Organophosphate and carbamate poisoning

INTRODUCTION — 

Organophosphates and carbamates are potent cholinesterase inhibitors capable of causing severe cholinergic toxicity following cutaneous exposure, inhalation, or ingestion. Although structurally distinct (figure 1), organophosphates and carbamates exhibit similar clinical manifestations with toxicity and require similar management following overdose.

An overview of organophosphate and carbamate poisoning will be presented here. A summary table to facilitate emergency management is provided (table 1). A general approach to suspected drug intoxication and terrorism is discussed separately.

●(See "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose" and "Approach to the child with occult toxic exposure".)

●(See "Chemical terrorism: Rapid recognition and initial medical management" and "Identifying and managing casualties of biological terrorism".)

EPIDEMIOLOGY — 

Organophosphates (OP) have been used as insecticides since the 1950s. The use of these agents has declined since the 2000s, in part due to the development of carbamate insecticides, which are associated with similar but shorter-lasting toxicities [1].

Worldwide, an estimated 3,000,000 people are exposed to OP or carbamate agents each year, with up to 300,000 fatalities [2-4]. In the United States annually, there are approximately 3500 exposures to these agents reported to poison centers, resulting in fewer than 7 deaths [5-9].

SOURCES OF EXPOSURE — 

Organophosphate (OP) or carbamate toxicity generally results from accidental or intentional ingestion of, or exposure to, agricultural pesticides [2,4,10]. Other potential causes of toxicity include ingestion of contaminated fruit, flour, or cooking oil, and wearing contaminated clothing [10-12].

Specific agents linked to human poisoning include both carbamate (methomyl and aldicarb) and OP (parathion, fenthion, ethion, malathion, and diazinon) insecticides. Chlorpyrifos, the OP agent of Dursban, is found in some popular household roach and ant sprays, including Raid and Black Flag (figure 2). The United States Environmental Protection Agency (EPA) banned many household uses of chlorpyrifos in 2001 and has restricted its use on certain crops, including tomatoes, apples, and grapes [13].

Several OP "nerve" agents (eg, tabun [GA], sarin [GB], soman [GD]) were developed in Germany during the 1940s but were not used for military purposes [14]. The 1995 sarin attack on the Tokyo subway system by the religious cult Aum Shinrikyo and subsequent international events have heightened awareness regarding the prevention, recognition, and treatment of casualties due to OP nerve agent exposure [15-17]. Since 2018, assassination attempts involving Novichok, a newer class of OP nerve agent that also affects peripheral nerves, have been perpetrated in Europe [18-20].

Medical applications of OPs and carbamates include reversal of neuromuscular blockade (neostigmine, pyridostigmine, edrophonium) and treatment of glaucoma, myasthenia gravis, and Alzheimer disease (echothiophate, pyridostigmine, donepezil). (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Anticholinesterases' and "Overview of the treatment of myasthenia gravis", section on 'Pyridostigmine' and "Treatment of Alzheimer disease", section on 'Cholinesterase inhibitors'.)

MECHANISM OF ACTION

●Organophosphates (OP) – OP compounds contain carbon and phosphorous acid derivatives (figure 1). These agents are well absorbed through the skin, lungs, and gastrointestinal tract. They bind and inactivate acetylcholinesterase (AChE), also known as red blood cell (RBC) acetylcholinesterase. AChE is the enzyme responsible for hydrolysis of acetylcholine to choline and acetic acid, and inhibition leads to an overabundance of acetylcholine at the neuronal synapses and the neuromuscular junction [21,22].

After a period of time that is dependent on the chemical structure of the OP, the acetylcholinesterase-OP compound undergoes a conformational change known as "aging," which renders the enzyme irreversibly resistant to reactivation by an antidotal oxime (figure 3) [23].

In addition, plasma cholinesterase (also called butylcholinesterase [BuChE] or pseudocholinesterase) and neuropathy target esterase (NTE) are inhibited by OPs; however, the clinical significance of these interactions is less certain [24,25].

●Carbamates – Carbamate compounds are derived from carbamic acid (figure 1). Like OPs, carbamates are rapidly absorbed via all routes of exposure. Unlike OPs, these agents are transient cholinesterase inhibitors, which spontaneously hydrolyze from the cholinesterase enzymatic site within 48 hours. Carbamate toxicity tends to be of shorter duration than that caused by equivalent doses of OPs, although the mortality rates associated with exposure to these chemical classes are similar [1].

