Organophosphate (OP) compounds are a diverse group of chemicals used in both domestic and industrial settings. Examples of organophosphates include the following:
Thus, organophosphate toxicity can result from household or occupational exposure, military or terrorist action, or iatrogenic mishap. Exposure to organophosphates is also possible via intentional or unintentional contamination of food sources. Although no clinical effects of chronic, low-level organophosphate exposure from a food source have been shown, advancements in risk assessment and preparedness are ongoing.[1, 2]
Signs and symptoms of organophosphate poisoning can be divided into three broad categories: (1) muscarinic effects, (2) nicotinic effects, and (3) central nervous system (CNS) effects. See Presentation.
Organophosphate toxicity is a clinical diagnosis. Confirmation of organophosphate poisoning is based on the measurement of cholinesterase activity; but typically, these results are not readily available. See Workup.
Treatment begins with decontamination. Airway control and oxygenation are paramount. The mainstays of pharmacological therapy include atropine, pralidoxime (2-PAM), and benzodiazepines (eg, diazepam). 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. See Treatment and Medication.
Organophosphate compounds were first synthesized in the early 1800s when Lassaigne reacted alcohol with phosphoric acid. Shortly thereafter in 1854, Philip de Clermount described the synthesis of tetraethyl pyrophosphate at a meeting of the French Academy of Sciences.
Eighty years later, Lange, in Berlin, and, Schrader, a chemist at Bayer AG, Germany, investigated the use of organophosphates as insecticides. However, the German military prevented the use of organophosphates as insecticides and instead developed an arsenal of chemical warfare agents (ie, tabun, sarin, soman).
A fourth agent, VX, was synthesized in England a decade later. During World War II, in 1941, organophosphates were reintroduced worldwide for pesticide use, as originally intended.
Severe organophosphate intoxication from suicide attempts and outbreaks of unintentional poisoning, such as the Jamaican ginger palsy incident in 1930, led to the discovery of the mechanisms of acute and chronic toxicity of organophosphates. In 1995, a religious sect, Aum Shinrikyo, used sarin to poison people on a Tokyo subway. Mass poisonings still occur today; in 2005, 15 victims were poisoned after accidentally ingesting ethion-contaminated food in a social ceremony in Magrawa, India.
Nerve agents have also been used in battle, notably in Iraq in the 1980s. Sarin, delivered by rockets, was used in the chemical warfare attack in Damascus, Syria in 2013.[3] Additionally, chemical weapons still pose a very real concern in this age of terrorist activity.
In farm workers, chronic occupational exposure to organophosphate insecticides has been linked to neuropsychological effects in some studies. These have included difficulties in executive functions, psychomotor speed, verbal, memory, attention, processing speed, visual-spatial functioning, and coordination.[4]
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. Over a period of time, phosphorylation is followed by loss of an organophosphate leaving group and the bond with AChE becomes irreversible, a process known as aging.
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:
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.[5]
United States
In 2016, the American Association of Poison Control Centers reported 1994 single exposures to organophosphate insecticides alone, with 17 major outcomes and one death. In addition, 537 single exposures to organophosphate insecticides in combination with carbamate or non-carbarbamate insecticides were reported, with two major outcomes and no deaths.[6]
International
Pesticide poisonings are among the most common modes of poisoning fatalities. In countries such as India and Nicaragua, organophosphates are easily accessible and, therefore, a source of both intentional and unintentional poisonings. The incidence of international organophosphate-related human exposures appears to be underestimated.[7]
Worldwide mortality studies report mortality rates from 3-25%.[8] 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.
Organophosphates (OPs) may affect children or other at-risk populations differently. The increased susceptibility has not been elucidated but may involve delayed or persistent effects. More work in this area is in progress and should help identify the true risk potential.[9]
Signs and symptoms of organophosphate poisoning can be divided into the following three broad categories:
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, bronchorrhea; emesis; excess lacrimation; and salivation). Muscarinic effects by organ system include the following:
Nicotinic signs and symptoms include muscle fasciculations, cramping, weakness, and diaphragmatic failure. Autonomic nicotinic effects include hypertension, tachycardia, mydriasis, and pallor.
CNS effects include the following:
Clinical presentation may vary, depending on the specific agent, exposure route, and amount. Signs and symptoms are due to both muscarinic and nicotinic effects.
