Does oxidative stress contribute to toxicity in acute organophosphorus poisoning? - a systematic review of the evidence

Introduction: Organophosphorus (OP) insecticide self-poisoning is a global problem, killing tens of thousands of people every year. Oxidative stress has been proposed to play a pathological role in OP poisoning, but whether it plays a direct toxic role is currently unclear. Objectives: To determine whether there is consistent evidence of oxidative stress in patients with acute OP insecticide self-poisoning, and whether there are animal or human trial data that indicate that treatment of oxidative stress provides clinical benefit, which would suggest a direct toxic effect of oxidative stress. Methods: We conducted a systematic review using the PubMed, EMBASE and MEDLINE databases, and the Cochrane Database of Systematic reviews, based upon the following search terms and keywords: organophosphate poisoning, oxidative stress and antioxidant. All articles relevant to the aims of the study were included. Articles related to chronic OP poisoning, to use of medicines without antioxidant benefits, or to subjects other than oxidative stress were excluded. The search returned 256 results of which 17 studies were considered relevant and grouped under the following categories: observational human studies (n = 11) and intervention studies in animals (n = 4) and humans (n = 2). Oxidative stress markers in human studies: Oxidative damage to lipids and proteins was reported in all eleven human studies. Eight of nine studies reported variable increases in a weak marker of lipid peroxidation, malondialdehyde. In two case-control studies, erythrocyte membrane malondialdehyde concentrations were 380% and 160% higher in cases than controls, while plasma malondialdehyde concentrations were similar to 63% higher in cases than controls in three case-control studies. In a prospective study, plasma malondialdehyde did not increase significantly from baseline in moderate or severely poisoned patients. Five case-control studies measured thiol residues as markers of protein oxidative damage and found variable changes after poisoning. No evidence of oxidative DNA damage was found in the one study that investigated it. Antioxidant intervention studies in animals: After treatment with an antioxidant, all four studies showed an improvement in either markers of oxidative damage or antioxidant activity. One mouse study with a relatively low risk of bias showed that administration of acetylcysteine 200 mg/kg reduced malondialdehyde by 35% and increased survival by more than 60%. Antioxidant intervention studies in humans: We found two small randomised controlled trials reporting the use of acetylcysteine as an adjunct to standard treatment in acute OP poisoning. The trials found that acetylcysteine reduced atropine requirements by 77% and 55%, but did not affect clinically relevant outcomes. Conclusions: Several studies showed evidence of OP insecticide-induced oxidative damage and antioxidant activity, suggesting that endogenous antioxidant defences are triggered in acute OP poisoning. However, the markers of lipid peroxidation used were weak, there was high inter-individual variability between studies in results and quality, and marked variation between the OP insecticides involved. Animal data provide some evidence that antioxidants alleviate adverse effects of acute poisoning, suggesting that oxidative stress may directly cause clinical harm. Acetylcysteine appeared beneficial in animal studies, but this could be mediated via increased synthesis of the endogenous detoxifying agent, glutathione, rather than through a direct antioxidant effect. The two human clinical studies were too small to provide any clear evidence to support the use of acetylcysteine in OP poisoning. Further research into the mechanisms of oxidative stress in acute OP poisoning, combined with large unambiguous clinical trials of antioxidants, are required before they can be used routinely in treatment.