Lakshman Karalliedde

Neurotoxic Effects of Organohosphorus Insecticides

Acute neurotoxic effects during the cholinergic phase of organophosphorus insecticide poisoning and delayed neurotoxic effects appearing two to three weeks later are well recognized. We observed 10 patients who had paralysis of proximal limb muscles, neck flexors, motor cranial nerves, and respiratory muscles 24 to 96 hours after poisoning, after a well-defined cholinergic phase. The compounds involved were fenthion, monocrotophos, dimethoate, and methamidophos. Four patients urgently required ventilatory support. The paralytic symptoms lasted up to 18 days. A delayed polyneuropathy later developed in one patient. Three patients died. Electromyographic studies showed fade on tetanic stimulation, absence of fade on low-frequency stimulation, and absence of post-tetanic facilitation, suggestive of a postsynaptic defect. This neuromuscular junctional defect may have been the predominant cause of the paralytic symptoms, with neural and central components contributing to various degrees. Our patients appeared to have a distinct clinical entity (a so-called intermediate syndrome) that developed after the acute cholinergic crisis and before the expected onset of the delayed neuropathy.

Pesticide poisoning in the developing world—a minimum pesticides list

In parts of the developing world, pesticide poisoning causes more deaths than infectious diseases. Use of pesticides is poorly regulated and often dangerous; their easy availability also makes them a popular method of self-harm. In 1985, the UN Food and Agriculture Organisation (FAO) produced a voluntary code of conduct for the pesticide industry in an attempt to limit the harmful effects of pesticides. Unfortunately, a lack of adequate government resources in the developing world makes this code ineffective, and thousands of deaths continue today. WHO has recommended that access to highly toxic pesticides be restricted--where this has been done, suicide rates have fallen. Since an Essential Drugs List was established in 1977, use of a few essential drugs has rationalised drug use in many regions. An analogous Minimum Pesticides List would identify a restricted number of less dangerous pesticides to do specific tasks within an integrated pest management system. Use of safer pesticides should result in fewer deaths, just as the change from barbiturates to benzodiazepines has reduced the number of deaths from pharmaceutical self-poisoning.

Early management after self-poisoning with an organophosphorus or carbamate pesticide - a treatment protocol for junior doctors

Severe organophosphorus or carbamate pesticide poisoning is an important clinical problem in many countries of the world. Unfortunately, little clinical research has been performed and little evidence exists with which to determine best therapy. A cohort study of acute pesticide poisoned patients was established in Sri Lanka during 2002; so far, more than 2000 pesticide poisoned patients have been treated. A protocol for the early management of severely ill, unconscious organophosphorus/carbamate-poisoned patients was developed for use by newly qualified doctors. It concentrates on the early stabilisation of patients and the individualised administration of atropine. We present it here as a guide for junior doctors in rural parts of the developing world who see the majority of such patients and as a working model around which to base research to improve patient outcome. Improved management of pesticide poisoning will result in a reduced number of suicides globally.

Where Is the Evidence for Treatments Used in Pesticide Poisoning? Is Clinical Toxicology Fiddling While the Developing World Burns?