CLINICAL FEATURES

Acute toxicity — Onset and duration of acetylcholinesterase (AChE) inhibition varies depending on the organophosphate's (OP) rate of AChE inhibition, the route of absorption, lipophilicity, and enzymatic conversion to active metabolites. For most agents, oral or respiratory exposures generally result in signs or symptoms within three hours, while symptoms of toxicity from dermal absorption may be delayed up to 12 hours. Lipophilic agents such as dichlofenthion, fenthion, and malathion are associated with delayed onset of symptoms, delayed onset of coma/respiratory failure (up to five days, potentially occurring in initially awake patients with mild cholinergic symptoms), and prolonged illness (greater than 30 days), which may be related to rapid adipose fat uptake and delayed redistribution from the fat stores [26,27]. The great variability in toxicity and treatment response among organophosphorus agents, however, is not well understood [28].

●Cholinergic excess – Acute toxicity from OPs presents with manifestations of cholinergic excess, predominantly bradycardia, miosis, lacrimation, salivation, bronchorrhea, bronchospasm, urination, emesis, and diarrhea (table 1). Primary toxic effects involve the autonomic nervous system, neuromuscular junction, and central nervous system (CNS) [29]. The parasympathetic nervous system is particularly dependent on acetylcholine regulation since both the autonomic ganglia and end organs of the parasympathetic nervous system are regulated by nicotinic and muscarinic cholinergic receptor subtypes, respectively (figure 4).

Diaphoresis occurs because sweat glands are regulated through sympathetic activation of postganglionic muscarinic receptors. At times, however, mydriasis and tachycardia may be observed, as sympathetic ganglia also contain nicotinic receptors (figure 4).

The muscarinic signs can be remembered by use of one of two mnemonics [30]:

•SLUDGE/BBB – Salivation, Lacrimation, Urination, Defecation, Gastric Emesis, Bronchorrhea, Bronchospasm, Bradycardia

•DUMBELS – Defecation, Urination, Miosis, Bronchorrhea/Bronchospasm/Bradycardia, Emesis, Lacrimation, Salivation

These mnemonics do not take into account the critical CNS and nicotinic effects of OPs. The nicotinic effects include fasciculations, muscle weakness, and paralysis via acetylcholine stimulation of receptors at the neuromuscular junction. This mechanism is analogous to the depolarizing effects of succinylcholine in producing neuromuscular blockade. Nicotinic and muscarinic receptors also have been identified in the brain and may contribute to central respiratory depression, lethargy, seizures, and coma (figure 4).

●Respiratory failure – Fatalities from acute OP poisoning generally result from respiratory failure due to a combination of depression of the CNS respiratory center, neuromuscular weakness, excessive respiratory secretions, and bronchoconstriction.

●Cardiovascular collapse – Fatalities also occur due to cardiovascular collapse, possibly from inappropriate vasodilation, although the mechanism is not completely understood [31].

●Dysrhythmias – Cardiac dysrhythmias, including heart block and QTc prolongation, are occasionally observed in OP poisoning [32]. It is unclear whether these dysrhythmias are due to direct toxicity or secondary hypoxemia.

●Myocardial ischemia – Case reports and small case series suggest that up to one-third of patients with severe OP poisoning manifest signs of myocardial ischemia, such as an elevated troponin or changes in the electrocardiogram (ECG) [33,34]. Peak troponin concentrations occur at presentation in most cases. Risk appears to be greatest in older patients and those with severe poisoning but low in patients with mild poisoning.

●Kidney injury – Several case reports describe acute kidney injury (AKI) requiring kidney replacement therapy in the setting of severe OP poisoning [35,36]. Causality has not been established, and it remains unclear whether the AKI is due directly to the OP or the general effects of critical illness, but in severe OP poisoning, it is prudent to monitor kidney function.

●Pancreatitis – Acute pancreatitis may complicate poisoning caused by either OPs or carbamates [37].

Intermediate (neurologic) syndrome — The "intermediate syndrome" consists of characteristic neurologic findings, including neck flexion weakness, decreased deep tendon reflexes, cranial nerve abnormalities, proximal muscle weakness, and respiratory insufficiency [38-40]. Ten to 40 percent of patients with OP poisoning develop this distinct neurologic disorder 24 to 96 hours after exposure and resolution of cholinergic excess.

