Hyo-Wook Gil

Association between plasma paraquat level and outcome of paraquat poisoning in 375 paraquat poisoning patients

Objectives. Paraquat poisoning by ingestion is often fatal. Many studies have investigated treatment modalities and predictor parameters, but there is no standard treatment. Plasma paraquat concentration seems a valid predictable parameter of survival. In order to achieve uniform treatment, including extracorporeal elimination and antioxidant therapy, the outcome of paraquat poisoning based on plasma paraquat level needs to be investigated. Methods. This study included 375 paraquat poisoning patients who were diagnosed by means of plasma paraquat concentration within 24 hours after ingestion in the Institute of Pesticide Poisoning of Soonchunhyang University Cheonan Hospital, Korea, from January 2005 to December 2006. All patients were treated according to a uniform protocol including extracorporeal elimination and antioxidant therapy. Plasma paraquat concentration was measured by high-performance liquid chromatography. Results. The mean age of the paraquat-intoxicated patients was 48.42 ± 6.75. One hundred ten patients (29.3%) survived. The upper limit of plasma paraquat concentration in survivors was 2.64 at 3 hour. All patients with plasma paraquat level above 3.44 died. The minimum paraquat level of the deaths was very low (0.12 μg/ml at 5 hours; 0.02 μg/ml at 12 hours; 0.01 μg/ml at 24 hours). Conclusions. Our data showed that plasma paraquat concentration is good predictor of survivors but is not good predictor of non-survivors in the low plasma paraquat level.

The clinical features of acute kidney injury in patients with acute paraquat intoxication

BACKGROUND Paraquat (PQ) is a non-selective herbicide that generates reactive oxygen species in vivo. We hypothesized that acute kidney injury (AKI) in patients with acute PQ poisoning would provide a model for the clinical features of ROS-induced AKI. METHODS From January 2007 to December 2007, 278 patients with acute PQ intoxication were included in the study. AKI was defined based on the RIFLE classification. The serial changes of creatinine (Cr), the incidence of AKI and the mortality according to the RIFLE classification were analysed. RESULTS An initial serum Cr >1.2 mg/dL was a significant predictor of mortality [odds ratio 9.00, 95% C.I. (4.747, 17.061), P < 0.01]. The incidence of AKI was 51.4% among the 173 patients who had an initial serum Cr < or =1.2 mg/dL. Among them, 34.7% were the failure group and oliguric AKI was observed in 10 patients. The average peak serum Cr level, among the 13 survivors in the failure group, was 4.38 mg/dL at the fifth day, after ingestion, and their Cr level normalized within 3 weeks. None of the 13 survivors had permanent loss of renal function. The estimated amount of PQ ingestion was a predictor of the incidence of AKI. The mortality risk was significantly higher in the failure group than in the group without failure. CONCLUSION The clinical feature was characterized by fully developed AKI at the fifth day after PQ ingestion and normalized within 3 weeks without exception.

Paraquat Intoxication in Subjects Who Attempt Suicide: Why They Chose Paraquat

Background/Aims Paraquat (PQ) has been used in suicide attempts; an estimated 2,000 toxic ingestions occur annually, with 60-70% mortality. We sought to determine why PQ is such a common agent for suicide attempts in Korea. Methods We analyzed 250 cases (143 males, 107 females) of attempted suicide by PQ ingestion from January to December 2007. The procurement of the PQ was divided into two categories: purchased and preexisting. Results Men were more likely to have purchased PQ than women (66% vs. 22%, p=0.042). Additionally, men were more likely to be unmarried (n=34, 23.9% vs. n=10, 9.3%) or divorced or separated (n=16, 11.3% vs. n=5, 4.6%) than the women (p<0.001). The group who intentionally selected PQ (38.4%) consisted of 96 cases (54 males, 42 females) and the group who did not intentionally select PQ (61.6%) included 154 cases (89 males, 65 females). The incidence of PQ purchase was higher in the intentional selection PQ group (46.9% vs. 18.2%, p<0.01). Conclusions Only 38% of patients who attempted suicide with PQ intentionally selected PQ. Thus, greater control of PQ availability is needed, especially in patients at risk.

