinesterase levels required mechanical ventilation (Yamashita et al, 1997).
h) BUTYRYLCHOLINESTERASE ACTIVITY - A prospective study was conducted to determine the usefulness of butyrylchoinesterase (BuChE) activity along with plasma organophosphate (OP) concentration to predict outcome following severe organophosphate poisoning. The results were found to vary widely depending on the agent ingested. BuChE was only useful when the organophosphate was known, along with the sensitivity and specificity of a given insecticide. In this study, a value of < 600 mU/mL was highly sensitive (100%) for death in the chlorpyrifos group, but had a specificity of 17.7%. In the dimethoate group, it was found to have a sensitivity of 48% with a specificity of 86.4%. The authors concluded that BuChE may be useful in a limited number of patients, but its utility in most cases would make it clinically unacceptable based on its poor performance as a prognostic test. It was also found that OP concentration on admission may predict outcome, but it was dependent on the OP insecticide ingested. Findings indicated that OP concentration was useful for dimethoate exposed patients, but it had limited specificity for patient's exposed to chlorpyrifos exposures (Eddleston et al, 2008).

a) IATROGENIC CAUSES - 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, 1989; Wills, 1972; HEW, 1976).
b) Plasma pseudocholinesterase activity may be decreased by such chemicals as morphine, codeine, thiamine, ether, and chloroquine (Wills, 1972).
c) DISEASE STATES - 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).
d) PREDISPOSING CONDITIONS - 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, 1989; Wills, 1972; HEW, 1976):
e) Elevated levels of erythrocyte acetylcholinesterase may be seen with reticulocytosis due to anemias, hemorrhage, or treatment of megaloblastic or pernicious anemias (Hayes, 1982).

a) PRALIDOXIME - Pralidoxime reverses depression of blood cholinesterase activities. Without the use of pralidoxime, plasma cholinesterase increased an average of 15.6 percent over fourteen days in one group of organophosphate-exposed workers. Serial levels 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.

a) Determination of amylase isoenzymes is necessary to confirm the pancreatic origin (Hsiao et al, 1996).

a) One study found that urine alkyl phosphate levels were more sensitive markers of exposure than whole-blood ChE activity. Levels of diethyl phosphate (DEP) and dimethyl phosphate (DMP) ranging from 0.1 to 1.0 mg/L were associated with trivial depressions in ChE (Richter et al, 1992a).

1) Dimethyl Phosphate (DMP)
2) Diethyl Phosphate (DEP)
3) Dimethyl Thio Phosphate (DMTP)
4) Diethyl Thio Phosphate (DETP)
5) Dimethyl Dithio Phosphate (DMDTP)
6) Diethyl Dithio Phosphate (DEDTP)

a) OCCUPATIONAL EXPOSURE MONITORING - 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) A modified grading scale based on a scheme proposed by Namba (1971) was prospectively validated among 39 organophosphate poisoning patients admitted to an ICU (Bardin & Van Eeden, 1990).

a) A retrospective study evaluated several clinical scoring tools, Acute Physiology and Chronic Health Evaluation (APACHE) II, III and Simplified Acute Physiology Score II (SAPS II), as prognostic indicators of organophosphate poisoning (OPP). During the study period, 48 patients with OPP were admitted to the ICU for at least 24 hours. The mean APACHE II, III, SAPS II and GCS scores at admission were 11.5 +/- 7.21, 42.1 +/- 24.49, 25.1 +/- 15.76, and 11.1 +/- 4.1, respectively. Overall, these clinical scoring tools correlated with length of ICU stay, dose and duration of atropine and pralidoxime therapy, serum cholinesterase concentration and mortality (Sungurtekin et al, 2006).