Risk factors for the intermediate syndrome appear to include exposure to a highly fat-soluble OP and may be related to inadequate doses of oximes [41]. The intermediate syndrome has rarely been described following carbamate poisoning.

With adequate supportive care, including prolonged mechanical ventilation, most patients have complete resolution of neurologic dysfunction within two to three weeks. Clinical deterioration and improvement appear to correlate with red blood cell (RBC) AChE activity. Nerve conduction studies on patients with intermediate syndrome reveal unique postsynaptic abnormalities that differentiate this disorder from delayed neurotoxicity (discussed immediately below) [42]. (See "Evaluation of peripheral nerve and muscle disease".)

Delayed and long-term neuropathology

●OP-induced delayed neuropathy (OPIDN) – OPIDN typically occurs one to three weeks after OP exposure and presents with transient, painful "stocking-glove" paresthesias followed by a symmetrical motor polyneuropathy characterized by flaccid weakness of the lower extremities, which ascends to involve the upper extremities. Sensory disturbances are usually mild. Delayed neurotoxicity primarily affects distal muscle groups, but in severe neurotoxicity, proximal muscle groups may also be affected [43]. Most cases of mild delayed neurotoxicity improve with time; in severe cases, an upper motor neuron syndrome with spasticity of the lower extremities usually causes permanent disability.

Electromyograms and nerve conduction studies of affected patients reveal decreased firing of motor conduction units [44]. Histopathologic sections of peripheral nerves reveal Wallerian (or "dying-back") degeneration of large distal axons [45]. (See "Evaluation of peripheral nerve and muscle disease".)

The risk of developing OPIDN is independent of the severity of acute cholinergic toxicity and has been associated with ingestion of a small number of specific OPs, including chlorpyrifos (figure 5) [46-48]. Some OPs, such as parathion, are potent cholinergic agents but are not associated with OPIDN. Others, such as triorthocresyl phosphate (TOCP), produce few clinical signs of cholinergic excess but are frequently implicated in OPIDN (figure 5) [49]. Carbamates are only rarely associated with the development of OPIDN [50,51].

The mechanism of OPIDN may involve inhibition of neuropathy target esterase (NTE) rather than alterations in RBC AChE function [52]. The NTE enzyme, which is found in the brain, peripheral nerves, and lymphocytes, is responsible for the metabolism of various esters within the cell.

●Other neuropathology – Survivors of acute OP poisoning may have neurobehavioral deficits such as decreased memory, abstraction, and attention, and Parkinsonism, which may be permanent [53-55]. It is unclear if these neurocognitive effects are due to direct neurotoxicity of the OP themselves or related to hypoxia and other non-specific effects of serious illness.

DIAGNOSTIC EVALUATION

Clinical diagnosis — Organophosphate (OP) or carbamate poisoning is a clinical diagnosis in a patient with findings of cholinergic toxicity (ie, bradycardia, miosis, diaphoresis, lacrimation, salivation, bronchorrhea, bronchospasm, urination, emesis, diarrhea, fasciculations, muscle weakness, coma). (See 'Acute toxicity' above.)

The diagnosis is supported by a corroborating history, such as pesticide ingestions. However, in the absence of a known ingestion or exposure, the clinical features of cholinergic excess should indicate the possibility of OP poisoning. Many organophosphorus agents have a characteristic petroleum or garlic-like odor, which may be helpful in supporting the diagnosis.

If OP or carbamate poisoning is suspected, every effort should be made to precisely identify the agent since toxicity can have significant variability. Depending on whether the toxin contained dimethyl or diethyl groups (figure 1), the duration of toxicity and the therapeutic window during which oxime treatment is likely to be effective are markedly different. Dimethyl compounds (eg, monocrotophos, methyl parathion, dimethoate, dichlorvos, phosphamidon) are associated with worse outcomes and undergo rapid aging, making early initiation of oxime therapy critical [56]. Diethyl compounds (eg, chlorpyriphos, parathion, quinalphos) may exhibit delayed toxicity and may require prolonged treatment [3].

