Management of acute organophosphorus pesticide poisoningBMJ 2007; 334 doi: http://dx.doi.org/10.1136/bmj.39134.566979.BE (Published 22 March 2007) Cite this as: BMJ 2007;334:629
- 1South Asian Clinical Toxicology Research Collaboration, Australian National University
- 2Regional Poison Center, Children's Hospital of Michigan, Detroit, MI 48201, USA
- Correspondence to: C K Aaron
Organophosphorus pesticides are used widely for agriculture, vector control, and domestic purposes. Despite the apparent benefits of these uses acute organophosphorus pesticide poisoning is an increasing worldwide problem, particularly in rural areas. Organophosphorus pesticides are the most important cause of severe toxicity and death from acute poisoning worldwide, with more than 200 000 deaths each year in developing countries.1 Although the incidence of severe acute organophosphorus pesticide poisoning is much less in developed countries, many patients with acute low dose unintentional or occupational exposures present to health facilities.2 3 We provide an evidence based review of the management of acute organophosphorus pesticide poisoning. Risk assessment in patients with acute unintentional poisoning is discussed, in addition to special considerations for severe poisoning.
Acute organophosphorus poisoning may induce multisystem toxicity leading to severe toxicity and death
Poisoning is diagnosed on the basis of history and clinical examination; biochemical investigations can have a role for confirming the diagnosis
Management consists of prompt resuscitation, antidotes as required (particularly atropine, oximes, benzodiazepines), and selective decontamination
Ongoing monitoring and high quality supportive care are essential
Healthcare staff treating exposed patients should exercise standard precautions
Sources and selection criteria
We searched several resources to identify relevant information on the diagnosis and management of acute organophosphorus poisoning: Medline, Embase, the Cochrane Library, and the Chemical Safety Information for Intergovernmental Organizations database (www.inchem.org/pages/pds.html); websites for registration of clinical trials, including the Current Controlled trials website (http://controlled-trials.com/) using the mRCT search feature; personal archives; and attendance at, and review of abstracts from, workshops and conferences on pesticide poisoning.
Levels of evidence in the review
The evidence supporting specific therapeutic approaches to patients with acute organophosphorus poisoning is listed after each management recommendation. We have adopted the classification used in the BMJ publication Clinical Evidence4:
Likely to be beneficial (LB)
Trade-off between benefits and harms (TO)
Unknown effectiveness (UE)
Unlikely to be beneficial (UB)
Likely to be ineffective or harmful (LIH)
Why do I need to know about acute organophosphorus poisoning?
Household and agricultural products containing organophosphorus pesticides are prevalent (box 1), allowing many opportunities for acute poisoning. Since the correlation between intent, dose, and severity of toxicity after acute poisoning is poor, each exposure requires a thorough review.2 A structured approach to risk assessment of exposed patients is necessary.5 Long term complications occasionally occur so a rigorous assessment is required given potential legal implications in unintentional, criminal, or occupational exposures.
Box 1: Sources of organophosphorus pesticides
Garden sheds—in particular insecticidal preparations, but also other products that are marketed as fertilisers but contain some organophosphorus pesticides, available as solid or liquid formulations
Surface and room sprays
Baits for cockroaches and other insects (for example, chlorpyrifos)
Shampoos against head lice (for example, malathion)
Pet preparations (for example, pet washes, collars)
Industrial or occupational
Crop protection and livestock dipping
Large scale internal control, including fumigation
Terrorism or warfare (nerve agents)
Sarin, for example, was used in the Tokyo subway attack, and both tabun and sarin were used during the Iraq-Iran conflict. Although nerve agents share a similar mechanism of toxicity with organophosphorus pesticides, their treatment is a specialised topic and not dealt with in this review
Patients with moderate to severe organophosphorus pesticide poisoning usually require management in an intensive care unit.2 6 7 Mortality from severe poisoning is high (>10%)1 compared with the overall mortality from pharmaceuticals (<0.5%).w1 Current evidence suggests that prompt and appropriate management optimises outcomes (LB).
What is the pathophysiology of acute organophosphorus poisoning?
