Anticholinesterase Intoxication

Chapter 92 Anticholinesterase Intoxication



Jamie M. Burkitt, DVM, DACVECC



KEY POINTS



• Organophosphate and carbamate insecticides are in common industrial and household use.

• Acute toxicity is due to inhibition of acetylcholinesterase at cholinergic synapses throughout the body.

• Supportive care is extremely important for recovery.

• The cornerstone of antidotal therapy for acute toxicity is atropine.

• Intermediate syndrome is a manifestation of acute organophosphate toxicity in which proximal limb, neck, and respiratory muscle weakness predominates.

• Organophosphate-induced delayed neuropathy occurs 1 to 4 weeks after a single organophosphate exposure or after long-term, low-dose organophosphate exposure in which pelvic limb weakness predominates.

• With appropriate management, prognosis is fair to good in all syndromes.


INTRODUCTION


Organophosphate and carbamate compounds are used commonly as industrial and household insecticides, and are also used in some deworming products and medications. Intoxication with these compounds is common in veterinary patients. As pesticides, they are widely available in powder, granular, or aerosol forms. Exposure may occur by ingestion, inhalation, or dermal contact. The lethal doses (LD50) vary widely by compound.



MECHANISM OF ACTION


Organophosphate and carbamate compounds inhibit the enzyme acetylcholinesterase (AchE) at the synaptic cleft; organophosphates bind AchE much more strongly than do carbamates. AchE is responsible for hydrolysis of acetylcholine (Ach) in cholinergic synapses of the autonomic nervous system, neuromuscular junction, and central nervous system (CNS). When an organophosphate or a carbamate inhibits AchE, excessive Ach accumulates in the synapse, leading to overstimulation of the postsynaptic neuron or muscle. This overstimulation is the cause of the classic symptoms of acute organophosphate or carbamate toxicity, listed in the next section. Within 12 to 24 hours of exposure, organophosphate compounds (but not carbamates) can become permanently bound to AchE, a process called aging. Organophosphates have been associated with two other distinct syndromes, intermediate syndrome and organophosphate-induced delayedneuropathy. Exactly how neuropathy. Exactly how the organophosphate toxin contributes to the development of these two syndromes is unclear, but it does not appear to be directly related to AchE inhibition.



ACUTE ORGANOPHOSPHATE AND CARBAMATE TOXICITY


Acute organophosphate or carbamate toxicity generally occurs within 0.5 to 6 hours after ingestion or inhalation of a product; dermal absorption time can vary, but clinical signs may be present within a few hours.



Clinical Signs


Classic clinical signs of acute toxicity are broken down into three basic categories:


1 Muscarinic signs: Diarrhea, urination, miosis, bronchospasm, emesis, lacrimation, and salivation (DUMBELS1). Bronchospasm and bronchorrhea (excessive bronchial secretions) can lead to severe dyspnea and hypoxemia. Bradycardia is common.

2 Nicotinic signs: Muscle tremors, twitching, and eventually weakness to paralysis occur.

3 CNS signs: Seizures, convulsions, and obtundation to coma occur.

Not all signs are present in all patients. Patients may be tachycardic if Ach effects at sympathetic ganglia predominate. Ventricular arrhythmia was associated with organophosphate toxicity in one cat.2



Diagnosis


A diagnosis of acute organophosphate or carbamate intoxication is made using patient history, clinical signs, and toxicologic data. Known or suspected organophosphate or carbamate exposure by ingestion, topical application, or inhalation should raise the clinician’s index of suspicion. A test dose of atropine can help distinguish muscarinic signs due to acute organophosphate or carbamate toxicity from similar signs caused by other diseases. The patient with anticholinesterase toxicity should not respond to a single test dose of atropine (0.02 mg/kg IV); if muscarinic signs resolve with this dose, the diagnosis is not likely to be organophosphate or carbamate toxicity.3,4


Clinicopathologic data are nonspecific, but azotemia, hematuria, leukocytosis, elevated creatinine kinase levels, hypokalemia, and hyperglycemia are common.5 Toxicologic evaluation may be performed on blood, gastric contents, urine, or source material to determine the involved toxin. Also, whole blood should be submitted to determine blood cholinesterase levels. Contact a veterinary toxicology laboratory to confirm ideal sample handling procedures. Blood likely needs to be heparinized and transported on ice. Normal blood cholinesterase levels vary significantly by species, so samples should be sent to a laboratory familiar with various reference ranges. Cholinesterase activity less than 50% of normal is suspicious for intoxication, and activity less than 25% of normal is confirmatory.3,6,7



Treatment



Decontamination


Decontamination strategies should be employed in patients with acute organophosphate or carbamate intoxication, and in patients known to have ingested a toxin even if they are not yet showing signs. Emesis should never be induced in patients with an altered state of consciousness, or in those for whom aspiration is a significant risk. Activated charcoal is useful for organophosphates and carbamates. All patients with the potential for topical exposure should be bathed with soap and water as soon as possible, and dried completely to prevent hypothermia (see Chapter 77, Approach to Poisoning and Drug Overdose).



