Medical Management of Acute Organophosphorus Pesticide Self-Poisoning

Abstract

Organophosphorus (OP) pesticide self-poisoning is a major clinical problem across the rural developing world, killing an estimated 200,000 people every year. Medical management is difficult, with case fatality often over 20%. In this review, we describe the limited evidence base that should guide therapy. Fifty years after first being used, we still do not know how the core treatment - atropine, oximes, and diazepam - should best be administered. Major constraints in collecting useful data have been the late recognition of great variety among OPs and the care that cholinesterase assays require for their results to be interpreted or compared between studies. However, consensus exists that early resuscitation with atropine, oxygen, respiratory support, and fluids is required to improve oxygenation of patients. The role of oximes is unclear - they may only benefit patients poisoned by some OPs or patients with moderate poisoning. Small studies have suggested possible benefit from new treatments, eg. magnesium sulphate, but much larger trials are needed. Gastric lavage may have a role but should only be considered once the patient is stable. RCTs are now underway in rural Asia to address particular aspects of therapy. However, some specific OP pesticides may ultimately prove very difficult to treat with current treatments such that focused bans may be the only method to substantially bring down the case fatality for OP poisoning. Improved medical management of OP poisoning will result in a marked reduction in the global number of deaths from suicide.

Search strategy

We carried out a systematic search for relevant studies by searching MEDLINE, EMBASE, UK National Research Register, Injuries Group Specialised Register, Clinicaltrials.gov and the Cochrane databases with the search terms ‘organophosphorus’ or ‘organophosphate’ and ‘poisoning’. We did not limit the search by language; however, we had a limited capacity for translating papers from Chinese where many studies have been performed. Translation of Chinese papers was therefore ordered according to their relevance as determined by review of the abstract in English. We also used information from our ongoing studies in Sri Lanka that have recruited 2000 OP poisoned patients and from discussions with clinicians seeing OP poisoned patients across Asia.

Organophosphorus (OP) pesticide self-poisoning is a major clinical and public health problem across much of rural Asia.^1-3 Of the estimated 500,000 deaths from self-harm that occur in the region each year,⁴ about 60% are due to pesticide poisoning.³ Multiple studies indicate that OP pesticides are responsible for around 2/3 of these deaths⁵ - a total of 200,000 a year.³

District hospitals in rural areas bear the brunt of this problem, seeing many hundreds of OP pesticide poisoned patients each year, with a case fatality often between 15 and 30%.^5,6 Unfortunately, these hospitals are often not staffed or equipped to deal with these very sick patients - intensive care beds and ventilators are lacking so that even unconscious patients are managed on the open ward (figure 1). Furthermore the evidence base for treatment is weak⁷ and where evidence of benefit does exist for particular antidotes, these antidotes have often been used in non-ideal regimens^8-10 or been locally unavailable.³

Figure 1. Management of a severely OP poisoned patient in a Sri Lankan district hospital.

The lack of ICU beds and ventilators means that unconscious patients are often intubated and ventilated on the open ward.

Despite the large numbers of deaths from self-harm, there is little evidence that intentional self-harm is more common in the rural tropics.^11,12 Instead, it seems that the act is simply much more dangerous.³ Better medical management and provision of antidotes and intensive care beds, together with bans of the most toxic pesticides,¹³ should bring down the case fatality for self-poisoning and markedly reduce the number of deaths from self-harm across the region.^3,7

Pathophysiology and presentation of OP pesticide poisoning

OPs inhibit the enzymes acetylcholinesterase (AChE, EC 3.1.1.7) in synapses and on red cells and butyrylcholinesterase (BuChE, EC 3.1.1.8) in plasma.¹⁴ Whilst BuChE inhibition appears harmless, AChE inhibition results in accumulation of acetylcholine (ACh) and ACh receptor overstimulation in synapses of the autonomic nervous system, central nervous system (CNS), and neuromuscular junction (NMJ).¹⁴ The subsequent autonomic, CNS, and NMJ features of OP poisoning are well known (box 1).

Box 1. Clinical features of OP pesticide poisoning ^15,73,74.

