Case
Scenario
An 8-year-old male presents to a rural emergency department complaining of blurred vision, difficulty walking, vomiting, and sweating. The symptoms have been present for an hour. He denies headache, shortness of air, chest pain, abdominal pain, myalgias, or arthralgias. He lives with his parents and 2 younger sisters on a local farm. On questioning, his parents tell you that his immunizations are up to date. He has no past medical history, and he is doing well in the third grade. Prior to the onset of symptoms, he had been in the barn doing some chores. On exam, the patient is a well-developed, well-nourished white male who is slightly pale and moderately diaphoretic. His vital signs are as follows: HR 70 per minute and regular, BP 96/50 mmHg, respirations 20 per minute and shallow, and temperature 98.4 F orally. Pupils are 2mm, equal and reactive. Extraocular muscles are all intact; fundoscopic exam is grossly normal but is limited due to miosis. Vision is 20/50 bilaterally. Oropharynx is clear with very prominent secretions. Neck is supple; lungs are clear; heart sounds are regular with S1/S2 without murmurs, rubs, or gallops. Abdomen is soft and non-tender with hyperactive bowel sounds. Extremities are without rash or edema with diffuse mild weakness. On more detailed questioning, the parents reported that they had recently had their crops dusted with chlorpyrifos, an organophosphate pesticide, and that unused bags had been stored in the barn. The child was subsequently diagnosed with acute organophosphate poisoning, treated appropriately, and discharged home the following day in stable condition.
Organophosphates as a class have become the most frequently used pesticides because of their rapid breakdown into environmentally safe products. However, they have far more immediate toxicity than DDT and other related products. There are more than 40 different organophosphate pesticides on the market today, and they each cause acute and sub-acute toxicity. They are used in agriculture, homes, gardens, and in veterinary practice. They all work by inhibiting acetylcholinesterase (AChE) and cause a similar spectrum of symptoms. In 2003 there were 6442 reported exposures of which 6010 were unintentional. 1695 of these cases were seen in emergency departments, and there were 16 reported fatalities (12).
Return to top of PageGeneral
Chemical Structure of Organophosphates
(Modified from reference 11)
Organophosphates are very efficiently absorbed from the skin, lungs, and gastrointestinal tract. The majority of organophosphate poisoning occurs by accidental or occupational exposure, but poisoning may also be due to suicide attempts, homicide attempts, or chemical warfare. In a child less than one year of age with an organophosphate poisoning, child abuse or neglect may be suspected. In anyone older than 6 years of age, a suicide attempt should be considered in the differential. Healthcare workers must be very cautious to prevent self-contamination when caring for an exposed patient. Although this risk is relatively low, it is often compounded by late recognition of the need for patient decontamination, large numbers of non-essential staff coming into contact with the patient, and the difficulty of carrying out medical procedures while wearing protective equipment. When caring for a patient with organophosphate poisoning, it is important to remember than any vomited material should be treated as a chemical spill (10). At the healthcare facility, level C personal protective equipment should be sufficient in most cases to protect healthcare workers from accidental exposure: an air-purifying respirator and nonencapsulated chemical-resistant clothing, gloves, and boots (5).
Return to top of PageOrganophosphates reversibly bind to and inactivate the enzyme acetylcholinesterase (AChE), inhibiting the breakdown of acetylcholine
and leading to an excess of acetylcholine in cholinergic synapses. This excess acetylcholine initially over-stimulates and then
paralyzes cholinergic transmission. The bond between organophosphates and AChE becomes irreversible after a period of approximately
24 to 72 hours, a process referred to as “aging”. Toxicity manifests in nicotinic and muscarinic effects in the central
and peripheral nervous system.
The following illustrations provide a representation of the normal function of cholinergic transmission at the motor endplate,
with AChE degrading ACh (illustration 1) and the cholinergic excess that occurs when AChE is inactivated by an organophosphate (illustration 2).
These two movies provide a representation of 1) the normal function of the cholinergic transmision at the motor endplate, with acetylcholinesterase degrading ACh to clear to synape and 2) the cholinergic overdrive theat occurs when AChE is inactivated by an organophosphates.
The clinical picture after poisoning depends on both the relative toxicity of the compound and the rate at which it is absorbed. Organophosphates are classified into low-toxicity (LD50 >1000 mg/kg), moderate-toxicity (LD50 50-1000 mg/kg) and highly toxic (LD50 <50 mg/kg) based on their relative affinity for AChE. Patients with congenitally low levels of AchE (or BchE) are at an increased risk of toxic exposure, regardless of the relative toxicity of the organophosphate involved. Some medical disorders that cause a decrease in enzyme levels include malnutrition, iron deficiency anemia, hepatic dysfunction, oral contraceptive use, and many chronic disease states. Drugs that are metabolized by BchE, such as succinylcholine, cocaine, and lidocaine may also cause a lowered threshold for toxic exposure. (4)
The rate of absorption is largely dependent on lipid solubility. Some organophosphates such as diazinon and parathion have significant lipid solubility allowing fat storage with delayed toxicity due to later release of the compound. Some need to be metabolized to a more active form to produce toxicity. Some agents (eg parathion) need to be activated by oxidation of the P=S bond to the phosphate form to produce toxic effects.