Role of atropine challenge — An atropine challenge may be helpful if doubt exists as to whether the patient has OP or carbamate poisoning. Administer atropine 1 mg intravenously (IV) in adults (or 0.01 to 0.02 mg/kg IV in children). The diagnosis of OP or carbamate poisoning is strongly supported if anticholinergic signs (tachycardia, mydriasis, decreased bowel sounds, dry skin) do not develop following atropine administration.

Measurement of cholinesterase activity — In patients with suspected OP or carbamate poisoning, red blood cell acetylcholinesterase (RBC AChE) activity may be useful if available. Significantly decreased activity essentially confirms the diagnosis. The percent decrease can assess the degree of toxicity and correlate with the duration of mechanical ventilation [57]. A decrease in plasma (or pseudo-) cholinesterase activity can also confirm the diagnosis but is less specific for poisoning and can decrease in many conditions such as malnutrition, liver disease, and iron deficiency anemia.

However, treatment should not be delayed while awaiting results since most hospital laboratories are unable to perform this test, and results may not return for days to weeks. Results may also be difficult to interpret as there is significant inter-individual and day-to-day intra-individual variability in baseline acetylcholinesterase activity.

Determination of RBC AChE activity can also be helpful in evaluating chronic or occupational exposure. (See "Overview of occupational health".)

Sequential measurement of RBC AChE activity (if rapidly available) may also be used to determine the effectiveness of oxime therapy in regeneration of the enzyme. An assay for butyrylcholinesterase (also known as pseudocholinesterase or plasma cholinesterase) activity is more readily performed but does not correlate well with severity and should not be used to guide therapy [58].

MANAGEMENT — 

A summary table to facilitate emergency management is provided (table 1). Management is based on clinical findings and should not be delayed pending confirmation with laboratory studies (ie, cholinesterase activity).

All patients: Supportive care

Respiratory failure, neuromuscular dysfunction, or coma — Patients with markedly depressed mental status require 100 percent oxygen and immediate tracheal intubation. Nondepolarizing neuromuscular blocking agents (eg, rocuronium) should be used instead of succinylcholine when performing rapid sequence intubation (RSI) in patients with organophosphate (OP) poisoning. Larger doses of neuromuscular blocking agents are often needed to overcome competitive inhibition at the neuromuscular junction. Succinylcholine should be avoided because it is metabolized by acetylcholinesterase (which is inhibited by OP compounds), exaggerating and prolonging neuromuscular blockade in poisoned patients. (See "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Nondepolarizing agents'.)

OP-poisoned patients may rapidly develop respiratory failure due to a combination of central nervous system (CNS) respiratory center depression, nicotinic receptor-mediated diaphragmatic weakness, bronchospasm, and copious secretions. Thus, even patients with normal mental status or normal vital signs may require early tracheal intubation.

In a patient with coma, apnea, or neuromuscular paralysis, we suggest a benzodiazepine (eg, diazepam 10 mg IV in adults; 0.1 to 0.2 mg/kg in children). Prophylactic diazepam has been shown to decrease neurocognitive dysfunction and CNS-mediated respiratory depression after OP poisoning in animal models [59-62]. This led, in part, to the United States military development of a 10 mg autoinjector of diazepam for use in the setting of chemical attack [63,64]. However, routine diazepam administration for all acutely-poisoned patients is controversial. Use of the Convulsive Antidote, Nerve Agent (CANA) autoinjector is discussed separately. (See "Chemical terrorism: Rapid recognition and initial medical management", section on 'Nerve agents'.)

Inhaled ipratropium 0.5 mg may be helpful for bronchospasm but is not a substitute for parenteral atropine. (See 'Atropine' below.)

Patients with neuromuscular dysfunction or with exposures to OPs known to cause delayed neurotoxicity (figure 5) should also be treated with oxime therapy. (See 'Pralidoxime' below.)

Seizures, agitation — OP-induced seizures or agitation should be treated with a benzodiazepine (eg, diazepam 10 mg IV in adults; 0.1 to 0.2 mg/kg in children) [65]. Phenytoin is not recommended as there is no evidence it has any effect on OP-induced seizures [66]. (See "Convulsive status epilepticus in adults: Management", section on 'First therapy: Benzodiazepines' and "The acutely agitated or violent adult: Pharmacologic management", section on 'Benzodiazepines'.)

