ORGANOPHOSPHATE (OP) POISININGDr. Aidah Abu Elsoud Alkaissi

Link;ping University/Sweden

An/Najah National University-Palestine

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ORGANOPHOSPHATE (OP) POISINING Initial treatment goal should consist of optimizing

oxygenation and controlling excessive airway secretions. Tachycardia is neither a contraindication nor an endpoint for

atropine administration. Patients exposed to organophosphate (OP) should be

observed for at least 12 hours in a high acuity setting.

Because of the risk of respiratory depression or recurrent symptoms after resolution of an acute cholinergic crisis, hospitalizing all symptomatic patients for at least 48 hours following resolution of symptoms is recommended.

The symptoms of OP poisoning can mimic other toxicities and disease processes. The clinician must keep in mind that misdiagnosis is a potential medicolegal pitfall.

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ORGANOPHOSPHATE (OP) POISINING

Organophosphate (OP) compounds are a diverse group of chemicals used in both domestic and industrial settings.

Examples of organophosphates include insecticides (malathion, parathion, diazinon, fenthion,

dichlorvos, chlorpyrifos, ethion), nerve gases (soman, sarin, tabun, VX), ophthalmic agents (echothiophate, isoflurophate), and antihelmintics rugs used to kill parasitic worms

(trichlorfon). Herbicides (tribufos [DEF], merphos) are tricresyl

phosphate–containing industrial chemicals. 3

anticholinesterase Any substance that inhibits the enzyme cholinesterase, which is responsible for the breakdown of the neurotransmitter acetylcholine at nerve synapses. Anticholinesterases, which include certain drugs, nerve gases, and insecticides, cause a build-up of acetylcholine within the synapses, leading to disruption of nerve and muscle function. In vertebrates, these agents often cause death by paralysing the respiratory muscles.

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cholinesterase (acetylcholinesterase) An enzyme that hydrolyses the neurotransmitter acetylcholine to choline and acetate. Cholinesterase is secreted by nerve cells at synapses and by muscle cells at neuromuscular junctions. Organophosphorus insecticides (pesticide) act as anticholinesterases by inhibiting the action of cholinesterase.

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Acetylcholine (ACh) One of the main neurotransmitters of the vertebrate nervous system. It is released at certain (cholinergic) nerve endings and may be excitatory or inhibitory; it initiates muscular contraction at neuromuscular junctions. Acetylcholine receptors (cholinoceptors) fall into two main classes: muscarinic and nicotinic receptors. Once acetylcholine has been released it has only a transitory effect because it is rapidly broken down by the enzyme cholinesterase.

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PATHOPHYSIOLOGY

The primary mechanism of action of organophosphate pesticides is inhibition of carboxyl ester hydrolases, particularly acetylcholinesterase (AChE).

AChE is an enzyme that degrades the neurotransmitter acetylcholine (ACh) into choline and acetic acid.

ACh is found in the central and peripheral nervous system, neuromuscular junctions, and red blood cells (RBCs).

Organophosphates inactivate AChE by phosphorylating the serine hydroxyl group located at the active site of AChE.

The phosphorylation occurs by loss of an organophosphate leaving group and establishment of a covalent bond تساهمية .with AChE رابطة

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PATHOPHYSIOLOGY

Once AChE has been inactivated, ACh accumulates throughout the nervous system, resulting in overstimulation of muscarinic and nicotinic receptors.

Clinical effects are manifested via activation of the autonomic and central nervous systems and at nicotinic receptors on skeletal muscle.

Once an organophosphate binds to AChE, the enzyme can undergo one of the following:

Endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases

Reactivation by a strong nucleophile such as pralidoxime (2-PAM)

Irreversible binding and permanent enzyme inactivation (aging) 8

PATHOPHYSIOLOGY

Organophosphates can be absorbed cutaneously, ingested, inhaled, or injected.

Although most patients rapidly become symptomatic, the onset and severity of symptoms depend on the specific compound, amount, route of exposure, and rate of metabolic degradation.

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MORTALITY/MORBIDITY

Worldwide mortality studies report mortality rates from 3-25%.

The compounds most frequently involved include malathion, dichlorvos, trichlorfon, and fenitrothion/malathion.

