Clinical Drug Experience Knowledgebase

Effectiveness of High Dose Pralidoxime in the Treatment of Organophosphorus Pesticide Poisoning - a Randomised Controlled Trial

Standard treatment of organophosphorus pesticide poisoning involves administration of intravenous atropine and oximes to counter acetylcholinesterase inhibition.1 Treatment with atropine is well established, but the efficacy and dosage schedule of oximes are controversial.2-5 A dose of 1g every four to six hours has been the standard regimen in Asian district hospitals but many clinicians remain unconvinced by its effectiveness.3 Randomised controlled trials (RCT) performed in Vellore during the nineties compared a 12g infusion over 3-4 days with a 1g bolus dose and then with placebo.6,7 The authors reported no benefit from pralidoxime and an increased mortality in those receiving the infusion, and have stated that pralidoxime should not be given to organophosphorus poisoned patients.2

Others consider that the dosage regimen was not ideal, with therapeutic concentrations being obtained rarely during the treatment.3,4 Furthermore, many patients presented late and had taken dimethyl pesticides - a class that does not respond well to oximes after several hours - biasing the study against finding benefit.

The proposed minimum effective plasma levels for pralidoxime of 4 mg/L were based on in vitro and animal experiments by Sundwall.8 Recent evidence, however, suggests that higher blood concentrations of pralidoxime are needed to antagonise the toxic effects of many pesticides and that a bolus loading infusion followed by a maintenance infusion would be the best regimen.9 The WHO have proposed that patients receive around 30mg/kg pralidoxime salt as a loading dose followed by an infusion of at least 8mg/kg/hr (roughly equivalent to 1-2 g bolus followed by 0·5 g/h in a 50kg south Asian patient).9,10 However, no trials have yet been performed to determine whether such a regimen reduces morbidity and mortality in severely poisoned patients.3 Since organophosphorus pesticides kill hundreds of thousands of people in rural Asia every year, it is essential to determine whether it benefits or harms such poisoned patients.

Our hospital has typically used a regimen of 1g q4h in organophosphorus poisoned patients but we were unconvinced about the effectiveness of this expensive drug since many patients required ventilation for >10 days. We informally treated several patients with the WHO-recommended regimen but saw little benefit. Since pralidoxime has a high therapeutic index, we then decided to conduct a RCT with still higher doses, i.e. to compare a 1 g infusion every hour (q1h, 24 g/day) with 1g every four hours (q4h, 6 g/day), after a 2 g loading dose, to assess the effectiveness of high dose pralidoxime in organophosphorus poisoned patients.