The effects of organophosphorus compounds on human physiology are multiple and complex. Organophosphorus compounds inhibit numerous enzymes, of which esterases seem to be the most clinically important. Inhibition of acetylcholinesterase leads to the accumulation of acetylcholine at cholinergic synapses, interfering with the normal function of the autonomic, somatic, and central nervous systems. This produces a range of clinical manifestations, known as the acute cholinergic crisis (box 2).8 9 Other esterases are also inhibited, causing clinically important illnesses (for example, neuropathy target esterase, producing organophosphorus induced delayed polyneuropathy (box 2)10 w2), whereas other esterases such as butyrylcholinesterase (also known as pseudocholinesterase or plasma cholinesterase) and carboxylesterase, do not cause clearly defined illness.8 Butyrylcholinesterase hydrolyses exogenously administered pharmaceuticals such as lidocaine and suxamethonium (succinylcholine), which may have an effect clinically. The organophosphorus-esterase complex undergoes either spontaneous reactivation, allowing normal enzymatic function, or irreversible inhibition (described as ageing), as shown in figure 1⇓. The rate of these competing reactions varies by more than 10-fold between individual organophosphorus compounds, which influences the clinical manifestations and response to treatments.8 13
Box 2: Clinical features of acute organophosphorus poisoning8-10
Acute cholinergic crisis
The acute cholinergic crisis is caused by the accumulation of acetylcholine at cholinergic synapses. The particular clinical features depends on the type of receptors and their location:
Muscarinic receptors: diarrhoea, urinary frequency, miosis, bradycardia, bronchorrhoea and bronchoconstriction, emesis, lacrimation, salivation (DUMBELS), and hypotension. Cardiac arrhythmias have also been reported
Nicotinic receptors: fasciculations and muscle weakness, which may progress to paralysis and respiratory failure,* mydriasis, tachycardia, and hypertension
Central nervous system: altered level of consciousness, respiratory failure,* and seizures; the relative contribution of cholinergic and other neurotransmitters is not well characterised
*Respiratory failure occurs as a result of centrally or peripherally mediated mechanisms. It may manifest either during the acute cholinergic crisis (type I paralysis) or during an apparent recovery phase (intermediate syndrome, or type II paralysis). Weakness of neck flexors is an early sign of significant muscle weakness and may be useful for predicting the onset of respiratory failure11 12
Organophosphorus induced delayed polyneuropathy
Organophosphorus induced delayed polyneuropathy is unrelated to acetylcholinesterase inhibition and occurs because of inhibition of other enzymes, in particular neurotoxic target esterase. It is characterised by demyelination of long nerves, when neurological dysfunction occurs 1-3 weeks after an acute exposure, particularly motor dysfunction but also sensory dysfunction, which may be chronic or recurrent
Although clinicians commonly think of organophosphorus compounds as an interchangeable class, noticeable differences are observed between individual agents in the clinical manifestations of acute poisoning.8 9 11 12 14 This may result from differences in pharmacokinetics,8 13 14 potency of enzyme inhibition,8 15 additional mechanisms of toxicity, such as oxidative stress,w3 dynamic physiological adaptations after prolonged stimulation,8 12 13 differences between patients,14 16 or a complex interplay of these and other unknown factors.8 11w3
How is organophosphorus poisoning diagnosed?
A history of acute exposure to an organophosphorus pesticide and development of characteristic clinical effects (box 2) is diagnostic of organophosphorus poisoning. When the history is not forthcoming, the differential diagnosis is broad and may include intoxication with carbamates or other poisons or pontine haemorrhage. Therefore a good history, a high index of suspicion, and a detailed clinical examination are essential. Although individual organophosphorus compounds manifest differently,14 the mnemonic DUMBELS and other clinical features described in box 2 are useful prompts for the signs and symptoms that should be considered. Onset of clinical toxicity is variable; however most patients who develop severe toxicity usually have symptoms within six hours. Patients remaining asymptomatic for 12 hours after ingestion are unlikely to develop major clinical toxicity.2 9 Exceptions are some highly lipophilic organophosphorus compounds (most importantly fenthion), which initially produce only subtle cholinergic features then, over several days, produce progressive muscle weakness, including respiratory failure requiring intubation for several days.12 14
When the diagnosis is in question or there is doubt about the significance of exposure, quantification of butyrylcholinesterase or acetylcholinesterase activity is helpful. Cholinesterase inhibition is generally noted before clinical effects.13w4 Butyrylcholinesterase is particularly useful because it is widely available and a sensitive marker of exposure given that it is preferentially inhibited by many organophosphorus compounds.13 15 w5 Acetylcholinesterase and butyrylcholinesterase are generally depressed within six hours of exposure to an organophosphorus compound, although the nadir may not be observed until 12-24 hours after ingestion (Roberts DM, unpublished observation).17 Baseline activity of the two esterases varies largely between patients,13 18 therefore the reference range of these assays is wide. The degree of cholinesterase inhibition may correlate with severity of poisoning. Erythrocyte acetylcholinesterase is structurally similar to synaptic acetylcholinesterase so its activity is thought to reflect synaptic acetylcholinesterase activity and is considered the most useful biomarker of severity.9 13 Acetylcholinesterase or butyrylcholinesterase activity that is less than 80% of the lower reference range, however, is probably indicative of a significant exposure to an organophosphorus pesticide13 18 w3; patients with an activity higher than this might still have been exposed, but only to a lesser degree. In severe clinical toxicity, erythrocyte acetylcholinesterase activity is less than 20% of normal.9 13 19 Butyrylcholinesterase has no relation to the severity of clinical toxicity because the affinity of organophosphorus for butyrylcholinesterase is highly variable and differs from that of acetylcholinesterase.13 17 18 The influence of other causes of depressed acetylcholinesterase or butyrylcholinesterase should also be considered, including drugs, chronic disease, and genetic polymorphisms.