Cardiovascular toxicity — Cardiac complications are typically not the major morbidity associated with OP poisoning, and management is best focused on treating cholinergic toxicity. Bradycardia and hypotension are usually present in moderate to severe poisonings, but tachycardia or hypertension may transiently occur due to direct sympathetic stimulation. All patients should have an electrocardiogram (ECG) and be placed on a continuous cardiac monitor.

Adequate volume resuscitation with isotonic crystalloid (eg, normal saline or Lactated Ringer solution) should be performed concomitantly with other resuscitative and diagnostic efforts.

In the setting of OP poisoning, myocardial ischemia appears to stem from non-occlusive disease. Treatment with aspirin is probably safe and prudent. We do not suggest other therapies. Based on limited evidence, we believe it is reasonable to monitor patients with severe poisoning for myocardial ischemia by obtaining serial ECGs and serum troponin concentrations approximately every 8 to 12 hours while the patient's condition remains critical. Given that many of these cases are managed in resource-limited settings, the appropriate level of monitoring will vary.

Should dysrhythmias develop, we suggest standard treatments based on the protocols of Advanced Cardiac Life Support. Ventricular tachycardia in the setting of OP poisoning may be related to QTc prolongation, and treatment with magnesium is reasonable. (See "Advanced cardiac life support (ACLS) in adults".)

Cholinergic toxicity — Patients with cholinergic toxicity due to OP or carbamate poisoning are treated with atropine and oxime therapy (typically pralidoxime). Epinephrine is a second-line therapy for patients who do not respond adequately to high-dose atropine therapy. (See 'Second-line therapy: Epinephrine' below.)

Various autoinjectors for rapid administration of atropine and pralidoxime for treatment of nerve agent poisoning are discussed separately. (See "Chemical terrorism: Rapid recognition and initial medical management", section on 'Nerve agents'.)

Atropine — Atropine competes with acetylcholine at muscarinic receptors, preventing cholinergic activation. Atropine does not treat neuromuscular dysfunction because it does not bind to nicotinic receptors. Atropine is widely available and penetrates moderately into the CNS. It is not necessary to provide oxygen prior to initiating treatment with atropine [67]. The evidence for atropine is based on decades of overwhelming clinical experience and observational data [65]. As examples, mortality rates in several studies ranged from 5 to 13 percent in patients treated with adequate atropinization, compared with approximately 40 to 90 percent when atropine is not administered, is unavailable (eg, resource-limited areas), or is inadequately dosed [68-74]. One of the initial studies reporting the use of atropine in 46 patients with either parathion or tetraethyl pyrophosphate poisoning found a mortality of 92 percent (23 of 25 patients) when atropine was not used, or given inadequately or late, compared with no deaths (21 patients) when given early and in adequate doses [74].

●Initial dose titration – The initial dose is based on the degree of cholinergic toxicity. For a patient with mild toxicity (ie, miosis and severe rhinorrhea but no other symptoms), the initial atropine dose is 1 to 2 mg intravenous/intramuscular/interosseous (IV/IM/IO) in adults and 0.02 to 0.05 mg/kg (maximum dose 2 mg) for children. For moderate to severe cholinergic toxicity (ie, respiratory distress, vomiting, weakness, fasciculations, coma, seizures, apnea, paralysis), atropine should be administered beginning at a dose of 2 to 5 mg IV/IM/IO for adults, and 0.05 mg/kg IV/IM/IO for children. If no effect is noted, the dose should be doubled every three to five minutes until pulmonary muscarinic signs and symptoms are alleviated.

Atropine dosing should be titrated to the therapeutic end point of the clearing of respiratory secretions and cessation of bronchoconstriction [75]. Tachycardia and mydriasis are not contraindications for atropine nor appropriate markers for therapeutic improvement, as they may indicate continued hypoxia, hypovolemia, or sympathetic stimulation. In patients with severe poisoning, hundreds of milligrams of atropine by bolus and continuous infusion may be required over the course of several days. The total amount of atropine used for carbamate poisoning is usually less than with OP poisoning.

Evidence for this individualized approach to treatment is from an open-label trial in which 156 patients treated with incremental doses of atropine plus infusion experienced lower mortality (6 versus 18 deaths) and fewer episodes of atropine toxicity than patients treated with a standard bolus dose plus infusion [76].