Features due to overstimulation of muscarinic ACh receptors in the parasympathetic system:

• bronchospasm

• hypotension

• bronchorrhoea

• bradycardia

• miosis

• vomiting

• lachrymation

• sweating

• urination/diarrhoea

• salivation

Features due to overstimulation of nicotinic ACh receptors in the sympathetic system:

• tachycardia

• hypertension

• mydriasis

Features due to overstimulation of nicotinic and muscarinic ACh receptors in the CNS:

• confusion

• coma

• agitation

• respiratory failure

Features due to overstimulation of nicotinic and muscarinic ACh receptors at the neuromuscular junction (NMJ):

• Muscle weakness

• Fasciculation

Patients usually present with features of parasympathetic overstimulation - termed the cholinergic crisis. A few may show signs of sympathetic stimulation, including tachycardia. However, tachycardia can also be caused by hypovolemia, hypoxia, previous administration of atropine, and alcohol withdrawal. Respiratory failure occurs due to bronchospasm, bronchorrhoea (both reversed by atropine) and NMJ and CNS dysfunction. Patients may also progress to a peripheral respiratory failure while conscious after apparently recovering from the cholinergic crisis - this has been termed type II respiratory failure or the intermediate syndrome.^37,75 This is an important cause of death in patients stabilised on admission.

Diagnosis is based on clinical suspicion, the characteristic clinical signs and smell of pesticide and solvents, and reduced BuChE activity in the blood.¹⁴ It is simple in regions where OP poisoning is common - most patients with pinpoint pupils, excessive sweating, reduced consciousness, and poor respiration have severe OP poisoning. The major differential is carbamate poisoning, which is clinically indistinguishable and treated identically except perhaps for withholding oxime treatment.¹⁵

Cholinesterase assays

A diagnosis of OP poisoning should ideally be confirmed with an assay to measure BuChE activity in the plasma.¹⁴ Unfortunately, the literature is filled with confusion about the use and interpretation of assays for AChE and BuChE (box 2).

Box 2. Problems with ChE activity assays.

There has often been marked confusion about the measurement of AChE and BuChE in OP poisoned patients.

Plasma BuChE assays

• ○Inhibition of BuChE, also called plasma or pseudo-cholinesterase, does not reflect clinical severity of the poisoning. Since many OPs are more potent inhibitors of BuChE than AChE, BuChE inhibition may occur to a greater extent than AChE inhibition. BuChE assays can be used to detect exposure to an OP or carbamate pesticide.
• ○BuChE is produced by the liver and blood levels recover at about 7% each day once the OP has been eliminated. Daily BuChE assays can be used to monitor when the BuChE starts to rise again, since this recovery indicates that the OP has been eliminated (figure 2).
• ○
  There is much variation between commercial assays that make comparisons between studies difficult:

  • ■
    The concentration of butyrylthiocholine (BTCh) substrate varies between assays. A high concentration of BTCh (eg 7 mM vs. 1 mM) will result in a 30% higher measured activity.⁷⁶
  • ■
    Measurement of BuChE without plasma is required to determine non-enzymatic hydrolysis of BTCh and hence background values. Not all commercial assays provide such a control. The background level of spontaneous BTCh hydrolysis is affected by pH and BTCh concentration, which both vary between assay kits.⁷⁶
  • ■
    Temperature control is important, because BuChE activity increases by some 4% per 1°C increase in temperature.⁷⁷

Red cell AChE assays

• ○These assays measure AChE expressed on the surface of red cells. Red cell AChE inhibition is a good marker of AChE inhibition in synapses and of poisoning severity. AChE is measured in whole blood with BuChE activity blocked by an inhibitor. AChE is present at very low levels in human plasma/serum.
• ○Red cell AChE, once aged, only recovers with erythropoeisis. Regeneration at <1% per day is therefore markedly slower than BuChE regeneration. It is not clear at what rate neuronal AChE recovers spontaneously, and thus red cell AChE may become a less useful marker of synaptic AChE activity over time.
• ○Reactions between AChE, OP and oximes will continue rapidly if a blood sample is left at room temperature after sampling. The measured AChE activity will then not represent the exact activity in the blood at the time of sampling; leaving samples for variable times will produce variation in the assay (figure 3). Blood samples must be diluted and cooled immediately after sampling, to stop the reactions. We routinely dilute 20-fold at the bedside by mixing 200 μl of blood freshly drawn into an EDTA tube into 4 ml of cold normal saline (at 4°C) and then place the sample in a -20°C freezer within 5 mins.
• ○Incubating an aliquot of the blood sample with a large quantity of oxime (eg 100 μmol/L obidoxime) for 15 mins before assay will reactivate any AChE that is not aged. Such an assay could potentially be used to determine whether a patient might still benefit from oxime therapy or from higher doses.

Summary

Monitoring a patient’s cholinesterase status after OP poisoning enables the verification of significant exposure to anti-cholinesterase agents. In future, such assays may facilitate the decision about when to stop oxime treatment and allow cautious weaning of a patient from a ventilator when the BuChE activity is increasing. Studies are underway to confirm the clinical usefulness of this approach

Some OPs inhibit BuChE more effectively than they inhibit AChE.¹⁶ Since BuChE activity does not relate to severity of poisoning, BuChE inhibition cannot be used to assess severity. It can however be used as a sensitive marker of 1) exposure to most OPs or other ChE-inhibiting compound and 2) when the OP has been eliminated from the body (figure 2).