Mortality rates depend on the type of compound used, amount ingested, general health of the patient, delay in discovery and transport, insufficient respiratory management, delay in intubation, and failure in weaning off ventilatory support.

Complications include severe bronchorrhea, seizures, weakness, and neuropathy.

Respiratory failure is the most common cause of death.

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SIGNS AND SYMPTOMS OF ORGANOPHOSPHATE POISONING

Can be divided into 3 broad categories, including:

(1) muscarinic effects, (2) nicotinic effects, and (3) CNS effects.

Mnemonic devices used to remember the muscarinic effects of organophosphates are SLUDGE (salivation, lacrimation, urination, diarrhea, GI upset, emesis) and DUMBELS (diaphoresis and diarrhea; urination; miosis; bradycardia, bronchospasm, emesis; excess lacrimation; and salivation).

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SIGNS AND SYMPTOMS OF ORGANOPHOSPHATE POISONING Muscarinic effects by organ systems include the

following:

Cardiovascular - Bradycardia, hypotension Respiratory - Rhinorrhea, bronchorrhea,

bronchospasm, cough, severe respiratory distress Gastrointestinal - Hypersalivation, nausea and

vomiting, abdominal pain, diarrhea, fecal incontinence

Genitourinary - Incontinence Ocular - Blurred vision, miosis Glands - Increased lacrimation, diaphoresis

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SIGNS AND SYMPTOMS OF ORGANOPHOSPHATE POISONING

Nicotinic signs and symptoms include muscle fasciculations, cramping, weakness, and diaphragmatic failure.

Autonomic nicotinic effects include hypertension, tachycardia, mydriasis, and pallor.

CNS effects include anxiety, emotional lability, restlessness, confusion, ataxia, tremors, seizures, and coma.

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PHYSICAL

Note that clinical presentation may vary, depending on the specific agent, exposure route, and amount.

Symptoms are due to both muscarinic and nicotinic effects.

Vital signs: Depressed respirations, bradycardia, and hypotension are possible symptoms.

Alternatively, tachypnea, hypertension, and tachycardia are possible.

Hypoxia should be monitored for with continuous pulse oximetry.

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PHYSICAL Paralysis Type I: This condition is described as acute paralysis secondary

to continued depolarization at the neuromuscular junction.

Type II (intermediate syndrome): Intermediate syndrome was described in 1974 and is reported to develop 24-96 hours after resolution of acute organophosphate poisoning symptoms and manifests commonly as paralysis and respiratory distress.

This syndrome involves weakness of proximal muscle groups, neck, and trunk, with relative sparing of distal muscle groups.

Cranial nerve palsies can also be observed.

Intermediate syndrome persists for 4-18 days, may require mechanical ventilation, and may be complicated by infections or cardiac arrhythmias.

Although neuromuscular transmission defect and toxin-induced muscular instability were once thought to play a role, this syndrome may be due to suboptimal treatment. 15

PHYSICAL

Type III: Organophosphate-induced delayed polyneuropathy (OPIDP) occurs 2-3 weeks after exposure to large doses of certain organophosphates (OPs) and is due to inhibition of neuropathy target esterase.

Distal muscle weakness with relative sparing of the neck muscles, cranial nerves, and proximal muscle groups characterizes OPIDP.

Recovery can take up to 12 months.16

PHYSICAL Neuropsychiatric effects: Impaired memory, confusion,

irritability, lethargy, psychosis, and chronic organophosphate-induced neuropsychiatric disorders have been reported. The mechanism is not proven.

Extrapyramidal effects: These are characterized by dystonia, cogwheel rigidity, and parkinsonian features (basal ganglia impairment after recovery from acute toxicity).

Other neurological and/or psychological effects: Guillain-Barré–like syndrome and isolated bilateral recurrent laryngeal nerve palsy are possible.

Ophthalmic effects: Optic neuropathy, retinal degeneration, defective vertical smooth pursuit, myopia, and miosis (due to direct ocular exposure to organophosphates) are possible.Ears: Ototoxicity is possible.

Respiratory effects: Muscarinic, nicotinic, and central effects contribute to respiratory distress in acute and delayed organophosphate toxicity

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PHYSICAL Muscarinic effects: Bronchorrhea, bronchospasm, and laryngeal

spasm, for instance, can lead to airway compromise.

