Plasma Paraquat Concentration Research Articles

Comparison of a Pulsatile Blood Pump and a Peristaltic Roller Pump During Hemoperfusion Treatment in a Canine Model of Paraquat Poisoning

This study examined the treatment efficacy and the damage to the blood during hemoperfusion for treating paraquat poisoning using two blood pump mechanisms. Paraquat-poisoned animal models were prepared. A conventional hemodialysis machine, AK90, with a peristaltic roller pump and a cardiopulmonary support system, T-PLS, with a pulsatile blood pump were used during the animal experiments. A total of 12 dogs were treated with hemoperfusion using a charcoal column. Six dogs were treated with hemoperfusion and T-PLS, and the other six were treated with AK90. A paraquat dose of 30 mg/kg was administrated by an intravenous injection. Both pumps maintained blood flow rates of 125 mL/min measured by an ultrasonic flowmeter. For anticoagulation, heparin was administrated by an initial bolus (250 IU/kg) and a continuous injection (100 IU/kg/h). During the experiments, T-PLS and AK90 showed a similar toxin removal efficacy. Both devices decreased the plasma paraquat concentration to 10% of the initial dose within 4-h hemoperfusion. The two pumps showed similar hemolysis properties with acceptable levels. Although T-PLS was developed as a cardiopulmonary bypass system, it can also be used as a hemoperfusion treatment device.

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.

No direct hepatotoxic potential following a multiple-low dose paraquat exposure in rat as related to its bioaccumulation

Paraquat (PQ) is a well-known toxic bipyridyl herbicide commonly used in agricultural countries. Pulmonary toxicity is the main cause of death but damage to other organs has also been reported. PQ is also classified as a “ direct hepatotoxicant” following an acute high dose exposure. The evidence of multi-low dose toxicity of PQ was scarce. Therefore, the aim of this study was to examine the effect of multiple low doses of PQ on the liver function and xenobiotic-metabolizing enzyme activities including CYP1A1, 2E1, and 3A4, and to correlate the effects with its tissue accumulation. PQ, at the dose range 4.0–6.0 mg/kg day, was subcutaneously administered to male Wistar rats for seven consecutive days. The prominent feature of toxic response was lung toxicity. Interestingly, PQ-treatment caused a dose- and time-dependent reduction of plasma transaminase activity. Hypobilirubinemia and hypoalbuminemia were also observed without significant alteration in the liver morphology. Of all the xenobiotic-metabolizing enzymes being studied, only the activity of CYP1A1-related 7-ethoxyresorufin- O-deethylase was reduced following the highest dose of PQ administration. Plasma and tissue concentrations and accumulation of PQ analyzed by HPLC were dose-dependent showing much higher concentration (approximately 13 times) in the lung than that in the liver whereas it was undetectable in the plasma at the same time point. It can be concluded that multi-low dose PQ might affect certain synthetic function of the liver or activity of some hepatic xenobiotic-metabolizing enzymes. Minimal PQ accumulation in the liver is one of the explanations for the lack of cytotoxic hepatic injury in this study. Plasma PQ concentration may not be a good marker of exposure and toxicity after a prolonged exposure to PQ.

Further Evidence of the Usefulness of Acute Physiology and Chronic Health Evaluation II Scoring System in Acute Paraquat Poisoning

Objective and Method. We have previously successfully applied the Acute Physiology and Chronic Health Evaluation (APACHE) II system to assess the severity of patients with acute paraquat poisoning, and this article investigates further evidence of the usefulness of APACHE II system in predicting the in-hospital mortality of 64 patients with acute paraquat poisoning over a period of 12 years. The predictive factors including APACHE II score, plasma paraquat concentration, severity index of paraquat poisoning (SIPP), and estimated ingestion dosage of paraquat for evaluating the outcome in paraquat-poisoned patients were assessed. Results. Overall mortality was 71.9%: 46 out of 64 patients died. Non-survivors (n = 46) had a higher APACHE II score (23.3 ± 12.7) than survivors (n = 18) (6.1 ± 4.2) (p < 0.001). The plasma paraquat concentration, SIPP, and estimated ingestion dosage of paraquat were significantly higher in non-survivors than in survivors (p < 0.05, in all comparisons). By multiple logistic regression analysis, only the APACHE II score and peak data of blood sugar in 24 h after admission were capable of predicting in-hospital mortality. By using the area under receiver operating characteristic curves (AURC), the APACHE II system yielded better discriminative power (AURC = 0.893) than SIPP (AURC = 0.674), plasma paraquat concentration (AURC = 0.676), and estimated ingestion dosage of paraquat (AURC = 0.673). An APACHE II score greater than 13 predicted in-hospital mortality with 67% sensitivity and 94% specificity. Conclusions. The APACHE II score is a simple, reproducible, and practical tool for evaluating the severity of acute paraquat poisoning.