Comparison between Kidney and Hemoperfusion for Paraquat Elimination

The mortality rate of acute paraquat (PQ) poisoning depends on the PQ concentration in the blood. It has been shown that the kidneys eliminate PQ effectively. However, early renal function deterioration is frequently observed in acute PQ intoxication. This study is designed to compare the efficacy of PQ elimination with hemoperfusion (HP) and kidneys, taking into account the functional deterioration of the kidneys. The amount of renal and HP excretion of PQ were measured during the procedure of HP in patients with acute PQ intoxication. The PQ clearance and the actual amount of PQ elimination by the HP cartridge during the HP procedure were 111±11 mL/min (range; 13.2-162.2 mL/min) and 251.4±506.3 mg (range; 4.6-1,655.7) each. While, the renal clearance and actual amount of renal elimination of PQ was 79.8±56.0 mL/min (range; 9.7-177.0) and 75.4±73.6 mg (range; 4.9-245.8). As the creatinine clearance decreased, the PQ elimination by HP was as effective as or more effective than the renal elimination. In conclusion, early HP must be provided for life saving treatment in patients with acute PQ intoxication.

Diagnostic and Therapeutic Approach for Acute Paraquat Intoxication

Paraquat (PQ) has known negative human health effects, but continues to be commonly used worldwide as a herbicide. Our clinical data shows that the main prognostic factor is the time required to achieve a negative urine dithionite test. Patient survival is a 100% when the area affected by ground glass opacity is <20% of the total lung volume on high-resolution computed tomography imaging 7 days post-PQ ingestion. The incidence of acute kidney injury is approximately 50%. The average serum creatinine level reaches its peak around 5 days post-ingestion, and usually normalizes within 3 weeks. We obtain two connecting lines from the highest PQ level for the survivors and the lowest PQ level among the non-survivors at a given time. Patients with a PQ level between these two lines are considered treatable. The following treatment modalities are recommended to preserve kidney function: 1) extracorporeal elimination, 2) intravenous antioxidant administration, 3) diuresis with a fluid, and 4) cytotoxic drugs. In conclusion, this review provides a general overview on the diagnostic procedure and treatment modality of acute PQ intoxication, while focusing on our clinical experience.

Surfactant volume is an essential element in human toxicity in acute glyphosate herbicide intoxication

Background: Glyphosate, one of the most commonly used herbicides worldwide, has been considered as minimally toxic to humans. However, clinical toxicologists occasionally encounter cases of severe systemic toxicity. The purpose of this study was to determine the effect of glyphosate-surfactants (“glyphosate-surfactant toxicity”) in patients with acute glyphosate intoxication. Methods: In all, 107 patients (69 men and 38 women, aged 52.3 ± 15.5 years) with acute glyphosate intoxication were enrolled in this study. From their medical records, we identified the formulation of ingested glyphosate products and derived clinical parameters, which focused on clinical outcome, admission days, duration in the intensive care unit, development of respiratory failure, cardiovascular deterioration, renal failure, altered mental status, and convulsions. The effect of surfactants on clinical complications was also assessed. Results: For surfactant ingestion volumes of 8 mL, the incidence of clinical complications was (in rank order) as follows: hypotension, 47.1%; mental deterioration, 38.6%; respiratory failure, 30.0%; acute kidney injury, 17.1%; and arrhythmia, 10.0%. These complications were influenced by the volume of surfactant and not the type of surfactant-ingredient in the herbicide product. Two patients died of refractory shock, metabolic acidosis, and respiratory failure. However, the final clinical outcomes of the surviving patients were benign, and cardiovascular, respiratory, kidney, and mental functions were fully restored to normal levels. Conclusions: Our results indicate that treatment of patients with acute glyphosate herbicide intoxication should take into account the volume and not the type of surfactants in herbicide formulations.

Mixtures of glyphosate and surfactant TN20 accelerate cell death via mitochondrial damage-induced apoptosis and necrosis.

Glyphosate, a common herbicide, is not toxic under normal exposure circumstances. However, this chemical, when combined with a surfactant, is cytotoxic. In this study, the mechanism of the additive effect of glyphosate and TN-20, a common surfactant in glyphosate herbicides, was investigated. After exposure of rat H9c2 cells to glyphosate and TN-20 mixtures, following assays were performed: flow cytometry to determine the proportion of cells that underwent apoptosis and necrosis; western blotting to determine expression of mitochondrial proteins (Bcl-2 and Bax); immunological methods to evaluate translocation of cytochrome C; luminometric measurements to determine activity of caspases 3/7 and 9; and tetramethyl rhodamine methyl ester assay to measure mitochondrial membrane potentials. Bcl-1 intensity decreased while Bax intensity increased with exposure to increasing TN-20 and/or glyphosate concentrations. Caspase activity increased and mitochondrial membrane potential decreased only when the cells were exposed to a mixture of both TN-20 and glyphosate, but not after exposure to either one of these compounds. The results support the possibility that mixtures of glyphosate and TN-20 aggravate mitochondrial damage and induce apoptosis and necrosis. Throughout this process, TN-20 seems to disrupt the integrity of the cellular barrier to glyphosate uptake, promoting glyphosate-mediated toxicity.