a) ELECTROPHYSIOLOGIC FEATURES - Electrophysiologic features of organophosphate poisoning in humans include early (4 hours or more postingestion) occurrence of spontaneous repetitive firing of single evoked compound muscle action potentials (CMAP), followed by a decrement-increment phenomenon at mild stages, and an absence of CMAP in severe stages.
b) Although not specific for peripheral neuropathy, one study of persons previously acutely poisoned with organophosphates found increased normalized vibrotactile thresholds as compared to an unexposed control group (McConnell et al, 1994). Abnormal vibrotactile thresholds have been found in chronically exposed pesticide applicators (Stokes et al, 1995).
c) Electrodiagnostic studies may be useful in assisting diagnosis of organophosphate poisoning, monitoring the effect of pralidoxime on neuromuscular transmission, and assessing phrenic nerve involvement in patients with diaphragmatic paralysis (Singh et al, 1998).

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

a) RESPIRATORY MUSCLE PERFORMANCE (RMP) - Measurements of RMP such as negative inspiratory force may be more valuable than erythrocyte acetylcholinesterase activity in determining readiness for extubation (Routier et al, 1989).
b) 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 organophosphate-induced delayed neuropathy or possible immunologic suppression is being further investigated (Mandel et al, 1989).
c) LYMPHOCYTE NTE - Lotti et al (1983) found that monitoring levels of neurotoxic esterase (NTE) in circulating lymphocytes aided in providing early warning of delayed neurotoxicity.
d) PLATELET NTE - Inhibition of platelet NTE occurred in a dose-dependent manner in mice poisoned with mipafox, a compound known to produce delayed neuropathy. Platelet NTE correlated with brain NTE and may ultimately be useful as a marker of neurotoxicity in humans (Husain, 1991).

a) Obtain and monitor 12-lead ECG. Patients with QTc prolongation or PVCs have a higher incidence of respiratory failure and a worse prognosis (Chuang et al, 1996; Jang et al, 1995).

a) Laryngoscopy can be done to evaluate possible vocal cord paralysis and to rule out epiglottitis or a foreign body when airway obstruction is present (Thompson & Stocks, 1997).

a) If pancreatitis is suspected, an abdominal CT-scan can be performed to evaluate diffuse pancreatic swelling (Hsiao et al, 1996).

a) One study recommended the routine use of abdominal ultrasonography in patients with organophosphate poisoning and abdominal pain. In this study, all organophosphate (n=31) or carbamate (n=18) poisoning cases admitted to an ED during a 2-year period were evaluated. Abdominal pain developed in 32 (65.3%) patients (22 [70.9%] organophosphate cases and 10 [55.5%] carbamate cases). Twenty-two patients developed moderate to severe abdominal pain with serious muscarinic symptoms; all of these patients underwent abdominal ultrasonography. Abdominal free fluid was noted in 14 (63.6%) of these cases. Two patients (14.2%) had massive free fluid collection throughout the abdomen. One patient developed pancreatitis and peritonitis. Three of the 14 patients were pregnant, gestational ages: 9, 15, and 28 weeks, respectively. Two of these women had intrauterine fetal demise (Aslan et al, 2011). Findings on ultrasonography rarely influenced patient treatment, so it should be performed selectively.

a) CASE REPORTS - Two patients with organophosphate poisoning were shown to have brain perfusion defects on Tc-99 HMPAO SPECT imaging which could not be detected on CT-scan (Gunes et al, 1994).

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

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

a) Spilled liquid may first be adsorbed with soil, sweeping compound, sawdust, or dry sand and then both the adsorbed material and the floor decontaminated with one of the above solutions (EPA, 1975a).
b) NOTE - Do NOT use a COMBINATION of BLEACH and ALKALI to DECONTAMINATE ACEPHATE or ACETYL ORGANOPHOSPHATE COMPOUNDS such as ORTHENE(R). Spills involving acephate organophosphates should be decontaminated by the following procedure - Isolate and ventilate the area; keep sources of fire away; wear rubber or neoprene gloves and overshoes; get fire-fighting equipment ready; contain any liquid spill around the edge and absorb with Zorb-All(R) or similar material; dispose of absorbed or dry material in disposable containers; scrub the spilled area with concentrated detergent such as TIDE(R), ALL(R) or similar product; re-absorb scrubbing liquid and dispose as above; dispose of cleaning materials and contaminated clothing; wash gloves, overshoes and shovel with concentrated detergent. Call the National Pesticide Telecommunications Network for further assistance at 1-800-858-7378 or on the web at http://nptn.orst.edu.