Some years ago, we explicitly stated what most clinical toxicologists already knew – that it was not possible to practice ‘evidence based medicine’ in clinical toxicology.(1) This was simply because there was next to no evidence: the published data on treatment included very few randomised clinical trials (RCTs) addressing clinical end-points, observational studies of clinical features were lacking in both quantity and quality, and diagnostic and prognostic tests were not prospectively validated. As a result, knowledge and management of many forms of poisoning was based largely on case reports and clinicians relied on textbooks of expert opinion for guidance.(1) We suggested that the solution was to collect prospective data and to apply the tools of clinical epidemiology to better describe the natural history of poisonings, identify high-risk individuals, and determine the effects of treatment and the relative toxicity of drugs within therapeutic classes.(2;3) There has subsequently been a major shift in the methods of evaluating evidence in the toxicology community.(4;5) However, we believe that too little evidence is still being generated where it is most required. The World Health Organization (WHO) estimate that, of the 26 million deaths a year in the developing countries of SE Asia, China and the Western Pacific, 725,000 (2.8% of total) are due to ‘injury’ and 552,000 of these episodes are self-inflicted (i.e. suicides).(​6) Deliberate self-poisoning with pesticides is the commonest method of fatal self-harm in this region.(7-9) + Sri Lankan studies (see added refs)). A recent Chinese study suggested that 175,000 deaths from pesticide self-poisoning occur annually in that country alone.(10) Assuming this data to be representative of the whole region, around 300,000 deaths from self-poisoning with pesticides are occurring each year in SE Asia and the Western Pacific. In addition, a further 160,000 people are dying from unintentional poisoning.(6) A comparison of two WHO estimates suggests that the problem has nearly doubled in size over the last decade,(6;11) a conclusion supported by similar or larger trends in data from individual districts.(12;13) Conservatively, half a million people are dying of pesticide poisoning each year in Asia and the Western Pacific. Most deaths are due to organophosphorus (OP) pesticides; other significant pesticides include paraquat and aluminium phosphide.(14) While primary prevention has great potential in the long run to reduce the number of deaths, improving medical management will also reduce the death rate and probably do it much faster. Current protocols for the management of pesticide poisoning are based on little evidence and are difficult to deliver in the resource-poor settings in which most poisonings occur. Evidence for pesticide poisoning is at the stage drug self-poisoning was 15 years ago. Some new pesticides have no human toxicity data at all. Even for older pesticides, there is little evidence, no systematic data collection, and low appreciation by both clinicians and textbook authors of the usefulness of clinical epidemiology research as a tool for improving the situation. There are large numbers of animal studies but few well-conducted human studies, and even fewer RCTs (the RCTs that have been done have all been small (15-18)) Systematic reviews suggest there is no good quality human evidence that any currently used antidote, other than atropine, is of benefit.(19-21) The potential for clinical research is enormous. Just for OPs, there are dozens of potential antidotes with many different mechanisms, which moreover have often shown synergistic benefit in animal models. New agents have been developed by the military and the pharmaceutical industry, and yet all have failed to progress to clinical trials. No new OP antidotes have been marketed in the last 30 years. Although large amounts of money are spent on antidote drug development in Western laboratories, no funding is going to conduct clinical trials. The millions of pesticide poisonings occurring in the developing world each year offer immense opportunities for clinical research. The benefits will be shared between the people of the developed and developing worlds alike. We believe that clinical toxicologists in the developed world should set up collaborations with developing world colleagues to establish centres of excellence in clinical toxicology research. Combining developed world laboratory resources and expertise in research methodology with developing world clinical experience of pesticide poisoning could answer many questions rapidly. At present, such a centre does not exist anywhere. The broad aims of such a centre would be: to expand the evidence base in clinical toxicology of pesticides and management of deliberate self harm, to develop methods that ensure that evidence moves rapidly into clinical practice, to explore models for prevention of poisoning, including pesticide regulation, to provide descriptive human toxicology data for different pesticides to allow comparisons of human toxicity, and to support and provide training in clinical management and research. The most important and direct outcome of such collaborations will be a reduction in the number of people dying from pesticide poisoning in developing countries. By tackling the problem on a number of synergistic fronts (antidote development, research into relative toxicity, preventive strategies and improved delivery of evidence based clinical care), the number of deaths could be more than halved. Pesticide regulation is an area where the developed world may stand to benefit greatly from research in developing countries. Most toxicological evaluation of safe exposure levels relies largely or solely on extrapolation from animal data. Human clinical and toxicokinetic data would determine if the assumptions used in these extrapolations are warranted and may also identify toxic effects that are specific to humans. Furthermore, the WHO has recommended that access to highly toxic pesticides be globally restricted. The few studies performed have shown that where this has been done for specific poisons, suicide rates have fallen (20). We have suggested that one means of achieving this is to have a WHO and FAO endorsed Minimum Pesticides List (analogous to the WHO Essential Drugs List which has been a very successful policy mechanism promoting rational drug use).(​22) Such a list would lead to an easily adopted strategy to assess all pesticides on the basis of indications, human and environmental toxicity and cost. However, to convince all governments of the benefits will require much firmer evidence on the health outcomes that can be expected from regulatory approaches. Although pesticide poisoning is relatively uncommon in the developed world, it remains an important clinical problem for two reasons. First, it is one of the more common causes of in-hospital death from poisoning. Each patient uses up a great deal of resources, often spending weeks in intensive care. Many are left with long term disabilities. Yet they are probably managed sub-optimally due to lack of good clinical data on treatment and prognosis. Second, throughout the world there is a growing concern about chemical weapons. The most commonly used weapons in recent years have been ‘nerve agents’, which are in essence OPs with relatively higher mammalian toxicity. The neurotoxicological complications reported in animals and the antidotes proposed are the same as those used for the pesticides. The antidotes were used in the Tokyo subway incident, were given to troops in the 1991 Gulf war, and are now being purchased in very large quantities and stockpiled at great expense by many countries including the USA, Australia and the UK. It is not known whether these antidotes are the most effective way of treating anticholinesterase poisoning or indeed if they are effective at all. Animal studies suggest a large number of promising antidotes for OPs, paraquat and other pesticides that deserve further evaluation. The establishment of a centre that develops a track record of doing clinical trials of OP antidotes to a high standard may well serve to overcome the drug-development impasse. The developed world has a great deal to gain from more effective, safer, cheaper and more easily administered antidotes to deal with mass casualty situations resulting from terrorist use of OP nerve agents. Conditions in terms of resources and manpower in the case of such an event are likely to be similar to those that prevail in rural hospitals in the developing world. Both humanitarian concern and self-interest suggest we should make a concerted effort to improve these conditions. The in-hospital case fatality rate in developing world poisonings is 10-20% or more, while in the developed world it is well under 0.5%. Clinical toxicologists aiming to make a real impact should put their efforts where they will make the most difference.