Respiratory failure is the most life-threatening effect and requires immediate intervention.

Nicotinic effects: These effects lead to weakness and paralysis of respiratory oropharyngeal muscles.Central effects: These effects can lead to respiratory paralysis.Rhythm abnormalities: Sinus tachycardia, sinus bradycardia, extrasystoles, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation (often a result of, or complicated by, severe hypoxia from respiratory distress) are possible.

Other cardiovascular effects: Hypotension, hypertension, and noncardiogenic pulmonary edema are possible.

GI manifestations: Nausea, vomiting, diarrhea, and abdominal pain may be some of the first symptoms to occur after organophosphate exposure.

Genitourinary and/or endocrine effects: Urinary incontinence, hypoglycemia, or hyperglycemia is possible.

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TREATMENTMEDICAL CARE

Airway control and adequate oxygenation are paramount in organophosphate (OP) poisonings.

Intubation may be necessary in cases of respiratory distress due to laryngospasm, bronchospasm, bronchorrhea, or seizures.

Immediate aggressive use of atropine may eliminate the need for intubation.

Succinylcholine should be avoided because it is degraded by acetylcholinesterase (AChE) and may result in prolonged paralysis.

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TREATMENT/ MEDICAL CARE Continuous cardiac monitoring and pulse oximetry should be

established; an ECG should be performed.

Torsades de Pointes should be treated in the standard manner.

The use of intravenous magnesium sulfate has been reported as beneficial for organophosphate toxicity.

The mechanism of action may involve acetylcholine antagonism or ventricular membrane stabilization.

Remove all clothing and gently cleanse patients suspected of organophosphate exposure with soap and water because organophosphates are hydrolyzed readily in aqueous solutions with a high pH.

Consider clothing as hazardous waste and discard accordingly.

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TREATMENTMEDICAL CARE

Health care providers must avoid contaminating themselves while handling patients.

Use personal protective equipment, such as neoprene gloves and gowns, when decontaminating patients because hydrocarbons can penetrate nonpolar substances such as latex and vinyl.

Use charcoal cartridge masks for respiratory protection when decontaminating patients who are significantly contaminated.

Irrigate the eyes of patients who have had ocular exposure using isotonic sodium chloride solution or lactated Ringer's solution. Morgan lenses can be used for eye irrigation.

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SURGICAL CARE

Patients with trauma or blast injury should be treated according to standard advanced trauma life support (ATLS) protocol. Patient decontamination should always be considered to prevent medical personnel poisoning

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MEDICATION

The mainstays of medical therapy in organophosphate (OP) poisoning include atropine, pralidoxime (2-PAM), and benzodiazepines (eg, diazepam).

A novel route of administration of intraosseous (bone injection gun, BIG) midazolam demonstrated rapid peak concentrations in swine compared with intravenous and intramuscular routes; the authors concluded this may play a role in quickly terminating seizures, especially in the prehospital arena.

Initial management must focus on adequate use of atropine. Optimizing oxygenation prior to the use of atropine is recommended to minimize the potential for dysrhythmias.

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MEDICATION

de Silva et al studied the treatment of organophosphate poisoning with atropine and 2-PAM (2-PAM2-Pralidoxime (enzyme that reverses cholinesterase inhibition) and, later the same year, with atropine alone.

They found that atropine seemed to be as effective as atropine plus 2-PAM in the treatment of acute organophosphate poisoning.

The controversy continued when other authors observed more respiratory complications and higher mortality rates with use of high-dose 2-PAM.

Low-dose (1-2 g slow IV) 2-PAM is the current recommendation. Studies are underway to assess the role of low-dose 2-PAM. Improved survival has been shown in moderately severe OP poisoned patients who received early, continuous 2-PAM infusion compared with those who received intermittent boluses. 24

MEDICATION

A meta-analysis and review of the literature performed by Peter et al emphasized optimal supportive care along with discriminate use of 2-PAM, especially early in the course of treatment of moderately to severely OP poisoned patients, are the hallmarks of treatment. More prospective data are required.

