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) 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).

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

a) Profuse sweating may occur as one of the muscarinic signs of organophosphate poisoning (Budavari, 1996; Kecik et al, 1993; Ganendran, 1974) . Pallor is sometimes noted (Done, 1979).
b) Sweating was present in 23% of patients with organophosphate poisoning in one study (Bardin et al, 1987).

a) Dichlorvos exposure can result in irritation and allergic contact dermatitis (ACGIH, 1991; Budavari, 1996).
b) Primary irritant, concentration-related pruritic, erythematous, vesicular dermatitis was reported in 4 patients who handled dogs wearing flea collars containing 9% to 10% dichlorvos. Patch testing with the products produced a bullous primary irritant reaction in all 4 patients and a normal control subject (Hayes & Laws, 1991; Cronce & Alden, 1968).
c) CASE REPORT: Skin contact with spilled 5% dichlorvos solution resulted in irritant dermatitis of the neck, chest, hands, and forearms in a 52-year-old truck driver. Dermatitis persisted for 10 weeks despite topical treatment with 1% hydrocortisone ointment. Systemic symptoms of bitter taste, burning tongue, headache, and rhinorrhea were noted. Blood cholinesterase levels were in the low normal range and increased 2 weeks later (Mathias, 1983).

a) Dermal sensitization has occurred with some organophosphates after skin exposure (Milby et al, 1964).
b) In general, organophosphates can react with proteins and are potential haptens for allergic reactions.

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: 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) Miosis occurred in 50 of 61 patients with organophosphate poisoning (82%) in one study (Bardin et al, 1987).
b) Severely poisoned individuals may show mydriasis (dilatation of the pupils) (Dixon, 1957).

a) More than 50% of patients with organophosphate poisoning in one study had excessive salivation (Bardin et al, 1987).

a) Bradycardia and hypotension occur after moderate to severe poisoning (Krishnamurthy et al, 2013; He et al, 2011; Budavari, 1996; Ganendran, 1974).
b) Hypotension (systolic blood pressure less than 90 mmHg) occurred in 20% of patients with organophosphate poisoning in one study (Bardin et al, 1987).

a) Hypertension can occur as a nicotinic effect of organophosphate poisoning (Lund & Monteagudo, 1986; Kecik et al, 1993).

a) The occurrence of a protracted toxic myocarditis has been suspected (Kiss & Fazekas, 1982; Wren et al, 1981; Chhabra & Sepaha, 1970).
b) In one study, 41 consecutive patients with severe dichlorvos poisoning were evaluated on admission and followed for 3 months. Concentrations of serum creatine kinase isoenzyme myocardium (CKMB) , cardiac troponin I, acetylcholine, epinephrine, and norepinephrine were obtained on hospital days 1, 3, and 5 and the day of hospital discharge. ECGs were performed every other day. Transthoracic echocardiography was performed at admission, in the acute phase, before discharge, and during follow-up. Four of these patients died. Sinus tachycardia developed in 37 patients (90%) and ST-T changes in 33 (80%). CKMB and troponin I concentrations peaked on the third day after overdose, and then declined to normal. Serum acetylcholine, epinephrine and norepinephrine concentrations peaked on the first day after admission, and then declined to normal. Echocardiography showed decreased wall motion of the left ventricle and intraventricular septum during the acute phase of poisoning, with reversal of these changes on recovery. Mean left ventricular ejection fraction was 42% +/- 5% during the acute phase of poisoning and improved to 59% +/- 4% on recovery (He et al, 2011).

a) Tachycardia is common (He et al, 2011; Kecik et al, 1993; Zweiner & Ginsburg, 1988a).
b) A heart rate of greater than 100 beats/minute was reported in 49% of patients with organophosphate poisoning in one study (Bardin et al, 1987). In a prospective, observational study, a heart rate of 100 beats/minute was reported in 90% (n=41) of patients with severe dichlorvos poisoning (He et al, 2011).

a) A heart rate of less than 60 beats/minute occurred in 21% of patients with organophosphate poisoning in one study (Bardin et al, 1987). Bradycardia was reported in 9.7% (n=41) of patients with severe dichlorvos poisoning (He et al, 2011)

a) Cyanosis may result from dichlorvos overexposure (Budavari, 1996).