Several methods for classifying the severity of acute organophosphorus poisoning other than cholinesterase inhibition have been developed using clinical data and laboratory investigations. To date, however, few of these methods have been validated or widely adopted. Figure 2⇓ shows a simplified method for considering the severity of organophosphorus poisoning. This classification is intended to guide clinical management rather than to be used for prognostication. Generalised approaches to prognostication in organophosphorus poisoning are difficult given that individual compounds vary noticeably in onset, severity, and clinical manifestations.14 Furthermore, such generalised approaches are not often useful for guiding management. This classification is based primarily on clinical variables so it can be used in resource poor environments when access to clinical investigations is limited.
In the case of skin exposures, the potential for toxicity is poorly defined. Organophosphorus compounds may be absorbed through the skin. Absorption is usually prolonged, leading to delayed onset of clinical toxicity and inhibition of butyrylcholinesterase.
What is the initial management of patients with acute organophosphorus poisoning?
Patients with acute exposures to organophosphorus compounds should undergo immediate assessment and management of disturbances in airway, breathing, and circulation (LB). Further steps are based on risk assessment and observations during continuous monitoring (fig 2⇑5 7 11), including dose ingested, time since ingestion, clinical features, patient factors, and available medical facilities.5 When antidotal therapy is indicated it should be given rapidly (LB). Although the amount ingested according to the history seems to be a poor predictor of the amount absorbed,16 17 all patients after deliberate ingestion should be managed initially as for severe poisoning. In concert with immediate assessment and resuscitation, all patients should undergo some degree of skin decontamination. Simply removing exposed clothing reduces the risk of exposure in patients and staff.
What antidotes are used in the management of acute organophosphorus poisoning?
The three most widely used classes of antidotes are muscarinic antagonists (usually atropine) (LB), oximes (usually pralidoxime or obidoxime) (UE), and benzodiazepines (LB).4 7 Atropine is carefully titrated to reverse muscarinic effects (box 2).4 7 As atropine has no effect on the neuromuscular junction and muscle weakness, oximes are used clinically to reverse neuromuscular blockade by reactivating the inhibited acetylcholinesterase before ageing. Oximes should be given as early as possible to limit the degree of ageing (fig 1⇑).8 Evidence supporting the efficacy of oximes and the dosing regimen is limited (UE).20 A recent randomised controlled trial using pralidoxime iodide (1 g is roughly equal to 650 mg pralidoxime chloride) concluded that after an initial 2 g bolus to both groups, high dose pralidoxime iodide (24 g/d for 48 hours, then 1 g every 4 hours until recovery) was more effective than a lower dosing regimen (1 g every 4 hours until recovery), although further studies were recommended.21 Despite limitations in the current data and based on clinical experience we recommend oxime use in patients with moderate to severe organophosphorus poisoning (UE)7 19 and benzodiazepines for patients with agitation and seizures (LB).19 The table⇓ lists organophosphorus triggered signs and symptoms and some suggested therapies (see also box 3 and figure 2).
Box 3: Specific treatments for the routine management of acute organophosphorus poisoning2 4 7 8 w6
For poisoning in adults initially give 1-3 mg atropine intravenously (0.02 mg/kg in children). The main end points of atropinisation are a clear chest on auscultation with resolution of bronchorrhoea (focal crepitations or wheeze may be noted when there has been pulmonary aspiration) and a heart rate of more than 80 beats/min. If these targets are not achieved by 3-5 minutes, double the intravenous dose. Continue to double the dose and give intravenously every 3-5 minutes until atropinisation has been achieved. Some patients may require large doses (hundreds of mg).