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

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.

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).
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).
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.

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.

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).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

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

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.

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.

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).

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.

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).

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).

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.

a) AUTOINJECTORS

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).

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).

a) Atropinization must be maintained until all of the absorbed organophosphate has been metabolized. This may require administration of 2 to 2,000 milligrams of atropine over several hours to weeks. One case of parathion overdose required 19,590 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).

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).

a) PRALIDOXIME/INDICATIONS
b) PRALIDOXIME/CONTROVERSY

a) PRALIDOXIME/ADMINISTRATION

a) PRALIDOXIME DOSE

a) SUMMARY
b) MINIMAL TOXICITY
c) NEUROMUSCULAR BLOCKADE
d) VISUAL DISTURBANCES
e) ASYSTOLE
f) WEAKNESS
g) ATROPINE SIDE EFFECTS
h) CARDIOVASCULAR

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).

a) VIALS
b) SELF-INJECTOR
c) CONVERSION FROM AUTOINJECTOR TO IV SOLUTION
d) OTHER SALTS

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).

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

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.

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).

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).

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.

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

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 autoinjectors 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)

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

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).

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).

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).

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 .

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).

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).

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).

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):

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.

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).

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) 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.

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).

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).

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).

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).

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).
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).

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

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.

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)

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.

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.

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).

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).

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).

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).

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).

a) Extracorporeal cardiopulmonary support, including intraaortic balloon pumping and percutaneous cardiopulmonary support, were used to treat a 50-year-old female 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).

1) He was treated with atropine and pralidoxime, and required mechanical ventilation for 16 days. Daily methidathion blood levels were measured, and could be described by the expression y(mcg/L) = 115 e(-0.13 x days) + 140 e(-0.36 x days) (Zatelli R, Zoppellari R & Mantovani G et al, 1992).

a) SPECIFIC SUBSTANCE
b) CHOLINESTERASE LEVELS

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Remove the patient and other animals from the source of contamination or remove dietary sources.

a) ASPCA Animal Poison Control Center, 1717 S Philo Road, Suite 36 Urbana, IL 61802
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) Contact information: (888) 426-4435 (hotline) or www.aspca.org (A fee may apply. Please inquire with the poison center). The agency will make follow-up calls as needed in critical cases at no extra charge.

a) EMESIS/GASTRIC LAVAGE -
b) ACTIVATED CHARCOAL/CATHARTIC -
c) DERMAL DECONTAMINATION -
d) OCULAR DECONTAMINATION -
e) INHALATION DECONTAMINATION -

a) Severe respiratory depression may lead to anoxia and death. Respiration must be supported with the necessary combination of oxygen, intubation or tracheostomy, and positive pressure ventilation.

a) SMALL ANIMALS: Give atropine sulfate 0.2 milligram/kilogram intravenously, intramuscularly or subcutaneously. Rabbits: 1 to 10 milligrams/kilogram. Subsequent doses may be given based on clinical impression of degree of respiratory distress and heart rate.
b) HORSE: Approximate dose is 0.5 to 1 milligram/kilogram given intravenously, diluted in fluids. Give atropine cautiously and do not overdose. Monitor the heart rate and mydriasis to assess effect.
c) CATTLE: Ruminants and swine: dose is 0.5 milligram/kilogram, one-fourth given intravenously and the balance given intramuscularly or subcutaneously. Repeated doses of half this amount may be given subcutaneously every 3 to 12 hours as needed. Monitor for rumen atony in cattle and sheep.
d) In cattle, atropine effect may last 1 to 2 hours. Call the nearest school of veterinary medicine to locate the large stockpiles of atropine necessary to treat large numbers of animals.