Clinical Implications of the Ethane in Exhaled Breath in Patients With Acute Paraquat Intoxication

Pulmonary fibrosis due to lipid peroxidation is a major symptom of paraquat intoxication. Ethane in the expired breath (exEth) reflects lipid peroxidation and may be a measure of the damage effected by oxygen radicals in acute lung injury. The purpose of this study was to evaluate the clinical efficacy of exEth as a measure of exposure to paraquat and as an indicator of lung damage. Exposure levels were evaluated by the amount ingested, semiquantitative measurement of urine paraquat levels, and plasma paraquat concentration. End-tidal breath was collected for measurement of ethane 24 h after paraquat ingestion. Renal function and blood gas analyses were conducted on the same day as the breath collection, and the final clinical outcome was defined as either recovery or death. Associations between exEth and paraquat exposure profiles and clinical outcomes were assessed using linear regression models. Twenty-one patients poisoned by paraquat were selected for the study during 2001 and 2002. exEth could not be used as a predictor of laboratory parameters such as Pa(O2), Pa(CO2), serum creatinine, and lung injury (as graded by high-resolution CT). A logistical analysis revealed that only the amount of paraquat ingested was a significant predictor of fatality (p = 0.021). The strength of the association between exEth and fatality was unaffected by the addition of potential confounders such as age, sex, and time interval and paraquat concentration. exEth cannot be used as either an independent predictor of survival or a specific marker of lung injury in patients with acute paraquat poisoning.

Severity assessment in acute paraquat poisoning by analysis of APACHE II score.

Several methods have been proposed to predict prognosis in patients with paraquat poisoning, but all have their limitations. This retrospective study evaluated the usefulness of Acute Physiology and Chronic Health Evaluation (APACHE) II scores in risk stratification for patients with paraquat poisoning. Data from 58 adults with a diagnosis of paraquat poisoning presenting to a general hospital over a 10-year period were analyzed. APACHE II scores were calculated at 24 hours after admission and data on related parameters during the first 24 hours were collected for study. The overall in-hospital mortality was 72.4% and mortality in the intensive care unit was 82.2%. APACHE II scores were higher in non-survivors (n = 42, 23.3 +/- 12.4) than in survivors (n = 16, 6.7 +/- 4.1; p < 0.001). All 26 patients (44.8%) who received mechanical ventilation died. Of the 32 patients who received hemoperfusion, 25 (78.1%) died. Plasma paraquat concentration, estimated ingested amount of paraquat, and APACHE II score were significantly higher in non-survivors than in survivors (p < 0.05 for all comparisons). There were significant correlations between APACHE II score and the following variables: plasma paraquat concentration, estimated ingested amount of paraquat, and the peak values during the first 24 hours after admission for fraction of inspired oxygen, alveolar-arterial oxygen gradient, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and serum creatinine (p < 0.05 for all comparisons). Higher APACHE II score was associated with greater mortality. All patients who had an APACHE II score greater than 20 died before discharge. This study has demonstrated that the APACHE II score is positively correlated with plasma paraquat concentration and ingested amount of paraquat. An APACHE II score of 20 or higher is a good predictor of in-hospital mortality.