a) Cardiac irregularities, up to complete heart block, may occur with dichlorvos overexposure (Hathaway et al, 1996). Cardiac dysrhythmias and conduction defects have been reported in patients with severe organophosphate poisoning (Kiss & Fazekas, 1982; Wren et al, 1981; Chhabra & Sepaha, 1970).
b) ECG abnormalities may include sinus bradycardia, AV dissociation, idioventricular rhythms, multiform premature ventricular extrasystoles, polymorphic ventricular tachycardia, prolongation of the PR, QRS and QT intervals, and "torsade de pointes" polymorphous ventricular dysrhythmias (He et al, 2011; Brill et al, 1984; Ludomirsky et al, 1982).

a) Respiratory effects may occur within minutes of inhalation exposure (Budavari, 1996). Increased bronchial secretions, bronchospasm, chest tightness, wheezing, heartburn, and dyspnea occur in severe and moderately severe organophosphate poisonings (Kecik et al, 1993; Hayes, 1965) .
b) Rhonchi or crepitations occurred in 48 patients with organophosphate poisoning in one study (Bardin et al, 1987).
c) From 2000 to 2013, 31 cases of acute illness caused by dichlorvos-impregnated resin strips (DDVP pest strips; available in the US as 16 g, 65 g, and 80 g sizes) were identified in the US (n=24) and Canada (n=7). Neurologic (eg, headache), respiratory (eg, dyspnea), and gastrointestinal (eg, nausea) effects were reported in 68%, 55%, and 42% of cases, respectively. Overall, low severity effects were observed in 26 (84%) patients. Five patients had moderate health effects, including asthma attack, respiratory distress requiring hospitalization, paresthesias, and incoordination. Twenty patients (65%) used DDVP pest strips for 4 hours or longer per day, which was much longer than recommended by the label (Tsai et al, 2014).

a) Noncardiogenic pulmonary edema is a manifestation of severe organophosphate poisoning (Chhabra & Sepaha, 1970; Kecik et al, 1993).
b) CASE SERIES: In a series of 13 cases, 9 of 12 patients who ingested 25 to 50 mL of 80% dichlorvos developed pulmonary edema. A tenth patient, an 11-year-old boy who accidentally ingested one mouthful of diluted dichlorvos, developed bilateral interstitial pulmonary edema 4 hours after ingestion, which resolved 48 hours later (Li et al, 1989).

a) Asthma may occur after the inhalation of nontoxic amounts of some organophosphates in sensitive patients with preexisting asthma (Bryant, 1985).
b) Bronchospasm may also be a pharmacologic effect of the muscarinic activity of organophosphates (Lund & Monteagudo, 1986).
c) CASE REPORT: A 26-year-old smoker without previous reactive airways disease developed bronchospasm, eye irritation, rhinorrhea, and mild depression of serum cholinesterase after exposure for 8 hours in a closed room that had been sprayed the day before with dichlorvos and xylene. He improved with steroids and bronchodilators but had persistent obstructive pulmonary disease on pulmonary function testing and recurrent bronchospasm with exercise for 1 year (Deschamps et al, 1994).

a) A respiratory rate greater than 30 breaths/minute was reported in 39% of patients with organophosphate poisoning in one study (Bardin et al, 1987).

a) Respiratory paralysis is the most serious consequence of the paralytic symptoms resulting from dichlorvos exposure. Cheyne-Stokes respiration can also result from the central nervous system effects of dichlorvos exposure (Brahmi et al, 2004; Hathaway et al, 1996) .
b) Acute respiratory insufficiency, due to any combination of depression of the respiratory center, respiratory paralysis, apnea, bronchospasm, ARDS, or increased bronchial secretions, is the main cause of death in many acute organophosphate poisonings (Kecik et al, 1993; Uzyurt et al, 1992; Sittig, 1991; Lerman & Gutman, 1988; Anon, 1984) .
c) Hypoventilation occurred in 20% of patients with organophosphate poisoning in one study (Bardin et al, 1987).