a) SEIZURES/LARGE ANIMALS: May be controlled with diazepam.
b) SEIZURES/DOGS & CATS:
c) CAUTION - Two cases of intoxicated cats given 0.1 milligram/kilogram diazepam for appetite stimulus resulted in acute increase of neurologic signs 20 minutes later which necessitated treatment (Jaggy & Oliver, 1990). These animals should be monitored continuously for 2 hours after diazepam is used.

a) WHEN TO ADMINISTER: For best results, administer within 24 hours of exposure; some benefit may be derived from continuing administration for several days or weeks, especially with dermal exposure.
b) CARBAMATES: Some authors do not recommend the use of oximes in cases of carbamate or uncertain poisoning. Other authors state that an oxime should be used when signs of a cholinesterase inhibitor are present even if the toxic agent is unknown.
c) ADMINISTER: Slowly and monitor for adverse effects.
d) DOSE: HORSES - Pralidoxime (2-PAM) is administered to horses at 20 to 35 milligrams/kilogram slowly intravenously every 4 to 6 hours.
e) DOSE: RUMINANTS - Pralidoxime (2-PAM) is administered to ruminants at 25 to 50 milligrams/kilogram, as a 20 percent solution during a 6 minute intravenous injection or as a maximum of 100 milligrams/kilogram/day by intravenous drip.
f) DOSE: SMALL ANIMALS - Pralidoxime (2-PAM) Administer 20 milligrams/kilogram intramuscularly or by slow intravenous injection (do not exceed 500 milligrams/minute) two to three times per day. Do not use morphine, succinylcholine, or phenothiazine tranquilizers with 2-PAM. Pralidoxime usually works best in the treatment regimen when used in conjunction with atropine.
g) If pralidoxime is not available, the combination of atropine and diazepam was found more effective than atropine alone in experimental malathion poisoning in buffalo (Gupta, 1984).
h) Obidoxime: May be used as an alternative to pralidoxime in some countries outside the US. Mieth & Beier (1973) recommended concurrent administration of obidoxime at a rate of 5 mg/kg up to a maximum dose of 2000 mg for cattle and 250 to 500 mg per pig or sheep with atropine. The obidoxime dose may be repeated after 90 to 120 minutes.

a) To combat muscle weakness and tremors, give diphenhydramine 4 milligrams/kilogram initially intravenously, then follow every 8 hours with additional doses of 2 milligrams/kilogram orally or intramuscularly as necessary. In the case of fenthion exposure, this treatment may be helpful when maintained for at least 2 weeks (Nafe, 1988).

a) Begin electrolyte and fluid therapy with isotonic solutions as needed at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour). Monitor for urine production and pulmonary edema.
b) HORSE: Administer electrolyte and fluid therapy as needed. Maintenance dose of intravenous isotonic fluids: 10 to 20 milliliters/ kilogram per day. High dose for shock: 20 to 45 milliliters/kilogram/hour.
c) CATTLE: Administer electrolyte and fluid therapy, orally or parenterally as needed. Maintenance dose of intravenous isotonic fluids for calves and debilitated adult cattle: 140 milliliters/kilogram/day. Dose for rehydration: 50 to 100 milliliters/kilogram given over 4 to 6 hours.

a) BICARBONATE: Add sodium bicarbonate to the intravenous fluids if metabolic acidosis is suspected. (If using lactated ringers solution and precipitate forms upon addition of bicarbonate, discard and substitute a different solution).

a) Collect 4 to 8 liters of fresh blood from a healthy adult horse that has not been bled in the last 30 days. Administer immediately to the recipient. Epinephrine should be available in case of transfusion reaction. Dose of epinephrine: 3 to 5 milliliters 1:1000 dilution intravenously.

