Improvement in Survival after Paraquat Ingestion Following Introduction of a New Formulation in Sri Lanka

Abstract

Background

Pesticide ingestion is a common method of self-harm in the rural developing world. In an attempt to reduce the high case fatality seen with the herbicide paraquat, a novel formulation (INTEON) has been developed containing an increased emetic concentration, a purgative, and an alginate that forms a gel under the acid conditions of the stomach, potentially slowing the absorption of paraquat and giving the emetic more time to be effective. We compared the outcome of paraquat self-poisoning with the standard formulation against the new INTEON formulation following its introduction into Sri Lanka.

Methods and Findings

Clinical data were prospectively collected on 586 patients with paraquat ingestion presenting to nine large hospitals across Sri Lanka with survival to 3 mo as the primary outcome. The identity of the formulation ingested after October 2004 was confirmed by assay of blood or urine samples for a marker compound present in INTEON. The proportion of known survivors increased from 76/297 with the standard formulation to 103/289 with INTEON ingestion, and estimated 3-mo survival improved from 27.1% to 36.7% (difference 9.5%; 95% confidence interval [CI] 2.0%–17.1%; p = 0.002, log rank test). Cox proportional hazards regression analyses showed an approximately 2-fold reduction in toxicity for INTEON compared to standard formulation. A higher proportion of patients ingesting INTEON vomited within 15 min (38% with the original formulation to 55% with INTEON, p < 0.001). Median survival time increased from 2.3 d (95% CI 1.2–3.4 d) with the standard formulation to 6.9 d (95% CI 3.3–10.7 d) with INTEON ingestion ( p = 0.002, log rank test); however, in patients who did not survive there was a comparatively smaller increase in median time to death from 0.9 d (interquartile range [IQR] 0.5–3.4) to 1.5 d (IQR 0.5–5.5); p = 0.02.

Conclusions

The survey has shown that INTEON technology significantly reduces the mortality of patients following paraquat ingestion and increases survival time, most likely by reducing absorption.

Abstract

Martin Wilks and colleagues compared the outcome of paraquat self-poisoning with the standard formulation against a new formulation following its introduction into Sri Lanka.

Editors' Summary

Background.

Paraquat is a non-selective herbicide used in many countries on a variety of crops including potatoes, rice, maize, tea, cotton, and bananas. It is fast-acting, rainfast, and facilitates “no-till” farming, but it has attracted controversy because of the potential for misuse, particularly in developing countries. Better training of workers has been shown to reduce the number of accidents, and additions to the liquid formulation have contributed to a reduction in cases where paraquat was drunk by mistake—blue color and a stench agent made it less attractive to drink, and an emetic to induce vomiting aimed to reduce the time it is retained in the body.

Why Was This Study Done?

Despite the changes made to the formulation, paraquat is still taken deliberately as a poison by agricultural workers in parts of the developing world. Although other pesticides cause more deaths overall, paraquat poisoning is more frequently fatal than other common pesticides. Syngenta, a commercial producer of paraquat, has developed a new paraquat formulation designed to reduce its toxicity. Syngenta introduced the new formulation in Sri Lanka, a country well known for its high level of suicides with pesticides, in 2004. This new formulation includes three components designed to reduce paraquat absorption from the stomach and intestines: a gelling agent to thicken the formulation in the acidic environment of the stomach and slow its passage into the small intestine; an increase in the amount of emetic to induce more vomiting more quickly; and a purgative to speed its exit from the small intestine, the main site of its absorption. The researchers wished to know whether the new formulation could contribute to improved survival in instances where paraquat had been ingested.

What Did the Researchers Do and Find?

The researchers gathered information on the time and circumstances of when paraquat was taken, the amount that was taken, the times, and details of any vomiting, treatment, and outcomes for cases of attempted suicide by paraquat poisoning at nine large hospitals in agricultural regions of Sri Lanka from December 2003 to January 2006. In total, 774 patients were tracked in this time. Syngenta introduced the new formulation in Sri Lanka on 1 October 2004. The researchers gathered information on the formulation involved in subsequent cases, by either interview or analysis of samples. After excluding some unusual or less certain cases, they analyzed data on 586 patients, of whom 297 had deliberately taken the standard formulation and 289 the new formulation.

Although the new formulation was still toxic, the data showed an increase in the proportion of cases surviving for at least three months—from 27% (standard formulation) to 37% (new formulation), an effect that was unlikely to be due to chance. More patients vomited within 15 minutes of taking the new formulation of paraquat. Patients who died generally survived longer if they had taken the new rather than the standard formulation. The researchers estimated that the new formulation is just over half as toxic as the standard formulation, meaning that a patient was likely to suffer the same level of ill effects after taking twice as much of the new formulation compared to the standard formulation.

What Do these Findings Mean?

This study was designed, funded, and led by Syngenta, the manufacturer of the standard and new formulations of paraquat but the study team included a number of independent Sri Lankan and international scientists. As the researchers observed the effects of the introduction of the new formulation across the entire country at the same time, they could not completely rule out other possible reasons for the differences in outcomes for those who had taken the two formulations, such as differences in treatment.

Despite this inherent drawback, the researchers estimate that during the study the new formulation saved about 30 lives. They conclude that the the new formulation does reduce the amount of paraquat absorbed by the body, although the study does not answer the question whether this was due to the gelling agent, the increased emetic in the new formulation or a combination of factors. The researchers suggest that the new formulation, by keeping patients alive longer, may allow doctors more time to treat patients. As no effective treatment exists at present, this benefit relies on a treatment being developed in the future.

The researchers note that the most important factor in predicting the outcome when paraquat has been taken deliberately is the dose. As a result, they suggest that the new formulation can only be one part of a wider strategy to reduce deaths by deliberate self-poisoning using paraquat. They suggest that such an integrated approach might include generic measures to reduce incidents of self-harm, reduced access to paraquat, reduced formulation strength, and improvements in treatment.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050049.

• The US Environmental Protection Agency has published its Reregistration Eligibility Decision for paraquat

• The Department of Health and Human Services of the US Centers for Disease Control and Prevention provides a fact sheet on how to handle paraquat and suspected cases of exposure

• The World Health Organisation has recently finished consulting on a draft Poisons Information Monograph for paraquat

• The International Programme on Chemical Safety (IPCS) has published a review of paraquat in its Environmental Health Criteria Series

• MedlinePlus provides links to information on health effects of paraquat