●Subsequent continuous infusion – In patients with moderate or severe toxicity, after desired response is achieved with atropine by bolus, we administer 10 to 20 percent of the total cumulative bolus dose as an IV continuous infusion per hour [76-78]. We adjust the infusion rate as needed to maintain adequate response (eg, clear lung auscultation, heart rate >80 beats/minute, systolic blood pressure >80 mmHg, dry axilla, pupils no longer pinpoint) without causing atropine toxicity (eg, confusion, pyrexia, absent bowel sounds, urinary retention). We adjust the infusion according to clinical response and taper until recovery. When atropine toxicity occurs, we hold the infusion until toxicity resolves and restart at 70 to 80 percent of the previous infusion rate.

Pralidoxime — We suggest that oxime therapy be given to all patients with an OP (or unknown cholinesterase inhibitor) exposure and evidence of cholinergic toxicity, neuromuscular dysfunction (including fasciculations), and patients with exposures to OPs known to cause delayed neurotoxicity (figure 5). Pralidoxime (2-PAM) and other oximes (eg, HI-6, obidoxime) are cholinesterase-reactivating agents that treat both muscarinic and nicotinic symptoms (figure 3) [3,22,79]. The dose for IV bolus therapy with pralidoxime is at least 30 mg/kg in adults, and 20 to 50 mg/kg for children (maximum individual dose 2000 mg) [23,80,81]. Pralidoxime should not be administered without concurrent atropine as that may worsen symptoms due to transient oxime-induced acetylcholinesterase inhibition [82]. A response to atropine should be established before pralidoxime is administered.

Pralidoxime should be administered slowly over 15 to 30 minutes. Rapid administration has occasionally been associated with cardiac arrest, and slow administration prevents muscle weakness from the transient inhibition of acetylcholinesterase as pralidoxime binds to the enzyme [83]. After the bolus dose, continuous infusion of 8 to 10 mg/kg per hour in adults and 10 to 20 mg/kg per hour for children appears to provide superior antidotal effects [80,84]. If IV administration is not feasible, pralidoxime can also be given IM or subcutaneously at a dose of 600 mg (15 mg/kg in children <40 kg) repeated as needed for persistent symptoms every 15 minutes to a maximum dose of 1800 mg (45 mg/kg in children).

Continuous IV therapy should be adjusted based upon the patient's clinical response. Severe poisoning may result in prolonged redistribution of the toxin, and several days of therapy may be required [85]. If rapidly available, an increase in serial red blood cell acetylcholinesterase (RBC AChE) activity supports the efficacy of oxime-induced AChE regeneration. A significant decline in RBC AChE activity suggests redistribution of OP out of adipose tissue and may signal the need for more pralidoxime.

Evidence for oximes to treat OP poisoning is inconsistent [86]. The great variability among clinical responses to pralidoxime in patients with OP poisoning is not well understood. In a large, prospective study, patients poisoned with diethyl compounds (eg, chlorpyrifos) had significantly lower mortality and intubation rates following treatment with pralidoxime than those poisoned with dimethyl agents (eg, dimethoate, fenthion) [28]. Conversely, in a small trial, no significant benefit and a trend towards harm were found in the group treated with pralidoxime compared with patients given placebo, regardless of the type of ingested OP [87]. Until this variability is better understood and other treatments become available, we believe that all patients poisoned with OPs should be treated with an oxime. Also, early oxime treatment may decrease the risk of developing intermediate syndrome or OP-induced delayed neuropathy (OPIDN), but evidence is lacking [88].

Second-line therapy: Epinephrine — A relatively small percentage of severely poisoned patients do not respond adequately to high-dose atropine therapy and need additional therapy. For patients whose heart rate remains below 80 beats per minute (bpm) or who remain hypotensive with an adequate heart rate (eg, 80 to 100 bpm) despite receiving high doses of atropine, we suggest an epinephrine infusion.

Little evidence is available to guide such decisions. In a study of 155 patients treated for OP poisoning, 21 (14 percent) did not have a heart rate response of at least 100 bpm despite high-dose atropine therapy and were additionally treated with an epinephrine infusion [69]. All patients treated with epinephrine had an increase in heart rate, with 14 (75 percent) meeting a prespecified goal of 100 bpm. Most patients needed epinephrine for less than 12 hours, and all patients were successfully weaned off epinephrine within 24 hours. Given limitations of the study design, no mortality benefits were associated with the addition of epinephrine.