Because large amounts of atropine may be required for patients with organophosphate poisoning, reconstitution of powdered atropine is a viable option, especially in mass-casualty settings.

Recently, Rajpal et al demonstrated the clinical safety and efficacy of sublingual atropine to healthy volunteers.

This may offer another route of administration for the OP poisoned patient, especially in a mass-casualty scenario.

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MEDICATION

Intravenous glycopyrrolate or diphenhydramine may provide an alternative centrally acting anticholinergic agent used to treat muscarinic toxicity if atropine is unavailable or in limited supply.

Additionally, Yavuz et al demonstrated reduced myocardial injury and troponin leak in fenthion-poisoned rats treated with diphenhydramine.

In a single-center, randomized, single-blind study by Pajoumand et al found a benefit to magnesium therapy in addition to standard oxime and atropine therapy in reducing hospitalization days and mortality rate in patients with organophosphate poisoning.

The mechanisms appear to be inhibition of acetylcholine (ACh) and organophosphate antagonism.

Larger randomized studies are needed to demonstrate magnesium efficacy in organophosphate (OP) poisoning. 26

MEDICATION

Possible future interventions include neuroprotective agents used to prevent nerve damage and bioscavengers aimed to prevent AChE inhibition by nerve agents or organophosphate.

Investigations into adjunctive and alternative therapies have mostly used animal models and have resulted in variable conclusions.

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MEDICATION

Anticholinergic agents These agents act as competitive antagonists

at the muscarinic cholinergic receptors in both the central and the peripheral nervous system.

These agents do not affect nicotinic effects.

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ATROPINE (ISOPTO, ATROPAIR)

Initiated in patients with OP toxicity who present with muscarinic symptoms.

Competitive inhibitor at autonomic postganglionic cholinergic receptors, including receptors found in GI and pulmonary smooth muscle, exocrine glands, heart, and eye.

The endpoint for atropinization is dried pulmonary secretions and adequate oxygenation.

Tachycardia and mydriasis must not be used to limit or to stop subsequent doses of atropine. The main concern with OP toxicity is respiratory failure from excessive airway secretions. 29

ATROPINE (ISOPTO, ATROPAIR)

Adult 1-2 mg IV bolus, repeat q1-5min prn for desire effects

(drying of pulmonary secretions and adequate oxygenation)Strongly consider doubling each subsequent dose for rapid control of patients in severe respiratory distressAn atropine drip titrated to above endpoints can be initiated until patient's condition stabilized

Pediatric 0.05 mg/kg IV, repeat q1-5min prn for control of airway

secretionsStrongly consider doubling each subsequent dose to rapidly stabilize patients with severe respiratory distress

Dosing Interactions Contraindications

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ATROPINE (ISOPTO, ATROPAIR)

Precautions Coadministration with other anticholinergics has additive effects Dosing Interactions Contraindications

Precautions Documented hypersensitivity; narrow-angle glaucoma Dosing Interactions Contraindications

Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in

humans; may use if benefits outweigh risk to fetus

Precautions Care should be taken in coronary heart disease, tachycardia, CHF, cardiac

arrhythmias, and hypertension; bladder catheterization may be required because of urinary retention

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GLYCOPYRROLATE (ROBINUL)

Indicated for use as an antimuscarinic agent to reduce salivary, tracheobronchial, and pharyngeal secretions.

Does not cross the blood-brain barrier. Can be considered in patients at risk for recurrent symptoms (after initial atropinization) but who are developing central anticholinergic delirium or agitation.

Since glycopyrrolate does not cross BBB, it is not expected to control central cholinergic toxicity. Bird et al suggested that atropine (rather than glycopyrrolate) was associated with lower, early OP-induced mortality

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GLYCOPYRROLATE (ROBINUL)

Adult 1-2 mg/kg IV prn to control peripheral

cholinergic effects (eg, bronchorrhea)

Pediatric 0.025 mg/kg IV prn to control peripheral

cholinergic effects (eg, bronchorrhea)

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GLYCOPYRROLATE (ROBINUL)

Antidotes, OP poisoning These agents prevent aging of AChE and

reverse muscle paralysis with OP poisoning.