Figure 2. Use of BuChE recovery as a marker of OP pesticide elimination in A) dimethoate and B) fenthion poisoning.

Dimethoate is hydrophilic and rapidly excreted from the body. Plasma BuChE activity therefore begins to climb again within two days of ingestion. By contrast, fenthion is fat soluble and slowly redistributes into the blood after initial distribution into the fat. As a result, fenthion remains detectable in the blood for many days and BuChE activity remains inhibited.

Red cell AChE is a good marker of synaptic function and atropine requirements in OP poisoned patients and therefore a good marker of severity.^17,18 A major problem with AChE assays is that the interaction between OP, AChE, and oximes continues to occur if the sample is left at room temperature for even a few minutes (box 2). To get reliable results, it is essential to stop the reaction immediately the blood sample is taken from the patient, by cooling and diluting it. Otherwise differences in time to sample cooling of only a few minutes for repeated sampling will cause marked variation and make interpretation difficult (figure 3).

Figure 3. Effect of sampling delays on AChE reactivation.

AChE activity was assayed in lysed whole blood samples following inhibition by a directly acting diethyl OP and left for up to 60 minutes after sampling and addition of pharmacological amounts of oxime. The samples were either diluted twenty-fold and cooled to 0°C within one minute, diluted twenty-fold and kept at 30°C, or simply left at 30°C, before assay. AChE activity was 2-4% of normal at baseline. Within 5 minutes of sampling, AChE activity in the untouched sample had recovered by around 18% of normal due to the oxime in the sample. Further recovery to around 35% of normal activity occurred over the next 60 min. Dilution in part prevented this recovery of AChE activity while dilution and cooling to 0°C prevented AChE recovery. Interpretation of repeated AChE assays looking at the effect of oxime treatment will be complicated if the samples are not uniformly and rapidly diluted and cooled.

Principles of therapy

Current therapy involves resuscitation of patients and the administration of oxygen, a muscarinic antagonist (usually atropine), fluids, and an AChE reactivator (an oxime, which reactivates the AChE by removing the phosphate group) (box 3).^19,20 Respiratory support is given as necessary. Gastric decontamination should only be considered after the patient has been fully resuscitated and stabilised.

Box 3. Summary of treatment ¹⁹.

• ■Review Airway, Breathing, and Circulation. Place patient in the Left Lateral Position, preferably with head lower than the feet, to reduce the risk of aspirating stomach contents. Provide high flow oxygen, if available. Intubate the patient if their airway or breathing is compromised.
• ■Obtain IV access and give 1-3mg of atropine as a bolus, depending on severity. Set up an infusion of 0.9% normal saline; aim to keep the systolic BP >80mmHg and urine output >0.5 ml/kg/hr.
• ■Record pulse rate, blood pressure, pupil size, presence of sweat, and auscultatory findings at time of first atropine dose.
• ■Give pralidoxime chloride 2 g (or obidoxime 250mg) IV over 20-30 mins into a second cannula; follow with an infusion of pralidoxime 0.5-1 g/hr (or obidoxime 30 mg/hr) in 0.9% normal saline.
• ■Five minutes after giving atropine, check pulse, blood pressure, pupil size, sweat and chest sounds. If there has been no improvement, give double the original dose of atropine.
• ■Continue to review every 5 mins - give doubling doses of atropine if there has been no response. Once parameters have begun to improve, there is no need to double each dose.
• ■Give atropine boluses until the heart rate is > 80 bpm, the systolic BP >80 mmHg, and the chest clear (while appreciating that atropine will not clear focal areas of aspiration). Sweating usually also stops. A tachycardia is not a contraindication to atropine since it can be caused by many factors (see Box 1). The pupils will commonly dilate; however, this is not a useful endpoint for initial atropinisation because there is a delay to maximum effect. However, very dilated pupils are commonly an indicator of atropine toxicity.
• ■Once the patient is stable, start an infusion of atropine giving per hour around 10-20% of the dose used to initially atropinise the patient. Observe the patient often to see if too much or too little is being given. If too little, cholinergic features will reappear after a while.¹⁹ If too much, patients will become agitated and pyrexial and develop absent bowel sounds and urinary retention. If this occurs, stop the infusion and wait 30-60 minutes for these features to settle before starting again at a lower infusion rate.
• ■Continued the oxime infusion until atropine has not been required for 12-24 hrs and the patient extubated.
• ■Continue to review respiratory function. Intubate and ventilate patients when the tidal volume or vital capacity fall below 5 ml/kg or 15 ml/kg, respectively, have apnoeic spells, or PaO2 <8 kPa (60 mmHg) on FiO2 of >60%.
• ■Review flexor neck strength regularly in conscious patients by asking them to lift their head off the bed and keep it there when pressure is applied to their forehead. Any sign of weakness is a sign that the patient is at risk of developing peripheral respiratory failure (intermediate syndrome). The tidal volume should be checked in such patients every 4 hrs. Values less than 5 ml/kg are an indication for intubation and ventilation.
• ■Treat agitation by reviewing the dose of atropine being administered and giving adequate sedation with benzodiazepines. An antipsychotic, such as haloperidol, can be used but may be less effective for alcohol withdrawal, a frequent co-morbidity in self-poisoned patients. Physical restraint of agitated patients in warm conditions risks severe hyperthermia - this is exacerbated greatly by atropine which inhibits normal thermoregulatory responses, including sweating. Adequate sedation is therefore important.
• ■Monitor frequently for recurring cholinergic crises due to leaching of fat soluble OPs from fat stores. Such crises can occur for several days to weeks post-ingestion of some OPs. Patients with recurring cholinergic features will need reloading with atropine.