Factors for Determining Survival in Acute Organophosphate Poisoning

Background/Aims Organophosphate poisoning has a high mortality rate. Recently, differences among organophosphorus insecticides in human self-poisoning were reported. This study investigated the prognostic risk factors and the mortality of different organophosphates following acute organophosphate poisoning. Methods This retrospective study included 68 patients with acute organophosphate poisoning. We investigated patient survival according to initial parameters, including the initial Acute Physiology and Chronic Health Evaluation (APACHE) II score, serum cholinesterase level, and hemoperfusion and evaluated the mortality according to organophosphate types. Results Thirteen of the 68 patients died. The agents responsible for mortality were different. The APACHE II score was a significant predictor of mortality (odds ratio [OR], 1.194; p<0.01; 95% confidence interval [CI], 1.089 to 1.309) and respiratory failure (OR, 1.273; p<0.01; 95% CI, 1.122 to 1.444). The mortality was 0% for dichlorvos, malathion, chlorpyrifos and profenofos. However, other organophosphates showed different mortality (16.7% for O-ethyl-O-4-nitrophenyl phenylphosphonothioate, 25% for phenthoate, 37.5% for phosphamidon, 50% for methidathion). The usefulness of hemoperfusion appears to be limited. Conclusions The initial APACHE II score is a useful prognostic indicator, and different organophosphates have different mortality.

Cellular Toxicity of Surfactants Used as Herbicide Additives

The cellular toxicities of surfactants, a solvent, and an antifreeze that are included in herbicide formulations were assessed by measuring their effects on membrane integrity, metabolic activity, mitochondrial activity, and total protein synthesis rate in a cell culture. Polyethylene glycol, propylene glycol, and monoethylene glycol exhibited no cellular toxicity even at a high concentration of 100 mM. Sodium lauryl ether sulfate and polyoxyethylene lauryl ether significantly damaged the membrane, disturbed cellular metabolic activity, and decreased mitochondrial activity and the protein synthesis rate; however, their toxicity was far below those of the severely toxic chemicals at comparable concentrations. The severely toxic category included polyoxypropylene glycol block copolymer, polyoxyethylene tallow amine, and polyoxyethylene lauryl amine ether. These surfactants were cytotoxic between 3.125 µM and 100 µM in a dose-dependent manner. However, the toxicity graph of concentration vs toxicity had a point of inflection at 25 µM. The slope of the toxicity graph was gentle when the concentration was below 25 µM and steep when the concentration was greater than 25 µM. In conclusion, our results suggest that the toxicity of surfactants be taken care of pertinent treatment of acute herbicide intoxication.

Effect of intravenous lipid emulsion in patients with acute glyphosate intoxication

Abstract Background. Although glyphosate intoxication has been considered minimally toxic in animals, severe toxicity has been observed in humans due to surfactant. We aimed to examine the potential therapeutic effects of intravenous lipid emulsion (ILE) on the patients with acute glyphosate intoxication. Methods. This study enrolled 64 glyphosate-intoxicated patients with allocation to two groups: those treated with ILE (ILE group, n = 22), and control patients treated with only supportive (conservative) care. Control patients were selected by matching for the amount ingested and time since ingestion. Twenty-two control patients were separately selected from the 42 patients receiving supportive care only. In ILE group, 20% lipid emulsion product was injected intravenously at the rate of 20 mL/h for the patients who ingested less than 100 ml of glyphosate. In the patients who ingested more than 100 ml of glyphosate, the loading dose was 500 ml for 2–3 h according to the status of the patients, followed by a maintenance dose of 1000 ml for the next 24 h. Results. Thirteen patients received high dose of ILE because the ingestion amount was more than 100 ml. None of the ILE group suffered from the complication of hypotension, while approximately 41% of the control group developed the complication. Additionally, arrhythmia was not observed in the ILE group. The incidence of mental change, respiratory failure, and acute kidney injury was similar between the two groups. Conclusions. ILE administration was associated with lower incidence of hypotension and arrhythmia in patients with acute glyphosate intoxication. ILE administration seems to be an effective treatment modality in patients who ingested sufficient amount of glyphosate herbicide that is expected to bring about significant toxicity.