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PRALIDOXIME (2-PAM, PROTOPAM)

Pralidoxime (2-PAM, Protopam) Nucleophilic agent that reactivates the phosphorylated

AChE by binding to the OP molecule. Used as an antidote to reverse muscle paralysis resulting from OP AChE pesticide poisoning but is not effective once the OP compound has bound AChE irreversibly (aged).

Current recommendation is administration within 48 h of OP poisoning. Because it does not significantly relieve depression of respiratory center or decrease muscarinic effects of AChE poisoning, administer atropine concomitantly to block these effects of OP poisoning.

Signs of atropinization might occur earlier with addition of 2-PAM to treatment regimen. 2-PAM administration is not indicated for carbamate exposure since no aging occurs.

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PRALIDOXIME (2-PAM, PROTOPAM)

Adult 1-2 g (20-40 mg/kg) IV in 100 mL isotonic

sodium chloride soln/D5W over 15-30 min; repeat in 1 h if muscle weakness is not relieved; then repeat q3-8h if signs of poisoning recurOther dosing regimens have been used, including continuous drip; start with bolus of 25-50 mg/kg and then 10-20 mg/kg/hConsultation with regional poison center is recommended for more specific case-based dosing recommendations 36

PRALIDOXIME (2-PAM, PROTOPAM)

Pediatric 20-40 mg/kg in 100 mL isotonic sodium

chloride soln/D5W IV over 15-30 min; repeat in 1-2 h if muscle weakness not relieved; repeat q10-12h prn to relieve cholinergic symptomsOther dosing regimens have been used, including continuous drip; start with bolus of 25-50 mg/kg (up to 2 g); then 10-20 mg/kg/h (up to 500mg)IO/IM/SC can be used if IV not feasible; can be used with atropine 37

BENZODIAZEPINES

These agents potentiate effects of gamma-aminobutyrate (GABA) and facilitate inhibitory GABA neurotransmission.

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BENZODIAZEPINES

Diazepam (Valium, Diastat, Diazemuls) For treatment of seizures. Depresses all

levels of CNS (eg, limbic and reticular formation) by increasing activity of GABA.

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BENZODIAZEPINES

Adult 5-15 mg IV q5-10 min prn, repeat prn;

consider higher doses if needed Pediatric 0.05-0.3 mg/kg/dose IV q5-10 min prn

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FOLLOW-UPFURTHER INPATIENT CARE

Because of risks of respiratory compromise or recurrent symptoms, hospitalizing all symptomatic patients for at least 24 hours in a high acuity setting is recommended. Patients who are asymptomatic 12 hours after organophosphate exposure can be discharged since symptom onset should usually occur within this time frame.

Optimal recommendations are made on a case-by-case scenario. Consider discussing each case with a medical toxicologist or the regional poison center.

Following occupational exposure, patients should not be allowed to return to work with organophosphates until serum cholinesterase activity returns to 75% of the known baseline level. Also, establishing base line cholinesterase levels for workers with known organophosphate (OP) exposure is recommended.

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DETERRENCE/PREVENTION

Health care providers must avoid contaminating themselves while handling patients poisoned by organophosphates. The potential for cross-contamination is highest in treating patients after massive dermal exposure. Use personal protective equipment, such as

neoprene or nitrile gloves and gowns, when decontaminating patients because hydrocarbons can penetrate nonpolar substances such as latex and vinyl.

Use charcoal cartridge masks for respiratory protection when caring for patients with significant contamination.

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COMPLICATIONS

Complications include respiratory failure, seizures, aspiration pneumonia, delayed neuropathy, and death.

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MEDICOLEGAL PITFALLS

Initial treatment goal should consist of optimizing oxygenation and controlling excessive airway secretions.

Tachycardia is neither a contraindication nor an endpoint for atropine administration.

Patients exposed to organophosphate (OP) should be observed for at least 12 hours in a high acuity setting. Toxicity after this is unlikely.

Because of the risk of respiratory depression or recurrent symptoms after resolution of an acute cholinergic crisis, hospitalizing all symptomatic patients for at least 48 hours following resolution of symptoms is recommended.

The symptoms of OP poisoning can mimic other toxicities and disease processes. The clinician must keep in mind that misdiagnosis is a potential medicolegal pitfall. 44