Nimal Senanayake

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.

Does pralidoxime affect outcome of management in acute organophosphorus poisoning

Acute organophosphorus (OP) poisoning is usually treated with atropine plus cholinesterase reactivators such as oximes, but controlled trials to assess the efficacy of oximes in OP poisoning have not been done. A period when the acetyl cholinesterase reactivator pralidoxime chloride was not available in Sri Lanka gave us the opportunity to compare atropine alone for treatment of moderate to severe OP poisoning (21 patients) with atropine plus pralixodime (24 patients). Outcome, as assessed clinically, was similar in the two groups. These results cast doubt on the necessity of cholinesterase reactivators for treatment of acute OP poisoning.

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.

Delayed cerebellar ataxia complicating falciparum malaria: a clinical study of 74 patients.

We report the clinical features of 74 patients with delayed cerebellar ataxia (DCA) following falciparum malaria, who were prospectively followed up at two centres. This unusual complication has an acute onset, with signs suggesting a predominantly midline cerebellar lesion without any evidence of cerebral involvement. There was a delay of a median 13 days between the onset of fever and the onset of ataxia. DCA has a good prognosis, with spontaneous and complete recovery within 3 months. In our opinion, it is an example of a post-infective neurological syndrome possibly mediated via an immune mechanism.

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.

Extrapyramidal manifestations complicating organophosphorus insecticide poisoning

Six patients who developed extrapyramidal manifesta tions following poisoning with the organophosphorus (OP) insecticide fenthion are reported. The extrapyramidal fea tures, in order of frequency, were dystonia, rest tremor, cog-wheel rigidity, and choreo-athetosis. The delay in onset of these signs, following poisoning, varied from 4 to 40 days, and they disappeared spontaneously in about 1 to 4 weeks in those who survived. The human extrapyrami dal system is rich in cholinergic neurons and acetyl cholinesterase (AChE). Inhibition of AChE by fenthion, which has ready access to central neurons on account of its lipid solubility, is postulated as the mechanism under lying the extrapyramidal manifestations.

Electrophysiological correlates of intermediate syndrome following acute organophosphate poisoning.

Introduction. Organophosphate (OP) poisoning is a major global health problem. The late onset of respiratory failure associated with intermediate syndrome (IMS) is a major contributor to the high morbidity, mortality, and cost of OP poisoning. This is particularly important as most poisoning occurs in the under-resourced developing world. Repetitive nerve stimulation studies. An understanding of the abnormalities observed in repetitive nerve stimulation studies during the progression and development of IMS spectrum disorder may help clinicians to utilize electrodiagnostic testing in the better management of their patients with acute OP poisoning. In addition, it will allow researchers to interpret future research that utilizes repetitive nerve stimulation as an outcome measure. A review of the clinical and experimental electrophysiological studies in the IMS shows that subclinical electrophysiological abnormalities are common, progressive, and precede the onset of the clinical IMS. Serial repetitive nerve stimulation studies have been most commonly used and are the most accessible for clinicians. Clinical and experimental studies demonstrate a progression through early initial decrement–increment patterns at high rates of stimulations, which correlate with moderate muscle weakness, to decrement–increment patterns at intermediate- and low-frequency stimulations. Progression to a combination of decrement–increment and repetitive fade patterns correlates with clinical deterioration; severe decrement pattern is usually observed immediately before the onset of respiratory failure. Although electrophysiological features closely parallel clinical severity during progression of IMS, the same is not true during recovery. Electrophysiological changes sometimes improve long before the patient recovers normal strength and respiratory function. Intermediate syndrome. Thus, IMS can be regarded as a spectrum disorder affecting the neuromuscular junction (NMJ) with two main forms: a forme fruste variety associated with mild weakness and the classical IMS with weakness of 3/5 or less than 3/5 on the Medical Research Council (MRC) grading; patients in the latter category are at risk of developing late onset respiratory failure. While IMS remains a clinically important entity, the early occurrence of abnormalities on repetitive nerve stimulation studies suggest that this is part of the continuum of nicotinic receptor stimulation. Conclusions. Reviewing the anatomical and the functional structure of the NMJ and neuromuscular transmission helps to provide an understanding of the pathophysiological nature of the neuromuscular transmission failure observed in IMS. This includes potential mechanisms of presynaptic feedback which may reduce acetylcholine release and postsynaptic receptor desensitization and provides some explanation for the time course of IMS. It also suggests other potential strategies to reduce OP-induced NMJ toxicity in which repetitive nerve stimulation is likely to be an important tool in judging efficacy.

Mortality due to poisoning in a developing agricultural country: trends over 20 years

The cause of death as recorded in 37 125 death certificates (DCs) issued in the Kandy District over 20 years at 5-year intervals beginning in 1967 were analysed to determine the trends in mortality caused by poisoning in the commu nity. Poisoning accounted for 718 (19.3 per 1000) deaths, the highest number being in the third decade of life (41.9%). Male:female ratio was 3:1. The agent responsible for 77% of the deaths was pesticides. Acids and chemicals accounted for 6.9% of the deaths. Other poisons each con tributing to less than 1% of the deaths were: plant poi sons, food items, drugs, kerosine oil and alcohol. Nearly half the deaths had occurred outside the town area, at home or in small hospitals in the periphery. Mortality due to poisoning showed an increasing trend during the 20 years, from 11.8 to 43/1000 deaths, and this increase was most marked in the periphery, from 8/1000 to 70/1000. This increase paralleled the increase in suicide figures in the country. Our findings call for a shift in emphasis in public education towards first-aid management of intoxi cation. Health services of developing countries should pro vide appropriate resuscitative equipment, and ensure a regular supply of antidotes and other medication to all rural hospitals. Management of pesticide poisoning should be emphasised in the curricula for medical graduates, nurses, and paramedics.

Acute organophosphorus insecticide poisoning in Sri Lanka

Records of 92 cases of acute organophosphorus (OP) insecticide poisoning were analysed. Of the patients 91% were under 30 years of age and 86% were males. The common agents were Dimethoate, Methamidophos, Malathion, Monocrotophos and Fenthion. Poisoning was due to ingestion with suicidal intent in the majority. In addition to the acute cholinergic features, the other important manifestations were delayed onset respiratory paralysis and delayed polyneuropathy. The overall mortality was 18%.