There have been few RCTs in OP poisoning and consequently a very limited evidence base.²⁰ Both atropine and oximes were introduced rapidly into clinical practice in the 1950s without clinical trials.^21,22 As a result, we do not know the ideal regimens for administration of either therapy. Trials of other interventions are hindered because the best way to give the basic treatments has not yet been determined and is in practice highly variable. This variability interferes with developing a widely accepted study protocol and limits the external validity of study results.

Factors affecting efficacy of treatment and outcome

The case fatality reported from different hospitals varies markedly - for example 2% in a Vietnamese ICU (Pham Due, personal communication) to 40% in a German ICU.^23,24 Since there are so few RCTs, it is tempting to try to compare the therapy given in different hospitals to assess the effectiveness of different treatments. Unfortunately, such comparisons are confounded by multiple factors (box 4).

Box 4. Factors that affect outcome in OP pesticide self-poisoning.

There are marked differences among the OP pesticides:

• ■Toxicity of the OP. OP toxicity is usually rated according to the oral LD50 in rats. This is roughly able to differentiate very safe and very toxic pesticides - for example parathion (LD₅₀ 13 mg/kg,⁷⁸ WHO: Class IA) is highly toxic while temephos (LD₅₀ 8600 mg/kg,⁷⁸ WHO: unlikely to cause acute hazard) has not been associated with deaths. However, large differences in human toxicity have been seen after poisoning with OPs of roughly similar animal toxicity,^6,16 and this classification does not take into account the modifying effects of treatment.¹⁶
• ■Impurities. The WHO toxicity classification assesses fresh pesticide from approved manufacturers. Pesticide storage in hot conditions can result in chemical reactions that produce toxic breakdown products. Such a process was blamed for the death of pesticide sprayers using malathion in Pakistan during the late 1970s.^79,80
• ■Formulation. A pesticide’s toxicity will vary according to formulation, which differs according to the OP and the locality. For example, one of the authors found malathion available as an 80% solution in street-side pesticide stalls of Yangon, Myanmar, but it is sold as a 3% powder in Sri Lanka.
• ■Alkyl sub-groups. Most pesticides have either two methyl groups attached via oxygen atoms to the phosphate (dimethyl OPs) or two ethyl groups (diethyl OPs) (figure 4). Ageing is markedly faster in dimethyl than diethyl poisoning, therefore to be efficacious oximes must be given quickly to patients with dimethyl poisoning (box 5). A few pesticides have atypical structures, with another alkyl group (eg propyl in profenofos) attached to the phosphate group via a sulphur atom. These OPs age even faster and oximes are probably not effective.
• ■Need for activation. Many compounds are inactive thions (with an ‘= S’ attached to the phosphate group) and have to be desulphurated to make the active ‘oxon’, via cytochrome P450 enzymes in the gut wall and liver. The P450 3A4 seems to be the most active enzyme when OPs are present in high concentrations, as occurs after self-poisoning.⁸¹
• ■Speed of activation and of AChE inhibition. The rate of activation of thion OPs varies between pesticides.^81,82
• ■Similarly there is a large variation in rate of AChE inhibition between OP pesticide oxons - see table 2 in reference ⁸.
• ■Duration of effect - fat solubility and half-life. Some fat soluble OP-thions (eg. fenthion) distribute extensively to fat stores after absorption. This appears to reduce the peak blood OP concentration and the early cholinergic features are often mild. Subsequent slow redistribution and activation cause recurrent cholinergic features lasting days or weeks. Peripheral respiratory failure is common with these OPs, probably due to continuing inhibition of reactivated or new AChE. Ageing only starts after AChE inhibition, so oximes may theoretically be beneficial for many days in such patients.

