Organophosphate Toxicity

Etiology

Organophosphate toxicity can occur either due to occupational or accidental exposure to pesticides, intentional self-harm exposure, or chemical warfare and terrorist attacks. Over 50,000 compounds have been developed and evaluated for pesticidal activity. In the United States, 37 organophosphate pesticides have been registered, all of which have the potential to cause toxicity. In the developing world, this number is higher due to less stringent regulation of these compounds. Organophosphate exposure can occur through inhalation, ingestion, or contact with skin. Although these compounds are readily absorbed in the body after inhalation and ingestion, systemic absorption following dermal exposure shows more significant variability. 

The onset, severity, and duration of toxicity depend on the ingested amount, absorption route, and the specific pesticide's toxicokinetics.[10] The World Health Organization (WHO) classifies these compounds into 5 groups, ranging from "Extremely hazardous" to "Active ingredients unlikely to present acute hazard in normal use." This classification is derived from the data based on the median lethal dose (LD₅₀), which represents the rat's oral lethal dose for 50% of individuals exposed to the active ingredient. However, the LD₅₀ classification is limited in differentiating more toxic compounds within the same class.

Epidemiology

According to a study conducted between 1995 and 2004, the annual reports of the Toxic Exposure Surveillance System (TESS), maintained by the American Association of Poison Control Centers, revealed that the number of incidents involving organophosphate exposure reached its peak in 1997 with 20,135 cases and then declined in the following years.[11] The annual report of the National Poison Data System for 2020 documented 2079 cases of organophosphate exposures, with no reported fatalities.[12] This substantial reduction in organophosphate exposure is primarily attributed to the decision taken by the U.S. Environmental Protection Agency to phase out the use of organophosphate insecticides in residential settings. This initiative commenced in 2000 and concluded in 2005.[11] However, it is worth noting that the information obtained from poison control centers' surveillance may not accurately reflect the total number of exposures in the United States. This is because these data are either self-reported or obtained from medical provider reports, which may underestimate and lack confirmation of the specific compound involved. 

Determining the total global exposure rate of organophosphate and its related toxicity accurately is challenging. In 2007, it was estimated that pesticide self-poisoning affected 371,594 individuals globally, accounting for about one-third of all suicides occurring worldwide.[7] In 1990, WHO estimated that there were 1 million unintentional pesticide poisonings, resulting in approximately 20,000 fatalities. A 2020 study estimated 740,000 unintentional pesticide poisonings, resulting in 7446 deaths across 141 countries.[13] The actual extent of exposure and toxicity is likely higher due to inadequate reporting and limited statistical data.

Pathophysiology

Acetylcholine is a neurotransmitter with widespread functionality in the nervous system. Acetylcholine is present in parasympathetic and sympathetic ganglia, all postganglionic parasympathetic nerves, the postganglionic sympathetic nerve innervating sweat glands, and skeletal neuromuscular junctions. Upon depolarization of an axon, acetylcholine is released into the synaptic cleft, which activates the postsynaptic receptors, resulting in the propagation of an action potential. Carboxylic ester hydrolases metabolize acetylcholine into acetic acid and choline through hydrolysis. This process occurs rapidly, with choline being reabsorbed into the presynaptic nerve to be used for the synthesis of additional acetylcholine. The main enzymes responsible for this metabolism are AChE and butyrylcholinesterase (BuChE). AChE is located in nervous and skeletal tissues, as well as on erythrocyte membranes. BuChE is present in plasma and various organs such as the liver, heart, pancreas, and brain. However, the function of BuChE remains partially understood. 

The key feature of organophosphate insecticides is their capacity to inhibit carboxyl ester hydrolases, primarily focusing on AChE inhibition. These insecticides inactivate AChE by phosphorylating the serine hydroxyl group on the enzyme. As AChE is essential in acetylcholine degradation, its inhibition results in an accumulation of acetylcholine within the synapse, resulting in excessive stimulation of both nicotinic and muscarinic receptors.