Decontamination

Topical exposure — In cases of topical exposure with potential dermal absorption, aggressive decontamination with complete removal of the patient's clothes, and vigorous irrigation of the affected areas should be performed. The patient's clothes and belongings should be discarded since they absorb OPs, and re-exposure may occur even after washing. Health care workers must take precautions to avoid accidental exposure, including providing treatment in a well-ventilated area [16,89,90]. (See "Chemical terrorism: Rapid recognition and initial medical management", section on 'Decontamination'.)

Ingestion — We generally do not perform gastric lavage. Nevertheless, some clinicians may perform gastric lavage in a patient who presents less than one hour following ingestion of an OP, after performing tracheal intubation and initiating therapy with atropine and an oxime. Gastric lavage involves substantial risk of aspiration in patients with increased secretions and decreased mental status, and this intervention has never been shown to decrease morbidity or mortality [75]. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Gastric lavage'.)

For a patient who presents within one hour of an OP or carbamate ingestion, we suggest administering activated charcoal (AC). The standard dose is 1 g/kg (maximum dose 50 g) and should be given following initial resuscitation and treatment. Evidence for single-dose AC within one hour of ingestion is indirect based on studies involving other substances and in vitro binding of OPs to AC [91]. A randomized trial suggests that after the second hour, single-dose or multi-dose AC provides no benefit to patients with OP or carbamate ingestions [92]. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

Forced emesis is contraindicated because of the risk of aspiration and seizures. Urinary alkalinization has been suggested, but there is no clear evidence that this intervention improves outcomes [93].

PROGNOSTIC SCORING — 

A prospective study including 1365 patients acutely poisoned with an organophosphate (OP) or carbamate found that a Glasgow Coma Score (GCS) (table 2) of less than 13 portends a poor prognosis [72]. The GCS was equally prognostic to the International Program on Chemical Safety Poison Severity Score (IPCS PSS). However, prognosis depends on the specific OP agent; as an example, one-half of the fenthion-poisoned patients who died had only mild symptoms at presentation. A retrospective study of nearly 400 OP-poisoned patients focused on intensive care unit-based scoring systems found that the Acute Physiology and Chronic Health Evaluation II (APACHE-II), Simplified Acute Physiology Score II (SAPS-II), and the Mortality Prediction Model II (MPM-II) outperformed the Poisoning Severity Scale in predicting death [73]. Similarly, the performance of these scoring systems was partly dependent upon the OP agent involved. (See "Predictive scoring systems in the intensive care unit".)

We suggest using one of the above clinical scoring systems to help determine prognosis, but only for those specific OP-pesticides that were included in the relevant study. Particular attention must be given to patients poisoned with lipophilic OPs such as fenthion and parathion, as these patients may exhibit delayed and prolonged poisoning symptoms.

DISPOSITION — 

A patient with organophosphate (OP) or carbamate exposure who is asymptomatic or minimally symptomatic (ie, only miosis) and improving after 12 hours of observation can be discharged or referred for mental health evaluation (if intentional ingestion). All other patients should be admitted to an intensive care unit for treatment and close monitoring.

Patients who have been treated with atropine and pralidoxime and have recovered should be monitored for at least 24 hours after they are asymptomatic and therapy has been stopped to ensure there is no recrudescence of symptoms from adipose tissue redistribution.

ADDITIONAL RESOURCES

Regional poison centers — Regional poison centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately.

US Pesticide Information Center — Further information on pesticide intoxication can be obtained in the United States (US) from National Pesticide Telecommunications Network at: 1-800-858-7378 or http://npic.orst.edu/.

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse" and "Society guideline links: Chemical terrorism".)

SUMMARY AND RECOMMENDATIONS

●Clinical features – Acute toxicity from organophosphates (OP) or carbamates presents with manifestations of cholinergic excess. The dominant clinical features of acute cholinergic toxicity include bradycardia, miosis, lacrimation, salivation, bronchorrhea, bronchospasm, urination, emesis, and diarrhea. (See 'Acute toxicity' above.)

Ten to 40 percent of OP-poisoned patients develop a distinct neurologic disorder 24 to 96 hours after exposure. This disorder consists of characteristic neurologic findings including neck flexion weakness, decreased deep tendon reflexes, cranial nerve abnormalities, proximal muscle weakness, and respiratory insufficiency. (See 'Intermediate (neurologic) syndrome' above.)