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

a) Dichlorvos overexposure may result in a panoply of nervous system effects, including headache, giddiness, confusion, slurred speech, ataxia, convulsions, loss of reflexes, loss of sphincter control, paralysis, and coma (Budavari, 1996; Hathaway et al, 1996; ITI, 1995).
b) From 2000 to 2013, 31 cases of acute illness caused by dichlorvos-impregnated resin strips (DDVP pest strips; available in the US as 16 g, 65 g, and 80 g sizes) were identified in the US (n=24) and Canada (n=7). Neurologic (eg, headache), respiratory (eg, dyspnea), and gastrointestinal (eg, nausea) effects were reported in 68%, 55%, and 42% of cases, respectively. Overall, low severity effects were observed in 26 (84%) patients. Five patients had moderate health effects, including asthma attack, respiratory distress requiring hospitalization, paresthesias, and incoordination. Twenty patients (65%) used DDVP pest strips for 4 hours or longer per day, which was much longer than recommended by the label (Tsai et al, 2014).

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

a) Seizures may be an early symptom after a significant exposure (Joy, 1982). Children may be more susceptible to seizures than adults.
b) CASE SERIES (PEDIATRIC): In one series, 8 of 37 (22%) children with organophosphate or carbamate poisoning had seizures (Zwiener & Ginsburg, 1988).
c) EEG changes similar to patterns present on interictal EEGs of temporal lobe epileptics have been described in cases of mild organophosphate poisoning (Brown, 1971).
d) CASE REPORT: A 19-year-old man who injected 1 ml (concentration 550 g/L) of dichlorvos into a cubital vein 2 hours prior to presentation developed nausea and abdominal pain approximately 1 hour after injection. The patient became unconscious, hypotensive, and tachycardic 2 hours after admission. He experienced 3 tonic-clonic seizures during the first 5 hours of admission. The patient developed decreased, unstable pseudocholinesterase levels and was treated with pralidoxime 500 mg/h until his pseudocholinesterase levels were 5279 IU (normal range 3714 to 11,513 IU), and the medication was discontinued. The patient was released after 2 days of stable plasma pseudocholinesterase levels, and upon follow-up, no abnormalities were reported (Buyukcam et al, 2011).

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

a) More than 50% of patients with organophosphate poisoning in one study had a disturbed level of consciousness: 5 of 61 patients were confused, 16 of 61 were confused and unable to sit or stand, and 16 of 61 were stuporous without reaction to speech (Bardin et al, 1987).
b) Acute or chronic exposure to organophosphates may impair concentration and induce confusion and drowsiness and may be a factor in plane crashes by agricultural pilots doing crop-dusting (Levin & Rodnitzky, 1976).

a) In severe poisoning, coma supervenes, followed rarely by generalized seizures (Brahmi et al, 2004; Grob & Garlick, 1950) . Deep tendon reflexes are weak or absent.

a) So-called Type II neurological effects involve paralysis appearing from 12 to 72 hours after exposure; this paralysis is unresponsive to atropine and may be due to persistent excess acetylcholine at nicotinic receptors (Wadia et al, 1987).
b) Type II paralysis occurred in 49% of patients with organophosphate poisoning (Wadia et al, 1987). Some believe that early aggressive gastric decontamination, followed by atropinization and high-dose pralidoxime therapy (1 gram every 4 to 6 hours or 500 mg/hour as a continuous infusion in severe cases) may reduce the incidence of the intermediate syndrome (Benson et al, 1992; Haddad, 1992) . Clinical trials will be necessary to confirm this hypothesis.
c) Paralytic signs include inability to lift the neck or sit up, ophthalmic muscle weakness, slow eye movement, facial weakness, difficulty swallowing, limb weakness (mainly proximal), areflexia, respiratory paralysis, and death (Wadia et al, 1987).
d) 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).
e) Paralysis of the diaphragm has occurred in rare cases (Rivett & Potgieter, 1987).
f) An intermediate syndrome was described in 10 patients from Sri Lanka who developed profound proximal muscle and cranial nerve weakness 1 to 4 days after exposure to fenothion, dimethoate, or monocrotophos (Senanayake & Karalliedde, 1987).