CLINICAL
EFFECTS
ACUTE EFFECTS:
The signs and symptoms of acute organophosphate poisoning are cholinergic in nature. Nicotinic and muscarinic receptors in the central and peripheral nervous system are affected. Clinical manifestations generally develop within minutes to hours following exposure; the time frame is dependent on the type of exposure. Symptoms occur most rapidly with inhalation, followed by GI absorption, then dermal exposure.
The muscarinic effects from postganglionic parasympathetic stimulation can be remembered by the mnemonic “DUMB-BELS”: diaphoresis
and diarrhea, urination, miosis, bradycardia, bronchospasm and bronchorrhea, emesis, lacrimation, and salivation and seizures.
The nicotinic effects at the neuromuscular junction cause muscle fasciculations, weakness, paralysis, and may
lead to respiratory failure due to involvement of the chest wall muscles and the diaphragm. CNS effects may be due to overstimulation
(seizures) or may present as CNS depression and/ or coma.
The most life-threatening symptoms are respiratory and cardiac in nature. The patient can have wheezing, chest tightness, and a productive cough. The bronchorrhea can be significant with frothy and/or bloody sputum and severe pulmonary edema. The most common cardiac findings are bradycardia and hypotension. Cardiac depression and cardiovascular collapse may occur, and toxic cardiomyopathy may be present in severe poisonings. Dysrhythmias that may be encountered include atrial fibrillation, AV blocks, torsades de pointes, or asystole.
Miscellaneous effects to be aware of include pancreatitis, hyperglycemia, hypothermia, and a characteristic garlic odor that may aid in diagnosis when an unknown toxin has been ingested.
The clinical picture correlates poorly with measured cholinesterase activity. However, as a general rule mild poisoning occurs in patients with cholinesterase activity that is 20-50% of baseline; they will complain of headache, dizziness, and the SLUDGE syndrome (Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis). When cholinesterase activity is 10-20% of baseline, the patient will likely experience generalized weakness, difficulty speaking, fasciculations, and miosis; this is moderate poisoning. In severe poisoning the cholinesterase level is generally less than 10% of baseline; these patients are likely to have the most severe symptoms as described above (4).
Intermediate syndrome occurs after a period of apparent full recovery, 24-96 hours following the intial organophosphate exposure. The symptoms include acute paralysis involving mainly proximal limb muscles, muscles of the face and neck, and respiratory muscles. There may also be associated cranial nerve palsies and decreased deep tendon reflexes. These symptoms are thought to be due to a combined pre- and post-synaptic neuromuscular dysfunction. The symptoms do not respond well to atropine or pralidoxime; treatment is mainly supportive. The compounds most commonly implicated in the intermediate syndrome are methyl parathion, fenthion, and dimethoate.
Blood samples should be obtained for testing of red blood cell cholinesterase (RBC) levels and plasma pseudocholinesterase levels. While RBC cholinesterase levels correlate more directly with clinical effect, plasma levels are more sensitive to exposure and the test is more readily available. It is recommended that RBC levels be used where available4. Because of the wide variability in the normal levels of cholinesterase in the general population, a level should be drawn prior to initiating treatment and at regular intervals thereafter. An observed rise in the levels of cholinesterase is more important clinically than the absolute value. Because of this large inter-personal variability in “normal” cholinesterase levels, it has been recommended that agricultural workers and those at risk for exposure to organophosphates have baseline levels drawn should they ever have a poisoning incident; however, in the absence of such baseline levels, utility has been proven for sequential analyses of cholinesterase levels to monitor the upward trend (3).
TREATMENT
OF ORGANOPHOSPHATE INTOXICATION
Treatment consists of decontamination, supportive care, symptom management, and reactivation of AchE when possible. Healthcare workers should take care to avoid contact with contaminated skin, clothing, or body fluids. Level C personal protective equipment as described above should be utilized; it is also important to note that rubber gloves are necessary as vinyl gloves provide no protection against organophosphates.
ABC’s: The patient may require intubation to protect the airway in severe poisoning. The patient should be well oxygenated before treatment of symptoms, as administration of atropine may precipitate ventricular dysrhythmias in a patient that has poor tissue oxygenation.
Decontamination: All clothing should be removed and bagged as hazardous materials. The patient should be washed thoroughly with soap and water. It is during this skin decontamination that healthcare workers are in the most danger of exposure. In the case of ingestion, GI decontamination can be accomplished via gastric lavage; activated charcoal may be used, although it is not expected to bond well to organophosphates. Many patients will be vomiting profusely and will not require further GI decontamination; in these cases it is important to treat any vomitus as a hazardous chemical spill.