Interestingly, a review of 31 children with organophosphate (OP) poisoning described that, in contrast to adults, the most common presentations were seizure and coma with relatively less muscarinic or nicotinic findings.[10] The authors hypothesized that the difference may be due to difficulty in detecting muscarinic findings in infants (eg, crying) and ingestion of contaminated produce instead of direct exposure to organophosphates.
Depressed respirations, bradycardia, and hypotension are possible findings. Alternatively, tachypnea, hypertension, and tachycardia are possible. Hypoxia should be monitored for with continuous pulse oximetry.
Three types of paralysis may result from organophosphate poisoning. Type I is described as acute paralysis secondary to continued depolarization at the neuromuscular junction.
Type II (intermediate syndrome) was first described in 1974 and is reported to develop 24-96 hours after resolution of acute organophosphate poisoning symptoms and to manifest 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.[11]
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.
Type III paralysis, or organophosphate-induced delayed polyneuropathy (OPIDP) occurs 2-3 weeks after exposure to large doses of certain organophosphates and is due to inhibition of neuropathy target esterase, which is a different esterase than the one responsible for the acute effects of organophosphates. 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.[11, 12]
Neuropsychiatric effects of organophosphate poisoning include the following:
Extrapyramidal effects are characterized by dystonia, cogwheel rigidity, and parkinsonian features (basal ganglia impairment after recovery from acute toxicity). Other possible neurologic and/or psychological effects include Guillain-Barré–like syndrome and isolated bilateral recurrent laryngeal nerve palsy.
Organophosphate toxicity may affect other organ systems as follows:
Organophosphate (OP) toxicity is a clinical diagnosis. Confirmation of organophosphate poisoning is based on the measurement of cholinesterase activity; typically, these results are not readily available in a clinically relevant timeframe. Although red blood cell (RBC) and plasma (pseudo) cholinesterase (PChE) levels can both be used, RBC cholinesterase correlates better with central nervous system (CNS) acetylcholinesterase (AChE) and is, therefore, a more useful marker of organophosphate poisoning.
The portable Test-mate ChE field test measures RBC AChE and PChE within 4 minutes. A study of patients with acute organophosphorus poisoning compared Test-mate ChE results with those of a reference laboratory test and found good agreement between the two. Results show the Test-mate ChE field kit is a reliable test that provides rapid measurement of RBC AChE in acute organophosphorus poisoning.[13]
If possible, draw blood for measurement of RBC and plasma cholinesterase levels prior to treatment with pralidoxime (2-PAM). Monitoring serial levels can be used to determine a response to therapy.
RBC AChE represents the AChE found on RBC membranes, similar to that found in neuronal tissue. Therefore, measurement more accurately reflects nervous system OP AChE inhibition.
Plasma cholinesterase is a liver acute-phase protein that circulates in the blood plasma. It is found in CNS white matter, the pancreas, and the heart. It can be affected by many factors, including pregnancy, infection, and medical illness. Additionally, a patient's levels can vary up to 50% with repeated testing.
RBC cholinesterase is the more accurate of the two measurements, but plasma cholinesterase is easier to assay and is more readily available.
Cholinesterase levels do not always correlate with severity of clinical illness. Moreover, a variety of conditions can result in falsely lowered cholinesterase levels (see Diagnostic Considerations).
The level of cholinesterase activity is relative and is based on population estimates. Neonates and infants have baseline levels that are lower than adults. Because an individual patient's baseline levels are rarely available, the diagnosis can be confirmed by observing a progressive increase in the cholinesterase value until the values plateau over time.
Other laboratory findings include the following:
A retrospective analysis of OP-poisoned patients by Liu et al found a direct correlation between the severity of poisoning and mortality and the presence of pretreatment metabolic and respiratory acidosis.[15]
A chest radiograph may reveal pulmonary edema but typically adds little to the clinical management of a poisoned patient.
ECG findings include prolonged QTc interval, elevated ST segments, and inverted T waves.[14] Although sinus tachycardia is the most common finding in the poisoned patient, sinus bradycardia with PR prolongation can develop with increasing toxicity due to excessive parasympathetic activation.
Remove all clothing from 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.
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.
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 plasma cholinesterase and may result in prolonged paralysis. In addition to atropine, pralidoxime (2-PAM) and benzodiazepines (eg, diazepam) are mainstays of medical therapy (see Medication).
Central venous access and arterial lines may be needed to treat the patient with organophosphate toxicity who requires multiple medications and blood-gas measurements.