a) SUMMARY: Although most symptoms develop rapidly, subjective improvement may be observed followed by the delayed development of peripheral neuropathy. Delayed neurotoxicity seems to be a rare complication, but its incidence may be underestimated (Cherniack, 1988; Wadia et al, 1987) . Based on a literature review, delayed polyneuropathy has been observed in several individuals following intentional and inadvertent exposure to dichlorvos (Lotti & Moretto, 2005).
b) SYMPTOMS: Typically, delayed neurotoxicity appears 6 to 21 days after acute exposure by ingestion, inhalation, or the dermal route and involves progressive distal weakness and ataxia in the lower limbs. Flaccid paralysis, spasticity, ataxia, or quadriplegia may ensue (Cherniack, 1988). The mixed sensory-motor neuropathy usually begins in the legs, causing burning or tingling, then weakness (Johnson, 1975).
c) OUTCOMES: Severe cases progress to complete paralysis, impaired respiration, and death. The nerve damage of organophosphate-induced delayed neuropathy is often permanent. The mechanism seems to involve phosphorylation of esterases in peripheral nervous tissue and results in a 'dying-back' pattern of axonal degeneration (Johnson, 1975; Cavanagh, 1963). Recovery requires weeks to months, and may never be complete (Done, 1979).
d) Lotti et al (1983) found that monitoring levels of lymphocyte neurotoxic esterase in circulating lymphocytes aided in providing early warning for delayed neurotoxicity. They found decreases of 50% in this enzyme before changes in blood acetylcholinesterase, plasma butyrylcholinesterase, or clinical manifestations(Lotti et al, 1983).
e) CASE REPORT: A 45-year-old man drank approximately 30 mL of a commercial emulsion containing 55% dichlorvos. He was treated with atropine and pralidoxime, and ventilator support. He was weaned from the ventilator after 21 days. Thirty days after intoxication, he developed severe bilateral weakness of his lower extremities and moderate bilateral weakness of his forearms. On day 40 postingestion, electrophysiological studies revealed a symmetrical pure motor neuropathy. Symmetrical axonal polyneuropathy was detected in both arms and mixed polyneuropathy in both legs. At 6 months, there was a slight improvement in his motor neuropathy (Lee et al, 2006).

a) HORNER'S SYNDROME

a) CASE REPORTS: Extrapyramidal symptoms developed in 4 seriously poisoned patients after 5 to 15 days. They were characterized by dystonia of arms and legs, resting tremor, hyperreflexia, and cogwheel rigidity. The features of extrapyramidal syndrome disappeared progressively with bromocriptine therapy and all 4 patients recovered completely (Brahmi et al, 2004).

a) CASE REPORT: A patient who injected an insecticide containing dichlorvos into his neck developed acute dystonic torticollis (Moody & Terp, 1988).

a) CASE SERIES: A case-control study of 100 adult patients given neuropsychological testing at least 3 months after acute organophosphate poisoning reported subtle effects that could not be detected by clinical exam or EEG. Although patients had worse scores on neuropsychological tests than control subjects, they were still within the normal range (Savage et al, 1988).
b) A series of 16 organophosphate-poisoned individuals had abnormal single-photon-emission tomography scans, with parietal perfusion deficits. One case involved dichlorvos alone (Yilmazlar & Ozyurt, 1997).

a) Persons with other signs of organophosphate poisoning have shown reduced cognitive efficiency and slowness of thought related to the degree of cholinesterase inhibition (Levin & Rodnitzky, 1976).
b) Impaired memory is a major CNS effect of organophosphate exposure and may occur in the absence of other overt clinical signs; it has been found in workers chronically exposed to organophosphates (Levin & Rodnitzky, 1976).
c) Slowed speech, problems in finding words, slurring, intermittent pauses, and preservation have been seen in persons who have other clinical signs of organophosphate poisoning (Levin & Rodnitzky, 1976).
d) CASE SERIES : A case-control study of 100 adult patients administered neuropsychological testing at least 3 months after acute organophosphate poisoning reported subtle effects that could not be detected via clinical examination or EEG. Although cases had worse scores on neuropsychological tests than controls, they were still within the normal range (Savage et al, 1988).