Changes in concentrations of type IV collagen and tissue inhibitor of metalloproteinase‐1 in patients with paraquat poisoning

Respiratory failure is one of the major causes of death in patients with paraquat poisoning. In paraquat-poisoned lungs, abnormal extracellular matrix regulation occurs. The aim of the present study is to determine whether serum concentrations of type IV collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) are altered during the course of paraquat poisoning and whether haemoperfusion therapy affects these concentrations. Twenty-one patients were admitted within 3 h after ingestion of paraquat and all patients received direct haemoperfusion therapy. Five out of 21 patients survived and 16 patients died within 28 days. Plasma paraquat concentrations in non-survivors (5740 +/- 380 microg l(-1)) were not significantly different from those in survivors ( 5920 +/- 280 microg l(-1)) before treatment. Haemoperfusion reduced these concentrations in both non-survivors (120 +/- 7 microg l(-1)) as well as survivors (136 +/- 9 microg l(-1)) on day 5. Serum concentrations of type IV collagen and TIMP-1 in survivors showed little change between day 1 (type IV collagen, 90.4 +/- 3.6 ng ml(-1); TIMP-1, 172.2 +/- 7.0 ng ml(-1)) and day 5 (type IV collagen, 92.6 +/- 4.2 ng ml(-1); TIMP-1, 174.2 +/- 7.2 ng ml(-1)). In contrast, these concentrations in non-survivors on day 5 (type IV collagen, 143.6 +/- 7.8 mg ml(-1); TIMP-1, 246.8 +/- 13.6 ng ml(-1)) were significantly higher than those on day 1 (type IV collagen, 88.4 +/- 4.2 ng ml(-1), P < 0.01; TIMP-1, 170.6 +/- 9.2 ng ml(-1), P < 0.05). These data suggest that serum concentrations of type IV collagen and TIMP-1 may be useful indicators for the development of respiratory failure in patients with paraquat poisoning.

Multiple logistic regression analysis of plasma paraquat concentrations as a predictor of outcome in 375 cases of paraquat poisoning.

Successful prediction of who may survive paraquat poisoning can prevent inappropriately aggressive treatment in those who have little hope of survival and those only minimally poisoned. We examined case records of patients admitted to one poisoning treatment unit over the last 5 years, and the English and French language literature on paraquat poisoning. Data were recorded from all patients where outcome and timed plasma paraquat concentrations were present. Of 375 patients (113 M, 62 F, 200 unknown), mean age 38.3 years (range 1-87 years), 49 had evidence of renal toxicity, and 41 received haemodialysis or charcoal haemoperfusion; 61 developed pulmonary sequelae; and 44 had lesions in the upper gastrointestinal tract. Median time from ingestion to death in the 241 deaths reported was 270 h (range 3-720 h). We plotted log(plasma paraquat concentration) against log(h since ingestion). The predicted probability of survival for any specified time and concentration was exp(logit)/[1 + exp(logit)], where logit = 0.58-2.33 x log(plasma paraquat)-1.15 x log(h since ingestion). This equation may be helpful in predicting who will survive after ingestion of paraquat up to at least 200 h after ingestion, and can now be used as a research tool for studies on efficacy of treatment of paraquat poisoning.

Levels of paraquat in fatal intoxications.

We describe here fatal levels of paraquat in plasma of victims due to the ingestion of the herbicide, paraquat, and the relationship between those levels and survival times after ingestion. We determined paraquat levels in plasma of 106 paraquat poisoning cases in Korea between June 1992 and December 1996 using a visible spectrophotometric method based on the alkali-dithionite reaction. Among 55 cases with known survival times, plasma paraquat levels of victims who died within one day of ingestion ranged from 2.3 to 636.6 microg/ml (average 127.6 microg/ml) while those of the victims who died between 1 approximately 4 days ranged from 0.9 to 25.1 microg/ml (average 7.0 microg/ml). Since preparations containing 24.5% paraquat dichloride are still used in Korea, our data for Korean victims who died within one day were 8.5 times higher than those in Baselt and Cravey's report for the same survival times. Our data also suggest that victims in whom a plasma paraquat concentration of more than 30 microg/ml was detected are likely to have died within 24 h after ingestion.

Haemoperfusion treatment in pigs experimentally intoxicated by paraquat.