  In contrast, other OPs (e.g. dichlorvos) do not require activation, are not fat soluble, and may have much more rapid onset of effect and duration of activity. Fat solubility is graded according to the Kow (logarithm octanol/water coefficient): <1.0 not fat soluble; >4.0 very fat soluble.⁸³ The above factors have important consequences for the speed of onset of OP poisoning after ingestion. Ingestion of an oxon OP that rapidly inhibits AChE will result in early onset of clinical features and respiratory arrest before presentation to hospital, increasing the risk of hypoxic brain damage and aspiration. The conversion of the thion OP parathion to paraoxon is so fast that patients can be unconscious in 20 minutes. Clinical features after poisoning by other thion OPs, such as dimethoate and fenthion, occurs later, giving the patient more time to present to hospital.

In particular, although many textbooks consider poisoning with various OPs to be broadly similar and equally responsive to treatment, differences in chemistry have major consequences for treatment efficacy.^16,25 The OP ingested determines how many patients survive to reach medical attention, how ill they are on admission, the effectiveness of oxime therapy, and the likelihood of getting recurring cholinergic crises or requiring ventilatory report (box 4). Such variation makes RCTs looking at particular OP pesticides essential for determining the effectiveness of treatment.

Initial stabilisation

Severe acute OP pesticide poisoning is a medical emergency. Therapy must follow the classical approach of ensuring the patient has a patent airway and adequate breathing and circulation. Ideally, oxygen should be provided at the first opportunity. However, there is little evidence to support the common belief that atropine must not be given until oxygen is available. This is particularly important in rural Asian hospitals without access to oxygen since early atropine administration to OP poisoned patients will reduce secretions and improve respiratory function.

The patient should be placed in the left lateral position, with the neck extended. This reduces the risk of aspiration, helps keep the airway patent, and may decrease pyloric emptying and absorption of poison.^26,27

There is a perceived risk of poisoning of health care workers during the initial stabilisation of OP pesticide poisoned patients.^28,29 There have been a few case reports from Western hospitals but none have demonstrated inhibition of AChE or BuChE in the health care workers consistent with substantial exposure to OPs.³⁰ It is possible that some symptoms, such as headaches and nausea, are due to anxiety or exposure to the organic solvent (eg. xylene) in which the pesticide is mixed.^30,31 Hundreds of thousands of severely OP poisoned patients are seen every year in basic hospitals across Asia with no special precautions taken and no reported problems. A reticence to treat OP pesticide poisoned patients inside hospital facilities puts the patient at significant risk. Current recommendations are to use universal precautions and to maximise ventilation, with frequent rotation of staff, so that effects of the solvent are minimised.³⁰

Muscarinic antagonist drugs

Although atropine remains the mainstay of therapy worldwide,^9,32 other muscarinic antagonists have been trialled in animals.³² An important difference between them is their penetration into the CNS.³³ Glycopyrrolate and hyoscine (scopolamine) methylbromide do not enter the CNS, while hyoscine has excellent penetration. Atropine lies somewhere midway.

The main adverse effect of atropine is an anticholinergic delirium in patients receiving too high a dose.³² Some physicians therefore prefer glycopyrrolate so as to treat the peripheral effects of OPs without causing confusion. However, its poor CNS penetration suggests that it will be ineffective at countering the coma and reduced respiratory drive seen in patients with the cholinergic syndrome. One small RCT comparing glycopyrrolate and atropine found no significant difference in mortality or ventilation rates, but it lacked sufficient power to detect important differences.³⁴

Hyoscine has been used to treat a patient with severe extra-pyramidal features but few peripheral signs.³⁵ Animal studies suggest that it is more effective than atropine at controlling OP nerve gas-induced seizures.³⁶ However, extra-pyramidal effects and seizures are not common features of OP pesticide poisoning.^16,37

Overall, until high quality RCTs have been done to show that another muscarinic antagonist has a better benefit/harm ratio, atropine should remain the muscarinic antagonist of choice due to its wide availability, affordability, and moderate ability to penetrate into the CNS.