a) Neurobehavioral and electrophysiological changes have been reported in adult rodents exposed to dichlorvos (Desi & Nagymajtenyi, 1999) Sabin & Gill, 1998 .

a) Nausea, vomiting, diarrhea, abdominal cramps, and salivation are common muscarinic signs of organophosphate poisoning. These symptoms may appear 15 minutes to 2 hours after ingestion of dichlorvos (Budavari, 1996; Hathaway et al, 1996) .
b) Vomiting and diarrhea occurred in 38% and 21% of patients with organophosphate poisoning, respectively, in one study (Bardin et al, 1987).
c) From 2000 to 2013, 31 cases of acute illness caused by dichlorvos-impregnated resin strips (DDVP pest strips; available in the US as 16 g, 65 g, and 80 g sizes) were identified in the US (n=24) and Canada (n=7). Neurologic (eg, headache), respiratory (eg, dyspnea), and gastrointestinal (eg, nausea) effects were reported in 68%, 55%, and 42% of cases, respectively. Overall, low severity effects were observed in 26 (84%) patients. Five patients had moderate health effects, including asthma attack, respiratory distress requiring hospitalization, paresthesias, and incoordination. Twenty patients (65%) used DDVP pest strips for 4 hours or longer per day, which was much longer than recommended by the label (Tsai et al, 2014).

a) Loss of sphincter control with involuntary defecation occurs with severe poisoning (ITI, 1995; Sittig, 1991).

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

a) A 19-year-old man who injected 1 ml (concentration 550 g/L) of dichlorvos into a cubital vein 2 hours prior to presentation developed nausea and abdominal pain approximately 1 hour after injection. The patient became unconscious, hypotensive, and tachycardic 2 hours after admission. He experienced 3 tonic-clonic seizures during the first 5 hours of admission. The patient developed decreased, unstable pseudocholinesterase levels and was treated with pralidoxime 500 mg/h until his pseudocholinesterase levels were 5279 IU (normal range 3714 to 11,513 IU), and the medication was discontinued. The patient was released after 2 days of stable plasma pseudocholinesterase levels, and upon follow-up, no abnormalities were reported (Buyukcam et al, 2011).

a) CASE SERIES (PEDIATRIC): Acute pancreatitis, as assessed by increased amylase and trypsin levels, was found in 5 of 17 consecutive children admitted for symptomatic organophosphate or carbamate poisoning. All had gastrointestinal symptoms, with severe abdominal pain in 2 children. The serum glucose levels were significantly increased compared with those of children without pancreatitis (Weizman & Sofer, 1992).

a) Loss of sphincter control with involuntary urination occurs with severe poisoning (ITI, 1995; Sittig, 1991). Increased urinary frequency may also occur (Done, 1979).

a) Metabolic acidosis has occurred in several cases of severe poisonings (Hui, 1983; Meller et al, 1981; Moore & James, 1981).
b) 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) Muscle weakness, fatigability and involuntary twitching (fasciculation) commonly occur (Hathaway et al, 1996; Kecik et al, 1993).
b) Fasciculations were present in 33 of 61 patients with organophosphate poisoning (54%) in one study (Bardin et al, 1987).

a) Muscle paralysis occasionally supervenes (Done, 1979). Paralysis of the respiratory muscles is the most serious consequence of the paralytic symptoms resulting from dichlorvos exposure (Hathaway et al, 1996).

a) Hyperglycemia and glycosuria (with or without ketosis) are present in severe poisoning (Kecik et al, 1993; Namba, 1972) .
b) Hyperglycemia has been reported in about 22% of children with organophosphate or carbamate poisoning; this may have been the result of acute pancreatitis (Weizman & Sofer, 1992)Zwiner & Ginsburg, 1988.

a) Hypoglycemia has been described in organophosphate poisoning (Hruban, 1963).
b) Cholinergic agents stimulate insulin secretion by the islets of Langerhans (Kajinuma et al, 1968).

a) Dichlorvos depletes glycogen stores by stimulating glycogen phosphorylase and inhibiting glycogen synthesis (HSDB , 2000).