Overstimulation of nicotinic receptors at the neuromuscular junction can result in fasciculations and myoclonic jerking, eventually leading to flaccid paralysis due to depolarizing blocks. Nicotinic receptors are also found in the adrenal glands, potentially causing symptoms such as hypertension, sweating, tachycardia, and leukocytosis with a left shift.[14][15][16][17]

Organophosphate poisoning induces symptoms based on its action at muscarinic receptors. These effects typically develop more slowly than nicotinic receptor effects, occurring through a G-protein–coupled receptor mechanism. Muscarinic receptors can be located in both the parasympathetic and sympathetic nervous systems. The sympathetic nervous system leads to the overstimulation of sweat glands, resulting in excessive diaphoresis. The parasympathetic effects of organophosphate poisoning can manifest in various systems, affecting the heart, exocrine glands, and smooth muscles. Muscarinic overstimulation can cause severe life-threatening conditions such as bradycardia, bronchorrhea, and bronchospasm, which can lead to breathing difficulties.[18]

Excessive acetylcholine in the CNS can cause CNS depression, leading to coma and seizures. In cases where patients ingest agricultural pesticides, the presence of co-formulants and alcohol also poses a concern. Pesticides are frequently combined with solvents and surfactants to form an emulsifiable concentrate rather than being in a pure organophosphate form. The extent of the toxicity associated with co-formulants remains uncertain. Considering that organophosphate toxicity can induce CNS depression and coma, the risk of aspirating these solvents is a considerable concern. Reports of aspiration pneumonitis and adult respiratory distress syndrome (ARDS) have emerged in cases of organophosphate toxicity. However, it remains uncertain whether these conditions are caused by the compound itself or its aspiration.[19]

Toxicokinetics

Organophosphate pesticides can be absorbed through multiple routes, including inhalation, ingestion, ocular contact, and dermal exposure, and inhalation results in the quickest absorption.[20] Although systemic absorption varies after dermal exposure, it can be heightened by various factors such as broken skin, dermatitis, and elevated environmental temperatures. Oral ingestion is often associated with intentional self-harm attempts in adults and can also be observed with accidental exposures in children. 

The exact time for peak plasma concentration after organophosphate exposure is unknown. However, a study involving human volunteers revealed that the time to peak plasma concentrations occurred approximately 6 hours after orally ingesting very low doses of chlorpyrifos.[21] Notably, these findings may not apply to all organophosphate compounds, especially in cases of high-volume ingestion, as seen in intentional self-harm attempts. Furthermore, the study involved pure chlorpyrifos, which differs from agricultural pesticides and may include additives impacting the absorption and distribution of the organophosphate. This study also utilized pure chlorpyrifos, in contrast to agricultural pesticides that may incorporate additives capable of influencing the absorption and distribution of the organophosphate. 

Most organophosphates exhibit lipophilic properties and possess a high volume of distribution. They distribute rapidly into adipose tissue, the kidneys, and the liver. Their extensive distribution provides protection from metabolism. The level of lipophilicity and the patient's adipose tissue can affect the outcome after poisoning. A 2014 Korean study examined the outcomes of 112 acutely poisoned patients, of whom 40 individuals were dealing with obesity. Individuals with a body mass index (BMI) of more than 25 experienced prolonged mechanical ventilation, extended stays in the intensive care unit (ICU), and an increased total length of hospital admission.[22]

The mobilization of unmetabolized organophosphates from fat stores can trigger a cholinergic crisis. This phenomenon is associated with highly lipophilic compounds and typically does not manifest in individuals with low lipophilicity and smaller volumes of distribution. Organophosphates can have a direct inhibitory effect on the AChE enzyme without necessitating initial metabolism after absorption. These direct-acting compounds are called oxons and differ from other compounds known as thions, which require metabolic activation within the body to become active. Thion organophosphate compounds are activated by cytochrome P450 (CYP450) enzymes, primarily located in the liver and intestine. The specific CYP450 enzymes involved may vary depending on the concentration and type of the organophosphate.[23]

When an organophosphate binds to the enzyme AChE, it undergoes cleavage, forming a stable yet reversible bond and rendering the AChE inactive. Although a regeneration process may occur, it proceeds more slowly than the inhibition and may take hours to days to restore AChE function completely. During its inactive state, the enzyme can potentially undergo the aging process, in which the initial reversible bond becomes irreversible, and enzyme regeneration can no longer occur. The time frame of aging varies among different organophosphate compounds. The antidote pralidoxime accelerates acetylcholine regeneration and reduces the number of inactive enzymes available for aging. Pralidoxime is effective only before the aging process, which is time-sensitive and dependent on the specific organophosphate compound involved.[24] Once aging takes place, AChE can no longer be regenerated, thereby necessitating de novo synthesis for enzyme replenishment.