Maintain atropinisation by infusion, starting with 10%-20% of the loading dose every hour. Regular clinical observations are necessary to ensure that atropinisation is achieved without toxicity (delirium, hyperthermia, and ileus)
Several oximes have been developed, but two are more commonly used for acute organophosphorus poisoning. They are administered as an infusion which continues until recovery (12 hours after atropine has been stopped or once butyrylcholinesterase is noted to increase).
Pralidoxime chloride—loading dose of 30 mg/kg intravenously over 20 minutes, followed by an infusion of 8 mg/kg/h. In adults it is usually given as a 2 g loading dose followed by 500 mg/h. Various salts are available and their dose is determined by converting this dose into equivalent dosing units
Obidoxime—loading dose of 4 mg/kg over 20 minutes, followed by an infusion of 0.5 mg/kg/h. In adults it is usually given as 250 mg loading dose followed by 750 mg every 24 hours
Benzodiazepines are usually given intravenously as required for agitation or seizures with doses starting at: 5-10 mg diazepam (0.05-0.3 mg/kg/dose), lorazepam 2-4 mg (0.05-0.1 mg/kg/dose), or midazolam 5-10 mg (0.15-0.2 mg/kg/dose)
Dermal spills—wash pesticide spills from the patient with soap and water and remove and discard contaminated clothes, shoes, and other materials made from leather (LB)
Gastric lavage—consider for presentations within one or two hours, when the airway is protected. A single aspiration of the gastric contents may be as useful as lavage (UE)
Activated charcoal without cathartic—50 g may be given orally or nasogastrically to patients who are cooperative or intubated, particularly if they are admitted within one or two hours or have severe toxicity (UE)
Other antidotes and treatments have been proposed for acute organophosphorus poisoning, but data supporting their efficacy are currently too limited to recommend routine use.4 Several clinical trials are in progress in Asia to tackle this limited evidence.22
Auto-injectors, developed for use in exposures to organophosphorus nerve agents, are available as a fixed dose of muscarinic antagonist and oxime. Because of differences between organophosphorus compounds in onset and clinical manifestations, the role of these auto-injectors in the management of acute organophosphorus pesticide poisoning is limited, but they can be utilised when other forms of antidotes are not available. Clinical experience suggests that the dose of atropine must be carefully titrated, and doses higher than those included in these formulations are usually required.7 The oxime HI-6 is increasingly being included in auto-injectors for the treatment of poisoning with nerve agents. It is a more effective reactivator of acetylcholinesterase inhibited by nerve agents compared with pralidoxime and obidoxime.
What considerations are needed for patients with mild or no clinical toxicity, including skin exposures?
Patients who present with a history of unintentional poisoning who are asymptomatic or have mild symptoms often do not require admission to hospital (fig 2⇑). Management priorities for these patients are rapid triage, a detailed risk assessment, and consideration of forensic implications. If the exposure is considered trivial, the patient can be observed at home or in the workplace. Other patients should be decontaminated and monitored for a minimum of 6-12 hours. If possible, cholinesterase activity should be measured to quantify the exposure. A normal cholinesterase activity six hours after exposure may be sufficient to exclude a major ingestion, although this approach has not been sufficiently assessed.
Patients with a single skin exposure rarely develop major clinical effects and probably do not require medical assessment. Volunteer studies document the risk of a skin exposure leading to significant clinical toxicity to be far below that of ingestion. Although the rate of organophosphorus absorption across the skin is slower than that across the gut, patients who are asymptomatic at 12 hours are unlikely to develop toxicity. Such patients should be given instructions to present for medical review if signs and symptoms noticeably worsen. If there is concern about a skin exposure, testing for changes in cholinesterase activity is recommended.
What considerations are needed for patients with moderate and severe poisoning?
Patients with moderate or severe organophosphorus poisoning should be admitted to an intensive care unit after resuscitation to allow careful titration of antidotes (fig 2⇑), intubation, ventilation, and inotropes or vasopressors if required.7 Specialist advice from a clinical or medical toxicologist is recommended; one can be contacted through the local poisons information centre in many regions (www.who.int/ipcs/poisons/centre/directory/en/). Close observations are also required because rapid clinical deterioration and death are reported in patients who seemed to be recovering from the acute cholinergic crisis.6 11 High quality general medical and nursing care is a priority as hospital stay may be long and secondary complications are an important cause of morbidity and mortality. If this level of care cannot be provided or the facility does not have ready access to antidotes, then the patient should be transported promptly to a more appropriate facility by staff able to provide advanced life support. The rate of recovery from severe organophosphorus poisoning, and therefore the duration of stay in intensive care and requirement for antidotes, varies widely depending on the patient, dose and type of organophosphorus pesticide, and provision of advanced supportive care.