1. Because of their similarity in renal morphology and physiology to humans, domestic pigs (gilts, 70 kg) were bolus treated by intramuscular injection of 74, 17, and 6 mg kg-1 and by oral loading (70 mg kg-1 n = 4) of paraquat. The concentration peak of plasma paraquat was reached at 1.5 - 2.5 h. Renal clearance of paraquat rose to its maximum at 5-6 h after intoxication and then sharply decreased indicating renal failure. All the intoxicated pigs died. 2. An additional 10 gilts were also orally treated with 70 mg kg-1 paraquat but received haemoperfusion from 2 h post intoxication for either 2 h (n = 6) or 6 h (n = 4). The 2 h haemoperfusion resulted in a 5.1% toxin removal but failed to save any of six poisoned pigs. Prolonged 6 h haemoperfusion successfully rescued three out of four intoxicated pigs. 3. The plasma paraquat concentrations of the three surviving pigs were above 2 mg l-1 at 10 h post intoxication. This level is not only similar to those of untreated animals that died later, but also well beyond the suggested limit for survival of poisoned patients. 4. Pigs proved to be a good animal model for studies in paraquat poisoning and/or haemoperfusion. It is also suggested that early haemoperfusion is effective in treating paraquat poisoning even in very severe cases due to its possible detoxicating effect in addition to toxin removal.

No changes in behaviour, nigro-striatal system neurochemistry or neuronal cell death following toxic multiple oral paraquat administration to rats.

We have examined whether the widely used herbicide, paraquat (1,1'-dimethyl-4,4'dipyridylium) may accumulate in rat brain following multiple oral dosing (5 mg paraquat ion/kg/day) for 14 days and whether this dosing regime may produce signs of neurotoxicity. This dosing regime may determine whether low dose exposure to mammals may be neurotoxic. Using [14C]paraquat to measure tissue and plasma paraquat concentrations, we observed significantly higher plasma and tissue paraquat concentrations in brain, liver, lungs and kidneys of rats which received multiple doses for 14 days, as compared to paraquat concentrations in tissues of rats which received only a single paraquat dose. Brain paraquat concentrations measured 24 h after dosing were tenfold higher in rats receiving 14 daily oral doses of paraquat, as compared to concentrations following a single oral dose. A neuropathological study of the rat brain yielded no evidence that multiple paraquat dosing resulted in neuronal cell damage. Particular attention was paid to the nigrostriatal system. The paraquat treated rats gained approximately 10% less body weight over the 15 day experimental period as compared with controls demonstrating that the dose of paraquat was toxic to the animals. Measurements of locomotor activity using open field tests or activity monitors did not reveal any statistically significant differences between control animals and those receiving paraquat. Fore- and hind-limb grip strength were not significantly different between the paraquat treated and control rats at any time point during the dosing regime, nor was there any evidence for locomotor coordination deficits in any of the animals receiving paraquat. Densities of dopamine D1 and D2, NMDA, muscarinic and benzodiazepine receptors in the cerebral cortex and striatum were not significantly different between controls and rats which had received multiple paraquat doses. Concentrations of catecholamine neurotransmitters in the striatum, hypothalamus and frontal cerebral cortex were also measured to examine whether there was evidence for catecholamine depletion in these brain regions. We did not observe any significant reductions in dopamine, noradrenaline or DOPAC concentrations in any brain region of paraquat treated rats as compared with controls. On the contrary, dopamine concentrations in the striatim were significantly elevated in paraquat treated animals following a 15 day paraquat dosing regime. We attribute these changes in catecholamine concentrations to the general toxicity of paraquat which produces a stress response. In conclusion, we could not find any evidence that multiple paraquat dosing can lead to changes in locomotor activity or grip strength. In addition, the absence of neuropathology or changes in neurochemistry in the nigrostriatal tract demonstrates that paraquat does not behave like MPP+(N-methyl-4-phenylpyridinium), the neurotoxic metabolite of MPTP.

Effects of ethanol on pharmacokinetics and intestinal absorption of paraquat in animals.