Continuous cardiac monitoring and pulse oximetry should be established; an electrocardiogram (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.
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.
The mainstays of medical therapy in organophosphate (OP) poisoning include atropine, pralidoxime (2-PAM), and benzodiazepines (eg, diazepam). 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.
Much larger doses of atropine are often needed for OP pesticide poisoning than when atropine is used for other indications. In order to achieve adequate atropinization quickly, a doubling approach typically used, with escalation of doses from 1 mg to 2 mg, 4 mg, 8 mg, 16 mg, and so on. A severe OP pesticide poisoning case has been known to deplete a hospital’s supply of atropine. Data from the sarin attack on the Tokyo subway suggest that patients poisoned by nerve agents require much less atropine than those poisoned by OP pesticides.
de Silva et al studied the treatment of OP poisoning with atropine and 2-PAM and, later the same year, with atropine alone.[16] They found that atropine seemed to be as effective as atropine plus 2-PAM in the treatment of acute OP 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 under way to assess the role of low-dose 2-PAM. Improved survival has been shown in patients with moderately severe OP poisoning who received early, continuous 2-PAM infusion compared with those who received intermittent boluses.[17]
A meta-analysis and review of the literature performed by Peter et al emphasized optimal supportive care along with discriminating use of 2-PAM, especially early in the course of treatment of moderately to severely OP poisoned patients, are the hallmarks of treatment.[18] More prospective data are required.
Intraosseous administration has been found as effective as intravenous infusion for rapid delivery of atropine and midazolam into the bloodstream, in studies in pigs. Unlike intravenous administration, intraosseous administration can be conveniently performed by rescuers wearing personal protective equipment to prevent contamination.[19, 20]
Because large amounts of atropine may be required for patients with OP poisoning, reconstitution of powdered atropine is a viable option, especially in mass-casualty settings.[21] 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.[22]
If atropine is unavailable or in limited supply, intravenous glycopyrrolate or diphenhydramine may provide an alternative anticholinergic agent for treating muscarinic toxicity; however, glycopyrrolate does not cross the blood-brain barrier and cannot treat central effects of OP poisoning. Additionally, Yavuz et al demonstrated reduced myocardial injury and troponin leak in fenthion-poisoned rats treated with diphenhydramine.[23] Nebulized ipratropium bromide can also be used to treat muscarinic effects in the lungs.
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 OP poisoning.[24] The mechanisms appear to be inhibition of acetylcholine (ACh) and OP antagonism. A phase II study of magnesium therapy in 50 patients with acute OP poisoning reported no adverse reactions.[25] Larger randomized studies are needed to demonstrate the efficacy of magnesium in this setting.
Possible future interventions include neuroprotective agents used to prevent nerve damage and bioscavengers aimed to prevent AChE inhibition by nerve agents or OP. Investigations into adjunctive and alternative therapies have mostly used animal models and have resulted in variable conclusions.[26, 27, 28] In a study of rats poisoned with sarin, Lewine et al reported that the addition of ketamine to standard countermeasures (atropine, 2-PAM, and midazolam) provides clinically relevant additional protection against the negative neurobiological consequences of sarin, even when initiation of treatment is delayed by almost an hour.[28]
Clinical Context: 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.
Clinical Context: 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
These agents act as competitive antagonists at the muscarinic cholinergic receptors in both the central and the peripheral nervous system. These agents do not treat nicotinic effects.
Clinical Context: 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 aged. Current recommendation is administration within 48 h of OP poisoning. Because it does not significantly relieve depression of the 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.
These agents prevent aging of AChE and reverse muscle paralysis with OP poisoning.
Clinical Context: For treatment of seizures. Depresses all levels of CNS (eg, limbic and reticular formation) by increasing activity of GABA.
These agents potentiate effects of gamma-aminobutyrate (GABA) and facilitate inhibitory GABA neurotransmission.
Because of risks of respiratory compromise or recurrent symptoms, hospitalizing all symptomatic patients for at least 48 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 (1-800-222-1222).
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 baseline cholinesterase levels for workers with known organophosphate exposure is recommended.[29]
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.
For patient education information, see the First Aid and Injuries Center, as well as Poisoning, Activated Charcoal, Poison Proofing Your Home, Chemical Warfare, and Personal Protective Equipment.
In a study of acute organophosphate insecticide poisoning in which 12 of the 71 patients died, multivariate logistic regression analysis identified the following as independent factors indicating a poor prognosis[30] :