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 ∼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.