The spectrum of intermediate syndrome following acute organophosphate poisoning: a prospective cohort study from Sri Lanka

Background Intermediate syndrome (IMS) is a major cause of death from respiratory failure following acute organophosphate poisoning. The objective of this study was to determine repetitive nerve stimulation (RNS) predictors of IMS that would assist in patient management and clinical research. Methods and Findings Seventy-eight consenting symptomatic patients with organophosphate poisoning were assessed prospectively with daily physical examination and RNS. RNS was done on the right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. The study was conducted as a prospective observational cohort study in the Central Province, Sri Lanka. IMS was diagnosed in ten out of 78 patients using a priori clinical diagnostic criteria, and five of them developed respiratory failure. All ten patients showed progressive RNS changes correlating with the severity of IMS. A decrement-increment was observed at intermediate and high frequencies preceding the onset of clinical signs of IMS. As the patient developed clinical signs of IMS, decrement-increment was progressively noted at low and intermediate frequencies and a combination of decrement-increment and repetitive fade or severe decrement was noted at high frequencies. Severe decrement preceded respiratory failure in four patients. Thirty patients developed forme fruste IMS with less severe weakness not progressing to respiratory failure whose RNS was characterized by decrement-increment or a combination of decrement-increment and repetitive fade but never severe decrements. Conclusions Characteristic changes in RNS, preceding the development of IMS, help to identify a subgroup of patients at high risk of developing respiratory failure. The forme fruste IMS with the characteristic early changes on RNS indicates that IMS is a spectrum disorder. RNS changes are objective and precede the diagnosis and complications of IMS. Thus they may be useful in clinical management and research.

Patterns of hospital transfer for self-poisoned patients in rural Sri Lanka: implications for estimating the incidence of self-poisoning in the developing world