Supportive Care


Supportive treatment of the intoxicated patient is imperative. Patients with organophosphate or carbamate toxicity can be dehydrated or hypovolemic from diarrhea, excessive salivation, and sustained muscle activity. Intravenous fluid support should be provided as patient perfusion and hydration parameters dictate. Electrolyte concentrations and acid-base status should be evaluated and corrected as needed. Seizures should be treated with diazepam (0.5 to 1 mg/kg IV to effect) or barbiturates. Excessive bronchial secretions and aspiration of saliva can lead to severe lower airway obstruction and subsequent hypoxemia. Hypoxemic patients should be treated with supplemental oxygen; tracheal intubation and positive-pressure ventilation may be required if oxygen supplementation alone is inadequate. Weakness can be so severe as to cause compromised respiratory muscle function, and patients with severe hypoventilation or apnea require tracheal intubation and positive-pressure ventilation.



Traditional Antidotes


Atropine is the mainstay of antidotal treatment for organophosphate or carbamate toxicity. Treat muscarinic signs such as bradycardia or excessive bronchial secretions with an initial dose of atropine at 0.1 to 2 mg/kg (¼ IV, remainder SC).3,8-10 Repeat 0.1 to 0.25 mg/kg IV q20-30min until clinical signs of atropinization occur: mydriasis, flushed skin, dry mouth, and mild sinus tachycardia (if the patient already is tachycardic, it cannot be used as an end point of atropinization). The total atropine dosage required to achieve these goals varies by the severity of intoxication. In humans, atropinization is maintained either with repeated administration as above, or with a constant rate infusion (CRI) at 0.02 to 0.08 mg/kg/hr.4 Patients should be monitored closely with continuous electrocardiograms and frequent blood pressure measurements, and atropine should be used cautiously in patients with ventricular arrhythmias because of the potential for ventricular fibrillation.


Pralidoxime (2-pyridine aldoxime methiodide [2-PAM]) is an antidote for the nicotinic signs of acute, moderate to severe anticholinesterase toxicity. It has little effect on muscarinic or CNS signs. Therefore atropine must be used to treat muscarinic signs, and diazepam is indicated for seizures (see Supportive Care in previous section). The efficacy of 2-PAM is debated in human clinical literature, and the drug may be less effective without concurrent atropinization. 2-PAM reactivates AchE by binding AchE and inducing a shape change, thereby dislodging the toxin so that it may be hydrolyzed and excreted more rapidly. It may also bind free organophosphate toxin and exert some anticholinergic effects.4 Because 2-PAM has some anticholinesterase activity, it can worsen signs in less severely intoxicated animals, and its use in mildly affected patients is not recommended. The dose is 10 to 20 mg/kg SC or IV as a slow infusion q12h.9,10 Refer to the package insert for other information.


2-PAM use in carbamate toxicity is controversial, because carbamates bind less avidly to AchE than do organophosphates, and are therefore more likely to be hydrolyzed and excreted without the aid of an antidote. Because pralidoxime has some anticholinesterase activity, it could theoretically antagonize AchE more severely than the carbamate itself. Experimentally, 2-PAM has been beneficial in severe, acute carbamate toxicity.11 The important exception is intoxication with the carbamate carbaryl, in which case 2-PAM consistently worsens subjects’ signs and is therefore contraindicated.1,11,12


2-PAM can be detrimental in cases of subacute to chronic organophosphate toxicity, because organophosphate molecules become permanently bound to AchE as they age. Once the toxin-AchE complex has aged, 2-PAM cannot dislodge the toxin; 2-PAM’s anticholinesterase properties may then predominate, exacerbating signs of toxicity. Aging occurs at different rates for different organophosphate molecules; in general, aging occurs more rapidly in O-O-dimethyl organophosphates (significant aging within 12 hours) than it does in O-O-diethyl organophosphates (may be partially reversible with 2-PAM for up to 24 to 48 hours).13


Moreover, the clinician must take all factors into consideration when deciding whether to treat a patient with 2-PAM. Factors to consider include severity of clinical signs, known or suspected identity of the toxin, and time elapsed since exposure. Most importantly, all patients receiving 2-PAM should be monitored closely during administration for exacerbation of clinical signs; if signs worsen, therapy should be discontinued.

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  3. Ventilator-Associated Lung Injury
  4. Allergic Airway Disease in Dogs and Cats and Feline Bronchopulmonary Disease

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Anticholinesterase Intoxication

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