a) MICE: Increased weight in the adrenal glands accompanied by depletion of epinephrine and norepinephrine was found in mice given high IP doses of dichlorvos. This effect was thought to be secondary to stimulation by the pituitary gland (Hayes & Laws, 1991).
b) RATS: Hyperglycemia and abnormal glucose tolerance tests have been produced in rats after exposure to dichlorvos(Hayes & Laws, 1991).

a) Dichlorvos may induce allergic contact dermatitis (ACGIH, 1991; Proctor et al, 1988).

a) Dermal sensitization to some organophosphates has been reported after skin exposure (Milby et al, 1964).
b) Some organophosphates can cause dermal sensitization, but most have not been adequately evaluated for this activity (Coye, 1984).

a) Dichlorvos does not appear in the milk of cattle or rats, even at doses high enough to produce severe poisoning (Hayes & Laws, 1991).

a) Listed as: Dichlorvos
b) Carcinogen Rating: 2B

a) CONCLUSIONS - In the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity for dichlorvos in male F344/N rats, as shown by increased incidences of adenomas of the exocrine pancreas and mononuclear cell leukemia. There was equivocal evidence of carcinogenic activity for dichlorvos in female F344/N rats, as shown by increased incidences of adenomas of the exocrine pancreas and mammary gland fibroadenomas.
b) There was some evidence of carcinogenic activity for dichlorvos in male B6C3F1 mice, as shown by increased incidence of forestomach squamous cell papillomas. There was clear evidence of carcinogenic activity for dichlorvos in female B6C3F1 mice, as shown by increased incidence of forestomach squamous papillomas.

a) Plasma cholinesterase seems to be a more sensitive index of exposure, and erythrocyte acetylcholinesterase activity may be better correlated with clinical effects (Muller & Hundt, 1980). Usually this biochemical manifestation of toxicity appears at lower dosage levels than the amounts producing symptoms or signs.
b) Symptomatic patients usually show depression of blood cholinesterase activities in excess of 50% of the pre-exposure value (Milby, 1971).
c) Depression in excess of 90% may occur in severe poisonings (Klemmer et al, 1978).
d) A 45-year-old man developed opioid-induced delayed polyneuropathy 30 days after drinking approximately 30 mL of a commercial emulsion containing 55% dichlorvos. Serum cholinesterase obtained after ingestion was 47 IU/L (normal 4250 to 7250) (Lee et al, 2006).
e) However, moderate-to-severe organophosphate poisoning has been diagnosed in patients with "normal" red blood acetylcholinesterase activity (Hodgson & Parkinson, 1985; Midtling et al, 1985; Coye et al, 1987). In these patients, acetylcholinesterase decreased by as much as 50%, but was still within normal range.
f) Therefore, the correlation between plasma cholinesterase levels and onset or extent of clinical effects may be poor, especially if the enzyme assays are done in different laboratories. Comparison with pre-exposure values may be helpful.

a) IATROGENIC CAUSES - of reduced acetylcholinesterase activity may be X-ray therapy, cancer chemotherapy, monoamine oxidase inhibitors, oral contraceptives, quinine, ecothiophate iodide, propanidid, neostigmine, chlorpromazine, pancuronium and carbamates (Brown SS, 1989; Wills, 1972; HEW, 1976).
b) Plasma pseudocholinesterase activity may be lowered by such chemicals as morphine, codeine, thiamine, ether and chloroquine (Wills, 1972).
c) Disease states associated with decreased levels of plasma cholinesterase include parenchymal liver disease, malnutrition (particularly with deficiencies of protein or thiamine), acute infection, some anemias, acute myocardial infarction and chronic debilitating conditions (Hayes & Laws, 1991).
d) PREDISPOSING CONDITIONS - Several clinical conditions can result in lower than normal levels of acetylcholinesterase and would presumably cause an individual to be more sensitive than a normal person to organophosphates. These predisposing conditions include the following (Brown SS, 1989; Wills, 1972; HEW, 1976).
e) Increased erythrocyte levels of acetylcholinesterase may be seen with reticulocytosis due to hemorrhage or the treatment of megaloblastic or pernicious anemias; increased plasma levels are associated with nephrotic syndrome (Hayes & Laws, 1991).

