Management of acute organophosphorus pesticide poisoning

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.

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

Fig 1 Interactions of organophosphorus compounds in vivo; relative rates of each reaction vary between organophosphorus compounds8

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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 11^w3

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.13^w4 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.

Fig 2 Decision tree for management of patients presenting with history of acute organophosphorus poisoning.5 7 8 9 11 *Patients may have variable degrees of miosis, salivation, diaphoresis, urinary frequency, or lacrimation, which may assist in diagnosis of organophosphorus poisoning. Because these manifestations are not considered to influence outcome they are not included in this decision tree. †Assessment of respiratory status includes respiratory rate and depth, presence of adventitious sounds such as rales and rhonchi, presence of bronchorrhoea, and objective measurements of pulse oximetry, arterial blood gases, and forced vital capacity or forced expiratory volume in one second. ‡Muscle weakness: difficulty in mobilisation or reduced forced vital capacity on spirometry before development of paralysis and respiratory failure. §Caution with patients with a history of exposure to fenthion (or highly fat soluble organophosphorus compounds). Patients with fenthion poisonings are usually characterised by minimal or absent cholinergic symptoms for 24-48 hours, after which they develop increasing muscle weakness and respiratory failure

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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).

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).