There have been no RCTs comparing different regimens of atropine administration for either loading or continuation therapy. As a result, the literature is filled with varying recommendations - a recent review found more than 30 dosing regimens, some of which would take many hours to atropinise a patient.¹⁰ The aim of early therapy is to reverse the cholinergic features and improve cardiorespiratory function as quickly as possible. We therefore use a regimen of doubling doses ¹⁵ (see box 2) to raise the pulse above 80 bpm, systolic BP above 80 mmHg, and reverse bronchospasm and bronchorrhoea rapidly. Using this regimen, it is possible to give over 70 mg of atropine in stages to a sick patient in less than 30 mins, allowing rapid stabilisation while minimising the risk of atropine toxicity.¹⁰

One study from south India³⁸ showed benefit from an infusion of atropine compared to repeated bolus doses but it used historical controls. However, infusions should reduce fluctuation in blood atropine concentration and require less observation of the patient, an important benefit in hospitals with few staff.

Oximes

Oximes reactivate inhibited AChE.⁸ Discovered in the mid-50s by Wilson and colleagues, pralidoxime was soon introduced into clinical practice with good effect for patients with parathion poisoning.²² Other oximes, eg. obidoxime, have been developed but pralidoxime remains the most widely used. It has four salts: chloride, iodide, methylsulfate, and methane sulfonate.³⁹ The chloride and iodide are used widely, while the latter two are used in France, Belgium, and UK. The chloride offers advantages over the iodide - in particular its smaller molecular weight (173 vs. 264) provides 1.5-times more active compound per gram of salt than the iodide. High doses of pralidoxime iodide also risk thyroid toxicity, especially if given over a sustained period.

Despite the apparent beneficial effects first noted with parathion poisoning, there has been much debate about the effectiveness of pralidoxime with many Asian clinicians unconvinced of benefit.^40-42 In particular two RCTs from Vellore, India, performed in the early 1990s found evidence that low dose infusions of pralidoxime might cause harm.^43,44 The lack of clinical benefit could relate to deficiencies in trial design (suboptimal dose, or bias in allocation) or indicate pralidoxime is simply not effective (due to failure to reverse all effects of OP, non-response of particular OP, excessive OP, or administration being too late in practice to reverse lethal toxic effects).^45,46

More recent observational studies of pralidoxime and obidoxime administration have indicated that AChE inhibited by various OP pesticides varies in its responsiveness to oximes (figure 5).^8,16,45,47 AChE inhibited by diethyl OPs, such as parathion and quinalphos, seems be effectively reactivated by oximes, while AChE inhibited by dimethyl OPs, such as monocrotophos or oxydemeton-methyl, seems to respond poorly. We have also noted that AChE inhibited by S-alkyl linked OPs, such as profenofos, is not reactivated by oximes at all (figure 5). This difference is likely to be due in part to variation in the speed of ageing (box 5) by these different OPs.

Figure 5. Variable response of AChE inhibited by different OPs to oximes.

AChE was reactivated fully (quinalphos, a diethyl OP), partially (oxydemeton-methyl, a dimethyl OP), or not at all (profenofos, an S-alkyl OP) by oximes after poisoning with different OPs. Arrow = time of first pralidoxime administration. Normal AChE activity is ∼600 mU/μmol Hb. In-vitro AChE shows how much of inhibited AChE can be reactivated, indicating how much of the AChE is not yet aged.

Box 5. Ageing of OP inhibited AChE.

Ageing is an important issue because it determines whether a patient poisoned by a particular OP will benefit from oximes.

Inhibited AChE spontaneously reactivates slowly. The half-life of reactivation varies according to the inhibiting OP: if dimethyl, the half-life is around one hour; if diethyl, the half-life is around 30 hrs. Oximes speed up this reaction. Unfortunately, if the OP is present in high concentrations, newly reactivated AChE will be rapidly re-inhibited. Whether reactivation or inhibition predominates depends on the type of OP and relative concentration and affinity of OP and oxime.

Inhibited AChE can also become ‘aged’, which involves loss of one of the two alkyl groups attached to the bound phosphate. Aged AChE cannot be re-activated by oximes. The half-life of ageing varies according to the inhibiting OP: if dimethyl, the half-life is around 3 hrs; if diethyl, the half-life is around 33 hrs.

This has important clinical consequences. If a patient who has ingested a dimethyl OP presents to hospital 3 hrs after ingestion, around 50% of the AChE will already be aged and unresponsive to oximes. A patient arriving after 12 hrs will have aged AChE by 94% and therefore be unresponsive to oximes. Such a situation is common where patients need to be transferred to a secondary hospital to receive oximes. The situation is better with diethyl OPs since it takes 33 hrs for 50% inhibition and there is opportunity for oxime effectiveness up to 5 days post-ingestion.

Ageing appears to occur much more quickly after poisoning with atypical OPs, such as profenofos, that have neither 2 methyl groups nor 2 ethyl groups (figure 4). The half-life of ageing seems to be much less than 1 hr, making oximes completely ineffective if the patient presents more than an hour or two after ingestion (figure 5).