The effect of ethanol on pharmacokinetics of paraquat was studied in rabbits by intravenous (i.v.) bolus injection of ethanol 0.5 g/kg (or normal saline, in the control group) followed by an i.v. dose of paraquat 20 mg/kg. A greater apparent volume of distribution (Vd), faster distribution rate constants and lower peak plasma concentration (P < 0.01) of paraquat were observed in the ethanol-treated than that in the control rabbits. The total clearance of paraquat was not significantly different between the two groups. The effect of ethanol on the intestinal absorption of paraquat was estimated by in situ intestinal perfusion technique in rats. The perfusate contained paraquat 50 micrograms/ml alone or with 1% or 2% ethanol. Inulin 320 micrograms/ml was added to the perfusate for the measurement of water net flux. The absorption clearance of paraquat as well as the absorption of water increased (P < 0.01) about two-fold in the presence of ethanol. The results of this study suggest that ethanol may potentiate paraquat toxicity by increasing intestinal absorption and tissue distribution. The critical lethal plasma concentration of paraquat is supposed to be lower in the presence of ethanol owing to increased volume of distribution.

Methemoglobinemia Following Ingestion of a Monolinuron/Paraquat Herbicide (Gramonol®)

A 59-year-old man ingested a mouthful of Gramonol with suicidal intent and was admitted to a local hospital six and a half hours later. It was noted that he looked "ashen grey" and was centrally cyanosed. The methemoglobin and plasma paraquat concentrations performed on arrival at the Regional Poisons Treatment Unit eight hours after paraquat ingestion were 52% and 1100 micrograms/L respectively; the administration of methylene blue reversed methemoglobinemia within two hours. The patient suffered extensive paraquat-induced oral, and probably esophageal, ulceration and developed multiple organ (particularly renal, respiratory and hepatic) failure and died some 10 days later. This is the most severe case of Gramonol poisoning reported both in terms of the amount of paraquat ingested and the concentration of methemoglobin formed. We believe that the methemoglobinemia in this patient was caused by monolinuron not paraquat.

Kinetics of toxic doses of paraquat and the effects of hemoperfusion in the dog.

Knowledge of the kinetics of an intoxicant is required for designing potential therapies in poisoned patients. In the case of paraquat, elucidating the kinetics has been made difficult by the paraquat-induced renal failure and the consequent dose- and time-dependent elimination of the herbicide. In the current study, we have modelled the plasma and urinary concentrations of paraquat in dogs given a toxic dose, the elimination of which was nonlinear. This enabled us, in turn, to simulate the apparent concentrations of paraquat in the deep tissue compartment, part of which is constituted by the major target organ for paraquat toxicity, the lung. Finally, we defined conditions, if any, under which charcoal hemoperfusion could reduce exposure of the deep compartment to paraquat by > or = 25%. We found that the plasma concentrations of paraquat could be described by a two compartment model with non-linear elimination from the central compartment. Use of a three compartment model did not improve the fit over that for a two compartment. The volume of distribution of paraquat at steady state approximated that of total body water. Simulated hemoperfusion performed for eight or eighty hours did not reduce exposure of the deep compartment to paraquat by > or = 25%, unless begun at times < or = two hours of the infusion commencing. This is consistent with our experimental data in the dog. The lack of efficacy of hemoperfusion is due to the rapid renal elimination of most of the absorbed dose of paraquat over the first 12 hours after its administration, and the later limitation of the rate of removal of paraquat from the body by the slow efflux rate from the deep to central compartment.

Efficacy of whole bowel irrigation using solutions with or without adsorbent in the removal of paraquat in dogs.

1. The efficacy of whole bowel irrigation with a solution containing either polyethylene glycol (PEG) with electrolyte or an adsorbent (Kayexalate with a cathartic (sorbitol) was investigated in 18 dogs who had been given 250 mg kg-1 paraquat dichloride via a jejunal tube to eliminate the influence of gastric absorption. 2. Plasma paraquat concentrations 2 and 3 h after the initiation of bowel irrigation and at the end of the study (5 h later) were significantly lower in the bowel irrigation groups than in the control (no bowel irrigation) group. 3. The total body clearances of paraquat in the bowel irrigation groups were significantly greater than in the control group. 4. There were no significant differences between the two different irrigation solution groups in plasma paraquat concentration, the area under the plasma concentration time curve and the total body clearance. 5. In the PEG with electrolyte group, about 70% of the administered dose of paraquat was removed by means of bowel irrigation (n = 4). 6. The adjunction of the adsorbent had no beneficial effects. 7. Haemodynamic changes associated with whole bowel irrigation were unremarkable except that right atrial and pulmonary arterial pressures were elevated in the latter part of the study.