OBJECTIVES Most data on self-poisoning in rural Asia have come from secondary hospitals. We aimed to: assess how transfers from primary to secondary hospitals affected estimates of case-fatality ratio (CFR); determine whether there was referral bias according to gender or poison; and estimate the annual incidence of all self-poisoning, and of fatal self-poisoning, in a rural developing-world setting. METHODS Self-poisoning patients admitted to Anuradhapura General Hospital, Sri Lanka, were reviewed on admission from 1 July to 31 December 2002. We audited medical notes of self-poisoning patients admitted to 17 of the 34 surrounding peripheral hospitals for the same period. FINDINGS A total of 742 patients were admitted with self-poisoning to the secondary hospital; 81 died (CFR 10.9%). 483 patients were admitted to 17 surrounding peripheral hospitals. Six patients (1.2%) died in peripheral hospitals, 249 were discharged home, and 228 were transferred to the secondary hospital. There was no effect of gender or age on likelihood of transfer; however, patients who had ingested oleander or paraquat were more likely to be transferred than were patients who had taken organophosphorus pesticides or other poisons. Estimated annual incidences of self-poisoning and fatal self-poisoning were 363 and 27 per 100,000 population, respectively, with an overall CFR of 7.4% (95% confidence interval 6.0-9.0). CONCLUSION Fifty per cent of patients admitted to peripheral hospitals were discharged home, showing that CFRs based on secondary hospital data are inflated. However, while incidence of self-poisoning is similar to that in England, fatal self-poisoning is three times more common in Sri Lanka than fatal self-harm by all methods in England. Population based data are essential for making international comparisons of case fatality and incidence, and for assessing public health interventions.

The hazards of gastric lavage for intentional self-poisoning in a resource poor location.

Objective. The 10–20% case fatality found with self-poisoning in the developing world differs markedly from the 0.5% found in the West. This may explain in part why the recent movement away from the use of gastric lavage in the West has not been followed in the developing world. After noting probable harm from gastric lavage in Sri Lanka, we performed an observational study to determine how lavage is routinely performed and the frequency of complications. Case series. Fourteen consecutive gastric lavages were observed in four hospitals. Lavage was given to patients unable or unwilling to undergo forced emesis, regardless of whether they gave consent or the time elapsed since ingestion. It was also given to patients who had taken non-lethal ingestions. The airway was rarely protected in patients with reduced consciousness, large volumes of fluid were given for each cycle (200 to more than 1000 ml), and monitoring was not used. Serious complications likely to be due to the lavage were observed, including cardiac arrest and probable aspiration of fluid. Health care workers perceived lavage as being highly effective and often life-saving; there was peer and relative pressure to perform lavage in self-poisoned patients. Conclusions. Gastric lavage as performed for highly toxic poisons in a resource-poor location is hazardous. In the absence of evidence for patient benefit from lavage, (and in agreement with some local guidelines), we believe that lavage should be considered for few patients – in those who have recently taken a potentially fatal dose of a poison, and who either give their verbal consent for the procedure or are sedated and intubated. Ideally, a randomized controlled trial should be performed to determine the balance of risks and benefits of safely performed gastric lavage in this patient population.

Effects of Organophosphates on Skeletal Muscle

Acute pesticide poisonings are estimated at 3 million a year, resulting in over 20,000 deaths world-wide,1,2 of which 99% occur in the developing countries.3,4 Of the pesticides, the organophosphorus (OP) compounds have become increasingly responsible for human toxicity. Much of the morbidity and mortality associated with organophosphorus intoxication is due to the effects of these compounds on skeletal muscle and in particular the muscles of respiration. Toxic OP compounds are known primarily as progressive inhibitors of esterases. In particular, formation of covalently modified (organophosphorylated) acetylcholinesterase (AChE) inhibits that enzyme’s normal catalytic function and accumulation of unhydrolysed acetylcholine leads to the

A Scale to Assess Severity in Organophosphorus Intoxication: POP Scale:

We have developed a clinical scale to assess severity of organophosphorus (OP) intoxication. Five common clinical manifestations of OP poisoning have been selected as parameters, each to be assessed on a 3 point scale varying from 0-2. Poisoning can then be graded as mild (score 0-3), moderate (score 4-7) or severe (score 8-11) when the patient first presents. The scale was validated using two consecutive series of 173 patients with OP poisoning. Correlations between the scores obtained on admission and three outcome variables, namely, death, the need for ventilatory support and the dose of atropine required in the first 24 hours after admission were significant. We believe that this scale would assist in grading severity of OP intoxication at first contact and help in predicting possible outcome.

Acute Organophosphorus Insecticide Poisoning During Pregnancy

Intoxication with organophosphorus insecticides following ingestion with suicidal intent in two patients who were in the second and third trimesters of pregnancy is reported. Successful management of the cholinergic and intermediate phases of poisoning enabled each pregnancy to proceed to term and end in normal vaginal delivery of a healthy baby.