Oximes are rapidly excreted from the body via the kidneys - pralidoxime has a t_1/2 of around 75 minutes.⁴⁸ The regimen recommended by many textbooks is 1g IV every 6 to 8 hrs for 1 to 3 days. Such a regimen will provide pralidoxime concentrations that vary up to 100-fold after each dose and that are suboptimal for over 90% of the time. We have noted that such a regimen provides non-ideal reactivation of diethyl OP inhibited AChE.^16,49

Interpretation of clinical evidence on oximes must take into account this variability between OPs in response to oximes and the inappropriate regimen of pralidoxime commonly used.⁴⁵ The clinical effects may also be limited by high levels of OP in the blood after ingestion of a large dose - the OP simply re-inhibits any AChE that the oximes reactivate. Oximes will also not be effective in improving outcomes if the patient develops severe complications such as aspiration pneumonia or hypoxic brain injury prior to treatment. This is likely to be relevant with fast acting OPs such as parathion and dichlorvos.

Despite the lack of good evidence for the clinical effectiveness of oximes, the WHO recommends that they be given to all symptomatic patients requiring atropine.⁹ To ensure a therapeutic concentration, they recommend a 30 mg/kg loading dose of pralidoxime chloride, followed by 8 mg/kg/hr by continuous infusion (often simplified to a 1-2g loading dose over 20-30 mins, followed immediately by 500mg/hr). It is important not to give the loading dose very rapidly since this causes vomiting (risking aspiration), tachycardia, and diastolic hypertension.⁸

An RCT has recently been published in abstract format from Baramati, India.⁵⁰ The authors studied the effect of very high dose pralidoxime chloride or iodide (2 g bolus then 1 g either every hour or every 4 hrs for 48 hrs, followed by 1 g every 4 hrs until recovery) in 200 moderately OP poisoned patients (excluding severely ill patients). This regimen was associated with reduced case fatality (1% vs. 8%; odds ratio [OR] 0.12, 0.003 to 0.90), fewer cases of pneumonia (8% vs. 35%; OR 0.16, 0.06 to 0.39) and reduced ventilation times (a median of 10 days compared to 5 days) in the high dose group. Surprisingly, they found a benefit for dimethyl as well as diethyl OPs, but laboratory studies to confirm the identity of the OP ingested, and degree of baseline AChE inhibition and subsequent reversal, were not performed to provide a mechanistic explanation. However, this study indicates that patients may benefit from even larger doses of pralidoxime than currently recommended.

Benzodiazepines

Patients with OP poisoning often develop an agitated delirium. The aetiology is multifactorial including contributions from the OP itself, atropine toxicity, hypoxia, alcohol withdrawal, and medical complications. While the mainstay of management is to prevent or treat underlying causes, some patients will require pharmacotherapy. Acutely agitated patients may benefit from treatment with diazepam which can be supplemented with low doses of the relatively non sedating haloperidol.⁵¹

Diazepam is first line therapy for seizures; however, seizures are uncommon in well oxygenated patients poisoned with pesticides.^16,37 Seizures are much more common with OP nerve agents.⁵² Animal studies suggest that diazepam reduces neural damage ⁵³ and prevents respiratory failure and death,⁵⁴ but human studies are lacking.

Gastrointestinal decontamination

Gastric lavage is often the first intervention poisoned patients receive on presentation to hospital, sometimes at the expense of resuscitation and antidote administration.⁵⁵ There is currently no evidence that any form of gastric decontamination offers benefit to OP poisoned patients.²⁰ Consideration of decontamination should only occur after the patient has been stabilised and treated with oxygen, atropine, and oxime.⁵⁵

Gastric lavage is the most commonly used form of decontamination in OP poisoning despite the lack of RCTs to confirm benefit.²⁰ The rate of OP absorption from the human bowel is not known; however, with some OPs the rapid onset of poisoning in animals⁵⁶ and humans ²⁴ suggests that absorption is rapid, occurring within minutes of ingestion. The time window for effective lavage is likely therefore to be short. Our current practice is to only perform lavage on patients who present within two hrs of ingesting a substantial amount of a toxic OP pesticide and who are intubated or conscious and willing to cooperate.

Repeated gastric lavages are recommended in China to remove pesticide remaining in the stomach.⁵⁷ It seems doubtful whether significant amounts of OP remain in the stomach after a single lavage, although non-randomised controlled studies from China have suggested benefit.^58,59 RCTs are required to determine whether single or multiple gastric lavages should be given to the OP poisoned patient.