a) PRALIDOXIME - Reverses depressions of blood cholinesterase activities. Without the use of pralidoxime, plasma cholinesterase rose an average of 15.6% over 14 days in one group of organophosphate-exposed workers. The authors suggest that obtaining serial levels rather than one initial level may be valuable in diagnosing organophosphate toxicity (Coye et al, 1986).
b) Plasma cholinesterase usually recovers in a few days or weeks; red blood cell acetylcholinesterase recovers in several days to 4 months depending on the severity of the decrease.

a) Institute continuous cardiac monitoring and follow ECG in symptomatic patients.
b) OCCUPATIONAL EXPOSURE MONITORING - One recommended monitoring scheme for persons chronically exposed to organophosphates involves measurement of both plasma cholinesterase and red blood cell acetylcholinesterase before exposure and every 3 months during exposure (Muller & Hundt, 1980).
c) Persons with erythrocyte cholinesterase levels 40% or less of their pre-exposure baseline values should be removed from exposure until their enzyme levels have returned to within 30% of the pre-exposure baseline (Proctor et al, 1988).
d) It is advised that persons chronically exposed to organophosphates undergo periodic evaluation for subclinical central and peripheral nervous system effects. EEG and EKG monitoring and tests of neuromuscular function may be more sensitive than cholinesterase assays to detect overexposures, but these have not been rigorously documented in occupational studies.

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

a) Staining activity for nonspecific esterase in monocytes was inhibited in workers exposed to triaryl phosphates at subclinical doses. The relationship of this finding to adverse clinical outcome, in particular to organophosphate-induced delayed neuropathy or possible immunologic suppression, is unknown but is being investigated further (Mandel et al, 1989).

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).

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 auto-injectors because it has been found to be a more effective reactivator of acetylcholinesterase inhibited by nerve agents compared with pralidoxime and obidoxime (Roberts & Aaron, 2007)

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, 2009; 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).

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).

a) Dichlorvos is generally undetectable in the serum or blood because of its rapid metabolism (Hayes & Laws, 1991).

1) Dichlorvos (DDVP)

a) TWA: 1 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: [skin]
f) Note(s):

a) IDLH: 100 mg/m3
b) Note(s): Not Listed

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

a) B2 : Probable human carcinogen - based on sufficient evidence of carcinogenicity in animals.

a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

a) 8-hour TWA:

a) 22 mg/kg -- true cholinesterase

a) 61 mg/kg (Lewis, 2000)
b) 135 mg/kg (OHM/TADS, 2002)
c) 133-139 mg/kg (Bingham et al, 2001)
d) 140-275 mg/kg (Verschueren, 2000)

a) 206 mg/kg (Lewis, 2000)

a) 24 mg/kg -- convulsions/effect on seizure threshold; effects on sense organs; dyspnea

a) 15 mg/kg -- degenerative changes to brain and coverings; effects on blood; true cholinesterase
b) 23,300 mcg/kg (Lewis, 2000)

a) female, 56 mg/kg (Budavari, 2000)
b) 17 mg/kg (Lewis, 2000)
c) 25-80 mg/kg (Verschueren, 2000)
d) 56-80 mg/kg (HSDB, 2002)
e) >70 mg/kg for 90 days (Bingham et al, 2001)
f) 56-98 mg/kg (Bingham et al, 2001)
g) Male, 80 mg/kg (Bingham et al, 2001; Budavari, 2000)
h) Female, 55 mg/kg (HSDB, 2002)
i) Female, 56 mg/kg (Bingham et al, 2001)

a) 750 mcg/kg
b) 75 mg/kg (OHM/TADS, 2002)
c) 70,400 mcg/kg (Lewis, 2000)
d) Male, 107 mg/kg (HSDB, 2002)
e) Female, 75 mg/kg (HSDB, 2002)

a) 10,800 mcg/kg (Lewis, 2000)
b) 12 mg/kg (OHM/TADS, 2002)

a) In cattle, this effect may last 1 to 2 hours. A steer may weigh over 1000 pounds and a herd of affected cattle may number in the hundreds. Call the nearest school of veterinary medicine to locate the large stockpiles of atropine necessary to respond to such a veterinary emergency.