a) ATROPINE SULFATE - Dose is 0.2 milligrams/kilogram subcutaneously or intramuscularly (Beasley et al, 1989). Doses of 0.25 to 0.5 milligram/kilogram have also been recommended (Porter & Snead, 1990).
b) Diphenhydramine 4 milligrams/kilogram intramuscularly three times a day has been reported to improve clinical signs (Porter & Snead, 1990).
c) Pralidoxime 20 milligrams/kilogram intramuscularly has been effective, but should be used with caution. One death in a Bald Eagle was attributed to pralidoxime (Porter & Snead, 1990).

a) MONITOR for several weeks after exposure; cats especially are prone to medical problems such as Hemobartonella secondary to the stress of the toxicity (Beasley et al, 1989).
b) Horses may have decreased blood cholinesterase levels for 30 days after exposure (Robinson, 1987).

a) The following pharmaceuticals should not be given to animals recently exposed or chronically exposed to organophosphates: phenothiazine derivatives, succinylcholine, carbachol, physostigmine and neostigmine, procaine, magnesium ion, inhaled anesthetics and aminoglycosides (Fikes, 1990). Different cholinesterase inhibitors have additive effects (Beasley et al, 1989).
b) Use of succinylcholine, theophylline, morphine, or phenothiazine derivatives in the treatment of animals poisoned with organophosphates is not recommended.

a) CARBENOPHENOTHION - At a dose of 5 mg/kg orally or 0.1% as a dip produces no adverse effects in sheep (McCarty et al, 1967).
b) COUMAPHOS - Adult cattle tolerate 25 mg/kg orally (McGregor et al, 1954).
c) CROTOXYPHOS - In adult cattle, a spray or powder of 1% crotoxyphos is considered safe. This product is also considered safe in swine (Palmer & Schlinke, 1971).

1) SUMMARY
2) Treatment should always be done on the advice and with the consultation of a veterinarian.
3) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
4) ASPCA ANIMAL POISON CONTROL CENTER
5) TEST DOSE - If diagnosis is uncertain, try a test of the preanesthetic dose of atropine sulfate for that species. If normal atropinization occurs, reconsider the diagnosis.

1) GENERAL TREATMENT

1) Ongoing treatment is symptomatic and supportive.

1) GENERAL

1) The most commonly reported organophosphate insecticides to cause toxicities were chlorpyrifos, diazinon, dichlorvos, malathion, phosmet, chlorfenvinphos, cythioate, fenthion, and disulfoton (Kirk, 1989).
2) Three 7-week-old kittens died within 12 hours of being exposed to a flea collar containing dichlorvos (Kirk, 1989).
3) A cat died following a single application of a powder containing 1% carbophenothion (Uilenberg & Gaulier, 1965).
4) Cattle treated externally with a 20% solution of azinphos methyl solution became intoxicated and several died (Fruttero, 1967).
5) Adult cattle sprayed with 1% carbophenothion experienced 50% lethality (Humphreys, 1988).
6) Following treatment with a 15% solution of malathion, 16 dogs died (McCurnin, 1969). Dogs dipped in a 2% solution of a 57% emulsifiable solution experienced no adverse effects (Humphreys, 1988).

1) One study examined the suitability of domestic animals as sentinels for nerve gas release. Several depots of gas are due to be destroyed in the United States in the 1990s and the authors propose using sampling of local domestic animals' acetylcholinesterase levels as a way of biomonitoring environmental contamination (Munro et al, 1991).

1) Animals should generally not be treated with more than one cholinesterase inhibitor within a two-week period. Organophosphates should not be used on pregnant cats or kittens under 3 months of age, and should be used with caution in sick, elderly, or debilitated animals.
2) Fenthion, used for flea control, has not been approved for use in cats. The 5.6 percent solution has been safely used in healthy adult cats; stronger solutions are unsafe (Boothe, 1990).

1) Fenthion, demeton, and trichlorfon have been associated with teratogenicity in rodents. Fenchlorphos produced effects such as skeletal malformations and cerebellar hypoplasia in blue foxes, swine, and rabbits (Fikes, 1990).