Ipecacuanha-induced emesis should not be used in OP pesticide poisoning.^20,60 OP poisoned patients can become unconscious rapidly, risking aspiration if ipecac has been administered previously. Mechanically-induced emesis with large quantities of water risks simply pushing fluid through the pylorus and into the small bowel, likely increasing the rate of absorption.⁶⁰

A recent RCT of single and multiple doses of superactivated charcoal in Sri Lanka failed to find a significant benefit of either regimen over placebo in more than 1000 OP pesticide poisoned patients.⁶¹ Since activated charcoal binds OPs in vitro​,​⁶² the lack of effect in patients is possibly due to rapid absorption of OPs. Alternatively, the ingested dose in fatal cases may be too large for the amount of charcoal administered, the charcoal administered too late, or the pesticide solvent interfere with binding.

Other therapies

Current therapy works though only a few mechanisms.⁶³ A number of other therapies have been studied but with inconclusive results. However, they do suggest that future research may reveal a number of cheap and affordable therapies working at separate sites that may complement current therapy.

Magnesium sulphate blocks ligand-gated calcium channels, reducing ACh release from pre-synaptic terminals and improving NMJ function, and reducing CNS excitotoxicity mediated via NMDA receptor activation.⁶⁴. There has been one trial in humans which reported reduced mortality with magnesium (0/11 [0%] vs. 5/34 [14.7%]; P<0.01).⁶⁵ However, the study was small, allocation not randomised (every fourth patient received the intervention), and the publication incompletely described the dose of magnesium sulphate used and other aspects of the methodology. Therefore these results should be interpreted with caution.

The α₂-adrenergic receptor agonist clonidine also reduces ACh synthesis and release from pre-synaptic terminals. Animal studies show a benefit of clonidine, especially in combination with atropine, but human studies have not yet been performed.⁶⁶

Sodium bicarbonate is often used for OP poisoning in Brasil and Iran, in place of oximes.).⁶⁷ Increasing blood pH (7.45-7.55) has been reported to improve outcome in animals through an unknown mechanism; however, a recent Cochrane review concluded that there is insufficient evidence at present to determine whether sodium bicarbonate should be used in human OP poisoning.⁶⁷

Removing OP from the blood may allow other therapies to work better. The role of haemodialysis and haemofiltration is not yet clear; however, a recent non-randomised controlled study from China⁶⁸ suggested benefit of haemofiltration after poisoning with dichlorvos, a poorly fat soluble OP that should have a relatively small volume of distribution. A systematic review of these therapies in OP poisoning is now underway but it is likely that RCTs are required.

BuChE binds to OP in the plasma, reducing the amount of OP available to inhibit the more important AChE in synapses. BuChE has been cloned and military research now aims to inject soldiers with the enzyme before exposure to OP nerve gases.⁶⁹ Such a prophylactic approach is not practical for OP pesticide self-poisoning. Turkish doctors have reported the use of BuChE in fresh frozen plasma (FFP).⁷⁰ A small controlled study (12 patients given FFP, 21 controls) reported benefit but it was not a RCT and allocation decisions were unclear.

However, it seems unlikely that BuChE will ever be an effective treatment for pesticide poisoning since it binds to OPs stoichometrically and will be swamped by the amount of OP commonly ingested. For example, 50 mLs of 40% dimethoate (MW 229) contains 20 g or 87.3 millimols of OP, which – if completely absorbed – would require an equivalent number of moles of BuChE (MW ∼70kD, therefore 6 kg) for inactivation. It is obvious that administration of such an amount is impossible.

A better approach might be to use recombinant bacterial phosphotriesterases, or hydrolases, such as Oph and OpdA.^71,72 These proteins enzymatically break down OPs (rather than stoichometrically binding to them) and protect animals from pesticide poisoning. Clinical development of such enzymes may reduce the level of OP in the blood, allowing other treatments to work better.

Conclusion

Medical management of OP pesticide poisoning is difficult, especially in the resource poor locations where most patients present. Current clinical practice is frequently not ideal with poor initial resuscitation and stabilisation and poor use of antidotes. On a positive note, the majority of original research publications on acute OP poisoning in humans have been published in the last decade. We anticipate that in the next decade evidence from ongoing research by a number of groups across Asia will finally provide clear guidance on how to treat OP pesticide poisoning. Hopefully, this new guidance will include the use of novel antidotes that might have a large impact on the mortality rate from OP poisoning and therefore the global number of deaths from self-harm.

Figure 4. Chemical classes of OP pesticides.

Structures of OP pesticides from diethyl (A,B,C), dimethyl (D), and S-alkyl (E,F) classes of OP. The majority of OP pesticides are thions, with a =S linked to the phosphate (A, C, F) that must be converted to the active oxon =O (eg. A to B). A few OP pesticides are already oxons (eg. D, E) and are active as soon as they are absorbed.