●Diagnosis – Organophosphate (OP) or carbamate poisoning is a clinical diagnosis in a patient with findings of cholinergic toxicity. Due to significant variability in toxicity and treatment, every effort should be made to precisely identify the agent when known. (See 'Diagnostic evaluation' above.)

Assessing clinical response after a challenge dose of atropine can also provide supporting evidence. (See 'Role of atropine challenge' above.)

Diagnosis can be confirmed by either direct measurement of red blood cell acetylcholinesterase (RBC AChE) activity or butyrylcholinesterase (also known as pseudocholinesterase or plasma cholinesterase) activity. Most hospital laboratories are unable to perform the former test, while the latter is more easily performed but does not correlate well with severity of poisoning. (See 'Measurement of cholinesterase activity' above.)

●Management – Management is based on clinical findings and should not be delayed pending confirmation with laboratory studies (table 1). Patients with markedly depressed mental status require 100 percent oxygen and immediate tracheal intubation. Nondepolarizing neuromuscular blocking agents (eg, rocuronium), often in larger doses, should be used instead of succinylcholine when performing rapid sequence intubation (RSI). Adequate volume resuscitation with isotonic crystalloid should be performed concomitantly with other resuscitative and diagnostic efforts. (See 'All patients: Supportive care' above.)

•Atropine – In a patient with cholinergic toxicity from OP or carbamate poisoning, we recommend atropine therapy (Grade 1A). For a patient with mild toxicity (ie, miosis and severe rhinorrhea but no other symptoms), the initial atropine dose is 1 to 2 mg intravenous/intramuscular/interosseous (IV/IM/IO) in adults and 0.05 mg/kg (maximum dose 2 mg) for children. For moderate to severe cholinergic toxicity (ie, respiratory distress, vomiting, weakness, fasciculations, coma, seizures, apnea, paralysis), atropine should be administered beginning at a dose of 2 to 5 mg IV for adults and 0.05 mg/kg IV for children. If no effect is noted, the dose is doubled every three to five minutes until pulmonary muscarinic signs and symptoms are alleviated. In patients with moderate or severe toxicity, after the desired response is achieved with atropine bolus, a continuous infusion is needed. (See 'Atropine' above.)

For patients whose heart rate remains below 80 beats per minute (bpm) or who remain hypotensive with an adequate heart rate (eg, 80 to 100 bpm) despite receiving high doses of atropine, we suggest an epinephrine infusion (Grade 2C). (See 'Second-line therapy: Epinephrine' above.)

•Oxime therapy – In a patient with an OP (or unknown cholinesterase inhibitor) exposure and cholinergic toxicity or neuromuscular dysfunction (including fasciculations) or exposure to OPs known to cause delayed neurotoxicity (figure 5), we suggest oxime therapy (Grade 2C). The pralidoxime dose is at least 30 mg/kg IV in adults and 20 to 50 mg/kg for children (maximum dose 2000 mg), followed by a continuous infusion. Pralidoxime should not be administered without concurrent atropine. (See 'Pralidoxime' above.)

•Benzodiazepines – OP-induced seizures or agitation should be treated with a benzodiazepine (eg, diazepam 10 mg IV in adults; 0.1 to 0.2 mg/kg in children). In a patient with coma, apnea, or neuromuscular paralysis, we also suggest a benzodiazepine (Grade 2C). Benzodiazepines may decrease neurocognitive dysfunction and central nervous system-mediated respiratory depression. (See 'Seizures, agitation' above and 'Respiratory failure, neuromuscular dysfunction, or coma' above and "Convulsive status epilepticus in adults: Management", section on 'First therapy: Benzodiazepines' and "The acutely agitated or violent adult: Pharmacologic management", section on 'Benzodiazepines'.)

•Decontamination – In cases of topical exposure with potential dermal absorption, aggressive decontamination with complete removal of the patient's clothes and vigorous irrigation of the affected areas should be performed. For a patient who presents within one hour of an OP or carbamate ingestion, we suggest administering activated charcoal (AC) (Grade 2C). The dose is 1 g/kg (maximum dose 50 g) and should be given following initial resuscitation and treatment. (See 'Decontamination' above.)