History and Physical

When dealing with potential toxicity cases, it is important to consider the specific compound involved and the timing of exposure, especially in cases of intentional ingestion, as significant elements of the patient's medical history. An attempt should be made to secure the pesticide container, if feasible, to provide this information to the Poison Control Center or a medical toxicologist, as there can be significant variability in toxicity among different compounds. The timing of symptom onset and the severity of toxicity depend on the route of exposure, degree or dosage, and the specific organophosphate compound involved. Moreover, the duration of toxicity is influenced by the toxicokinetics of the compound, including its lipophilicity. In some cases, recurring cholinergic effects may occur as the compound is released from fat stores.[25]

In severe organophosphate toxicity, the prototypical patient may exhibit unresponsiveness, pinpoint pupils, muscle fasciculations, and diaphoresis. Additional symptoms can include emesis, diarrhea, excessive salivation, lacrimation, and urinary incontinence. In cases of intentional self-poisoning of organophosphates, the presence of a garlic or solvent odor may persist. 

Several helpful mnemonics exist for recalling the signs and symptoms of organophosphate poisoning and the receptor responsible for them.

To remember the nicotinic signs of AChE inhibitor toxicity, the following days of the week can be used:

• Monday = Mydriasis
• Tuesday = Tachycardia
• Wednesday = Weakness
• Thursday = Hypertension
• Friday = Fasciculations

The frequently used mnemonic that encompasses the muscarinic effects of organophosphate poisoning is DUMBELS, as mentioned below.

• D = Defecation/diaphoresis
• U = Urination
• M = Miosis
• B = Bronchospasm/bronchorrhea
• E = Emesis
• L = Lacrimation
• S = Salivation

Additional acute symptoms may include anxiety, confusion, drowsiness, emotional lability, seizures, hallucinations, headaches, insomnia, memory loss, and circulatory or respiratory depression. In fatal cases, the most frequent cause of death is respiratory failure resulting from bronchoconstriction, bronchorrhea, central respiratory depression, and weakness or paralysis of the respiratory muscles. For patients who survive acute poisoning, a possibility of experiencing other long-term complications may arise.

Evaluation

As the diagnosis of organophosphate poisoning relies on clinical evaluation, initiating treatment before laboratory confirmation is essential. A high clinical suspicion for organophosphate poisoning is crucial, especially when there is no known history of exposure or ingestion. The most prevalent presentation of toxicity involves a patient with miotic pupils, diaphoresis, and respiratory distress. Some organophosphates emit a distinctive garlic or petroleum odor that can aid in diagnosis.

If organophosphate poisoning is on the differential but not confirmed, a trial of atropine may be administered. If symptoms improve following the administration of 0.6 to 1 mg of atropine, this raises suspicion of AChE inhibitor poisoning. However, due to the lack of studies, interpreting the sensitivity and specificity of this trial can be challenging, particularly in cases of severe poisoning. Therefore, further studies are needed to address this issue. In cases of significant poisoning, patients may not exhibit any response to a small dose of atropine, which can result in a false-negative test.

Although some laboratories can directly measure cholinesterase activity, these tests are often outsourced to facilities that may not provide results promptly to guide therapy. The 2 commonly measured cholinesterases are BuChE and red blood cell AChE (RBC AChE). BuChE activity is less specific than RBC AChE activity. Low BuChE activity may also be observed in individuals with hereditary enzyme dysfunction, hepatic disease, chronic illness, malnutrition, and iron deficiency anemia. The extent of enzyme inhibition varies depending on the specific organophosphate involved in the poisoning, and limited data exist for many compounds, thereby further complicating the interpretation of this test.

RBC AChE activity is believed to have a stronger correlation with the clinical features of organophosphate toxicity. In clinical settings, symptoms typically develop when more than 50% of this enzyme is inhibited, although this threshold can vary with specific compounds.[26] Notably, it is essential to collect blood samples in appropriate tubes, as fluoride can deactivate the enzymes, potentially yielding falsely low activity levels.