What precautions are needed for staff treating patients with acute organophosphorus poisoning?
Nosocomial poisoning of staff and family members exposed to patients with acute organophosphorus poisoning should be borne in mind. Few, if any, cases of significant exposure have been documented. Although mild symptoms such as nausea, dizziness, weakness, and headache have been reported in staff, these resolved after exposure to fresh air and were probably the result of inhalation of the hydrocarbon solvent, which is a coformulant in the pesticide product. Abnormal cholinesterase activities have not been reported in any staff or family members exposed to a patient with organophosphorus poisoning. Furthermore, estimates of exposure in healthcare staff are low compared with other occupations. Agricultural workers have higher exposures, but subsequent toxicity is rarely observed. Universal precautions including nitrile gloves are probably sufficient to protect staff.23 24 Symptomatic or concerned staff members can be treated as for minor exposure (fig 2⇑).
How does the management of carbamate poisoning differ from that of organophosphorus pesticides?
Carbamate pesticides also induce an acute cholinergic crisis through inhibition of acetylcholinesterase. Because carbamates are structurally different from organophosphorus compounds, acetylcholinesterase inhibited by carbamates does not age, allowing spontaneous reactivation and restoration of normal nervous function.13 Carbamates are considered to cause milder poisoning of shorter duration than organophosphorus pesticides. Evidence is, however, mounting that severe toxicity and death occur with some carbamates, in particular carbosulfan and carbofuran. Atropine and benzodiazepines are given as for organophosphorus pesticide poisoning (LB; fig 2⇑). Because carbamate inhibited acetylcholinesterase does not age, the role for oximes seems limited, but is controversial. Some in vitro and animal studies have suggested that oximes improve outcomes (with the exception of carbaryl), although clinical data are limited. It is not unreasonable for oximes to be given to patients with an unknown exposure and evidence of acetylcholinesterase inhibition (UE).
Unanswered research questions and ongoing research
Many other treatments have been trialled for use in patients with acute organophosphorus poisoning, but at present high quality data are insufficient to make evidence based recommendations. Examples include4:
Activated charcoal (UE): a randomised controlled trial comparing a single dose or multiple doses of activated charcoal with placebo (ISRCTN02920054) was completed in 2005.25 The full analysis is expected to be reported in 2007
α-2 adrenergic receptor agonists—for example, clonidine (UE)
Butyrylcholinesterase replacement therapy (UE)
Gastric lavage (UE): a randomised controlled trial comparing single with triple gastric lavage was planned to start in 2006 (ISRCTN24754520)
Extracorporeal blood purification, including haemodialysis, haemofiltration, and haemoperfusion (UE)
Magnesium sulphate: ISRCTN50739829 (UE)
Organophosphorus hydrolases (UE)
Blood alkalinisation—for example, sodium bicarbonate (UE)
ADDITIONAL EDUCATIONAL RESOURCES
Clinical evidence (www.clinicalevidence.org)
Contains information on acute organophosphorus poisoning
Cochrane Collaboration (www.thecochranelibrary.org)
Includes systematic reviews on the management of organophosphorus poisoning
Organophosphorus and carbamate pesticides (www.aic.cuhk.edu.hk/web8/pesticides.htm)
Summarises the mechanism of toxicity and clinical considerations for the treatment of acute organophosphorus pesticide poisoning
Recognition and management of pesticide poisonings (www.npic.orst.edu/RMPP/rmpp_ch4.pdf)
Contains a chapter on organophosphate insecticides
Information for patients
Medline plus (www.nlm.nih.gov/medlineplus/ency/article/002837)
Discusses clinical effects and management of diazinon poisoning
Medline plus (www.nlm.nih.gov/medlineplus/ency/article/003358.htm)
Provides general information on cholinesterase assays
We thank Nick Buckley for helpful comments. DMR is funded by a scholarship from the National Health and Medical Research Council (Australia). The South Asian Clinical Toxicology Research Collaboration is funded by a Wellcome Trust and National Health and Medical Research Council international collaborative research grant (No GR071669MA).
Contributors: DMR drafted the initial manuscript which was then improved after discussion between DMR and CKA. Both authors are guarantors.
Competing interests: None declared.
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