Atropine Sulfate: Atropine is used for its anticholinergic properties; it is used to counteract the symptoms of the poisoning only and does not reverse the effects of the organophosphate on acetylcholinesterase. Atropine should be given IV when available; alternative routes of administration include IM, via ET tube, or nebulized in the case of inhalation poisoning or any time that pulmonary symptoms dominate the clinical picture. The initial dosage is 1-2 mg in adults (0.01 mg/kg in children), repeated every 10 minutes until clearing of secrections (note that pupillary changes are not a sufficient marker for the endpoint of treatment). Treatment may require very large doses of atropine, up to several grams per day. Powdered atropine can be reconstituted to decrease the fluid load to the patient; using powdered atropine also ensures that the hospital will have an adequate supply of atropine in the case of a multiple-patient exposure. Tachycardia and dilated pupils are not contraindications for atropine administration when given for an acute organophosphate poisoning.
Pralidoxime (2-PAM): Organophosphates deactivate AChE by phosphorylation. After a period of time, this bond matures or “ages” and becomes irreversible. However, within the first 24-72 hours following acute poisoning, the AChE-OP compound has not aged and the phosphorylation can be reversed by administration of pralidoxime (2-PAM). This in essence re-activates the AChE. The effect of 2-PAM is most prominent at nicotinic sites although it will have activity on CNS and muscarinic receptors as well.
This movie provides a representation of 1) the interaction between an organophosphate molecule and the active site of acetylcholinesterase (AChE), 2) the regeneration of AChE by pralidoxime as pralidoxime binds with a portion of the organophosphate molecule, and 3) reactivation of the AChE molecule. Click on the button to start the movie.
This movie provides a representation of 1) the interaction between the organophosphate TEPP and the active site of a cholinesterase (AChE) molecule and 2) the regeneration of AChE by pralidoxime as pralidoxime binds with a portion of the organophosphate molecule, 3) reactivating the AChE molecule. Click on the button to start the movie
2-PAM should be given as soon as possible after a poisoning is recognized in order to re-activate the highest possible number of AChE molecules. Although 24-72 hours has been the traditional timeframe in which AchE undergoes aging, there is evidence to suggest that 2-PAM may be effective if given later than this (2). As 2-PAM has very little toxicity at therapeutic levels, it is better to err on the side of 2-PAM administration should an OP poisoning be suspected.
The adult dose of 2-PAM is 1 to 2 g IV over 15 to 30 minutes with repeat administration in an hour if muscle fasciculations and weakness are not resolved (6). The pediatric dose is 20 to 40 mg/kg IV over 30 minutes. Another method of administration of 2-PAM is via a loading dose followed by a continuous infusion of 10-20 mg/kg/hr in children and up to 500 mg/hr in adults. The end point of treatment should be determined by symptom resolution with concomitant lab testing for cholinesterase activity. It is important to note that fat-soluble organophosphates may have a prolonged release and potential to cause recurrent symptoms after therapy has been discontinued.
Adverse effects of 2-PAM are minimal unless plasma levels are high6. When present, these effects may include dizziness, blurry vision, and diastolic hypertension. Rapid intravenous administration may lead to respiratory or cardiac arrest.
Adjunctive treatment: The patient may require furosemide and intubation with PEEP for pulmonary edema that is refractory to atropine administration. In the case of hypotension that is not relieved by administration of atropine, trendelenburg, fluid resuscitation with normal saline, and vasopressors as indicated by monitoring of central venous pressure may become necessary. Benzodiazepines are first line for seizures; however, if seizures continue another anticonvulsant such as phenobarbital may be added.
In patients requiring rapid sequence intubation, succhinylcholine is contraindicated as it will have prolonged effects due to the inhibition of AChE (9). Some other contraindicated medications include gentamicin, morphine, theophylline, phenothiazines, and reserpine
Inpatient Monitoring: Most patients with organophosphate toxicity will require continuous airway and neuromuscular monitoring in the intensive care unit. Patients should be observed for approximately 24 hours after the last doses of atropine and 2-PAM are given, as delayed symptoms following treatment is possible, particularly with exposure to the fat-soluble agents
Current Treatment Research: Thiamine has been found to prolong the plasma half-life of 2-PAM by decreasing renal clearance; however, it has not yet been demonstrated if thiamine has any benefit as such in patients with organophosphate poisoning (6).
For military applications, it is possible that human butyrylcholinesterase may be beneficial when given prior to an exposure to an organophosphate nerve agent. This may prove useful in the prophylaxis of military personnel and other at-risk individuals against chemical warfare agents (1).
Author
Information: Debra Banks, MD