Healthcare providers may order a range of essential laboratory tests, including specific diagnostic tests for organophosphate poisoning, as well as other tests to assess the patient's overall health. These may include a complete blood cell count (CBC), a basic metabolic panel test, liver and kidney function tests, glucose level tests, arterial blood gas analysis, and pregnancy testing. The electrocardiogram (ECG) typically reveals sinus bradycardia due to parasympathetic activation.

Treatment / Management

Before assessing and treating a patient with organophosphate toxicity, all healthcare providers must don personal protective equipment to minimize the risk of self-contamination. Adhering to universal precautions helps maintain a low contamination rate among healthcare workers.[27] Once healthcare workers are assured of their safety through appropriate protective measures, the initial step involves decontaminating the patients. This is followed by washing the patient's skin thoroughly with soap and water 3 times. The primary goal of this approach is to quickly clean without needing specific decontamination fluids. Caution should be exercised when dealing with bodily secretions, including vomit and diarrhea, as organophosphates can be found in these fluids. All clothing worn by the patients should be taken off and disposed of. As long hair can trap highly lipophilic compounds, it should be cut if washing fails. Although decontaminating the patient is essential, it should not delay timely medical intervention for a patient in severe distress.[28](A1)

Airway control is of paramount importance while treating patients with organophosphate toxicity. In some patients, intubation may be required due to bronchospasm, seizures, or bronchorrhea. However, it is noteworthy that succinylcholine should be avoided during intubation as it cannot be metabolized and leads to prolonged paralysis. Patients should also receive intravenous access, cardiac monitoring, and pulse oximetry.

The primary treatment for organophosphate poisoning involves atropine, which competes with acetylcholine at the muscarinic receptors. Atropine is administered intravenously (IV) with an initial dose of 2 to 5 mg for adults and 0.05 mg/kg for children, aiming to achieve the adult dose. If the patient does not respond to the treatment, the healthcare team should double the dose every 3 to 5 minutes until respiratory secretions have cleared and there is no bronchoconstriction. At this point, the state of "atropinization" is achieved, which is characterized by the appearance of anticholinergic signs and symptoms in the patient, including dry skin and mucosa, decreased bowel sounds, tachycardia, no bronchospasm, reduced secretions, and mydriasis.[29] (A1)

The main objective of using atropine is to improve cardiorespiratory parameters in patients dealing with organophosphate toxicity. Assessment of heart rate, blood pressure, and respiratory status is more crucial than pupil size and skin moisture. Patients with severe poisoning may require the administration of hundreds of milligrams of atropine, either as bolus doses or continuous infusion, over the course of several days to weeks until the patient shows improvement. As atropine does not mitigate nicotinic effects, patients must be closely monitored for the potential development of neuromuscular junction dysfunction and respiratory failure. Monitoring parameters such as tidal volume and negative inspiratory force can assist in assessing the necessity for ventilatory support. 

The antidote pralidoxime (2-PAM) operates by reactivating the phosphorylated AChE by binding with the organophosphate. However, for the antidote to work effectively, it must be administered before the onset of aging, and this time frame is specific to each particular compound. This agent does not depress the respiratory center and can be used in conjunction with atropine. However, the evidence regarding the use of oximes for the treatment of organophosphate poisoning is inconsistent and subject to controversy. Studies have shown that the addition of 2-PAM to atropine did not improve mortality and carried potential risks.[30] Therefore, until a clearer understanding is reached and alternative treatments emerge, it is advisable to treat all patients poisoned with organophosphorus agents with an oxime. (A1)

Atropine must be administered to patients before 2-PAM to prevent the exacerbation of muscarinic-mediated symptoms. Healthcare providers recommend a bolus of at least 30 mg/kg for adults and 20 to 50 mg/kg for children over 30 minutes. As rapid administration of 2-PAM can lead to cardiac arrest, caution should be exercised while administering the medication to patients. After the bolus, a continuous infusion of the medication at a rate of at least 8 mg/kg/h for adults and 10 to 20 mg/kg/h for children should be initiated, which may be required for several days.[31][32](B3)

