Professor Indika Gawarammana
Professor- Department of Medicine, Faculty of Medicine, University of Peradeniya
Consultant Physician, Professorial Medical Unit, Teaching Hospital Peradeniya.

Predicting and treating Intermediate syndrome following Organophosphorus (OP) insecticide poisoning

Pesticide self-poisoning is a major clinical and public health problem in Sri Lanka, as it is in many rural regions of Asia. Pesticide poisoning causes an estimated 250-350,000 deaths each year in Asia. The widespread introduction of pesticides into agricultural practice of Sri Lanka during the Green Revolution of the 1950s and 60s was soon followed by an exponential increase in the number of cases of poisoning and deaths. At the beginning when fast acting, highly toxic pesticides were locally used in agriculture, many deaths occurred before patients got to hospital. Even at present, if patients do survive to admission, medical management is difficult, sometimes impossible, in even the very best hospitals. South Asian Clinical Toxicology Research Collaboration in collaboration with multiple government institutions managed to impose bans on many highly toxic pesticides which contributed to a major reduction of deaths from self- poisoning with pesticides. Over the last two decades the case fatality has reduced from around 20% to 3% at present.

One of the main causes of death from organophosphorus self-poisoning is respiratory failure secondary to intermediate syndrome. Intermediate syndrome is due to effects of organophophorus insecticides on the nicotinic receptors. Despite, there has been an overall reduction in case fatality, respiratory failure due to intermediate syndrome still contributes to a significant number of deaths. South Asian Clinical Toxicology Research has been working further to reduce deaths from intermediate syndrome. A two pronged approach was taken to tackle this problem. An extensive study looked at developing early predictive markers of intermediate syndrome. The study involved 220 prospective patients with OP poisoning. Our results indicated that the assessment of the neuromuscular junction by jitter analysis is useful in predicting IMS. OP poisoned patients with high jitter values were more likely to develop IMS than others. Further, jitter analysis shows abnormalities at the neuromuscular junction before there is failure of neuromuscular communication. Neuromuscular communication failure is seen as blocking in the jitter recording. The degree of impairment of the neuromuscular junction is also indicated by the blocking percentage. After OP poisoning jitter examination allows identification of those patients likely to develop IMS and allow efficient deployment of resources for their management. The second study investigated the usefulness of protecting nicotinic receptors prophylactically using rocuronium. The pathophysiology of Neuro-Muscular Junction (NMJ) dysfunction is uncertain; however, since it occurs despite adequate muscarinic receptor blockade with atropine, the main hypothesis is that it is due to overstimulation of pre- and/or post-synaptic NMJ nicotinic receptors by excess acetylcholine causing their down regulation and neuro-transmission failure. Neuro-Muscular Blocking Agents (NMBAs) may prevent nicotinic overstimulation and NMJ dysfunction, shortening duration of ventilation and reducing the risk of complication. If effective, a short period of controlled NMBA-induced paralysis and ventilation – while the OP insecticide is eliminated from the body-could replace 2-3 weeks of OP insecticide-induced NMJ damage, paralysis, and ventilation. We therefore set up a small pilot randomised controlled trial (RCT) to obtain preliminary data on the efficacy of nicotinic antagonists in patients with OP insecticide self-poisoning. We selected rocuronium due to its potency at both pre-synaptic and post-synaptic nicotinic receptor sand a maximum duration of ve days to balance the risk of neuropathy with the need for treatment when OP body load is at its highest. To investigate a dose response, we compared an initial near complete (95%) competitive inhibition of NMJ function with partial (50%) NMJ inhibition and with no inhibition.

Patients were randomized using closed envelopes into one of three study arms, to receive rocuronium that initially produced>95% inhibition of baseline NMJ function (Roc>95), rocuronium that initially produced 50% inhibition of baseline NMJ (Roc50), or no rocuronium (control, n=15/group). Forty-ve patients (89% male) with a history of OP insecticide ingestion and features of anticholinesterase poisoning were randomised. We were able to study NMBAs in OP insecticide poisoned patients but found no apparent benet from rocuronium administration in profenofos OP insecticide poisoned patients requiring early intubation and ventilation with at least 50% preserved NMJ function. It is possible that this was due to the ongoing cholinesterase inhibition and nicotinic receptor overstimulation outlasting the duration of nicotinic antagonists. In contrast, a pig model demonstrated benefit from this treatment. Further studies are required to demonstrate its benefit.

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