Patients experiencing seizures should be administered benzodiazepines. Although there is a single study suggesting the potential benefits of diazepam in preventing neuropathy, benzodiazepines are not generally recommended unless seizures are actively occurring.[33] In the case of specific organophosphate compounds with a limited volume of distribution, such as dimethoate and dichlorvos, extracorporeal elimination may be beneficial. However, there is limited data regarding the overall effectiveness of hemodialysis and hemoperfusion in all cases of poisoning. Due to the potential for recurring symptoms and respiratory distress, patients should be admitted to the hospital and closely monitored for a minimum of 48 hours within an ICU setting. Patients who remain asymptomatic for 12 hours may be considered for discharge.(B3)

Differential Diagnosis

When evaluating a patient with a complex clinical presentation, a thorough understanding of the differential diagnosis is essential. This comprehensive list encompasses a spectrum of conditions, which include:

• Gastroenteritis
• Myasthenia gravis
• Eaton-Lambert syndrome
• Guillain-Barre syndrome
• Botulism
• Mushroom toxicity, caused by the fungi Clitocybe and Inocybe
• Nicotine poisoning, including green tobacco sickness
• Hemlock poisoning, caused by Conium maculatum or poison hemlock
• Carbamate toxicity 
• Carbachol toxicity
• Methacholine toxicity
• Arecoline toxicity
• Bethanechol toxicity
• Pilocarpine toxicity
• Pyridostigmine toxicity
• Neostigmine toxicity

Prognosis

The mortality rates caused by organophosphate insecticides range globally from 2% to 25%. The insecticides most frequently associated with fatalities include fenitrothion, dichlorvos, malathion, and trichlorfon. Respiratory failure is the leading cause of death.

In 1993, the Peradeniya Organophosphorus Poisoning (POP) scale was developed and validated to assess clinical severity and determine prognosis in cases of organophosphate poisoning.[34] This scale was developed in India—a region with a high prevalence of toxicity and limited resources for individuals with severe illness. The POP scale considers 6 clinical parameters—miosis, fasciculations, respiration, bradycardia, level of consciousness, and seizures.

Table. The POP Scale

Healthcare providers evaluate the above parameters in patients before any medical intervention in toxicity cases. Higher scores are associated with more unfavorable outcomes, including mortality, the necessity for ventilatory support, and the dosage of atropine required within the initial 24 hours. However, the scale does not predict the likelihood of the intermediate syndrome development. Another study categorized organophosphate toxicity into 3 groups—mild (POP score 0 to 3), moderate (POP score 4 to 7), and severe (POP score 8 to 11). Within this classification, 78.33% of patients had mild poisoning, 21.66% had moderate poisoning, and none were severe. Notably, all patients falling within the moderate toxicity score range required ventilatory support, and the mortality rate for these patients was 30.8%.[35]

Complications

A condition called the "intermediate syndrome" has been identified, which causes muscle weakness that may lead to respiratory failure without cholinergic signs or fasciculations.[36] This syndrome typically occurs 24 to 96 hours after the onset of organophosphate poisoning and after the cholinergic crisis has ended. Patients experience proximal muscle weakness and cranial nerve palsy, which can progress to respiratory failure. Typically, consciousness remains preserved in patients unless other complicating factors, such as hypoxia, are present. This syndrome can persist for several weeks.

As neck flexors are often the first muscles affected, close monitoring for this syndrome is crucial. An examination can be efficiently conducted by instructing patients to lift their heads off the bed. Not all patients who develop the intermediate syndrome experience respiratory failure. Although the exact pathophysiology of this syndrome remains incompletely understood, it is believed to result from dysfunction in the neuromuscular junction.

Peripheral neuropathy can develop days to weeks after acute toxicity, and it is more frequently observed with specific compounds, including chlorpyrifos, dichlorvos, isofenphos, and methamidophos.[37] This neuropathy arises due to the inhibition of the neuropathy target esterase enzyme, which catalyzes the breakdown of the major phospholipid within cell membranes in nervous tissues. The symptoms associated with this condition include muscle cramping in the lower extremities, distal numbness, and paresthesias affecting the extremities, which can advance to the loss of deep tendon reflexes. Individuals who survive this condition may also experience neuropsychiatric deficits such as confusion, memory impairment, lethargy, psychosis, irritability, and Parkinson-like symptoms.