Acute renal failure in a case of paraquat poisoning with relative absence of pulmonary toxicity

A 37 year old male presented after the ingestion of paraquat ('Gramoxone', 20% w/v). Plasma paraquat concentrations indicated that he had a greater than 50% probability of death. The patient survived following a period of acute oliguric renal failure and with only mild pulmonary toxicity.

Evaluation of Severity Indexes of Patients with Paraquat Poisoning

1. Three indexes for evaluating the severity of paraquat poisoning based on plasma-paraquat concentration are presently in use; the curves of Proudfood et al. and Scherrmann et al. and the SIPP. Their effectiveness in determining the prognosis of patients with paraquat poisoning was evaluated. 2. To determine which index was more accurate, contigency tables of the three indexes were obtained and compared; Proudfoot's curve vs the SIPP Scherrmann's curve vs the SIPP. Proudfoot's curve and the SIPP were applied to patients admitted within 24 h after intoxication. Scherrmann's curve and the SIPP were applied to patients admitted more than 24 h after intoxication. The proportions of patients with true positive and true negative results to total patients were compared by a ratio test. 3. Proudfoot's curve was found to be more accurate than the SIPP for predicting the prognosis of patients admitted within 24 h (P less than 0.05). No significant difference, however, was noted between Scherrmann's curve and the SIPP in determining the prognosis of patients admitted after more than 24 h. 4. In conclusion, Proudfoot's curve proved a better index for predicting the outcome of patients who were admitted within 24 h. However, for the prognosis of patients admitted more than 24 h after the ingestion of paraquat, further study is required.

Efficacy of early hemoperfusion in the management of paraquat poisoning

Efficacy of Early Hemoperfusion in the Management of Paraquat Poisoning SM Pond, ECGM Hampson / University of Queensland, Department of Medicine, Princess Alexandra Hospital, Brisbane, Australia Our prospective, controlled study in the dog of the efficacy of repeated hemoperfusion, begun 12 hours after the 1V administration of an LDlo o dose of paraquat, showed that the procedure did not reduce mortality. One previously reported study in the dog showed that a single hemoperfusion, performed earlier after a lower, oral dose of paraquat, improved the survival figures. Therefore, we examined the efficacy of a single charcoal hemoperfusion, begun at the end of a two-hour infusion of paraquat dichloride (7.48 mg PQ ion&g) in four dogs (PQ/sHP-group) and compared the results with those from the group given PQ only {PQ group). All of the dogs in the PQ/sHP-group developed the clinical and laboratory manifestations of paraquat toxicity. Only two of the four died, at two and four days, in contrast to four of four in the PQ group. At 12 days the two survivors were clinically normal and on postmortem examination, 18 days after the paraquat dose, there were no significant abnormalities. At the end of the infusion, the plasma paraquat concentrations in the survivors were similar to those in the nonsurvivors and to those in the PQ group. The mean extraction and clearance of paraquat by the hemoperfusion cartridges were 0.6 _+ 0.2 (_+ SD) and 27.5 _+ 11.5 mL/min, respectively. The percentage of the total dose of paraquat adsorbed in the two survivors was 25% and 26%, whereas in the nonsurvivors, it was 6% and 13%. Most of the balance of the dose was excreted in the urine within the first 24 hours. Therefore, single hemoperfusion, begun at the end of a twohour infusion of an LDmo dose of paraquat, reduced mortality by 50%. If extrapolated to patients, the results imply that attempting hemoperfusion within two to four hours of an oral dose of paraquat may be worthwhile. At later time points, the procedure cannot be said to be efficacious.

Paraquat Poisoning

Paraquat is a bipyridyl compound with no known chronic toxicity or teratogenicity. It is poorly absorbed when inhaled, but causes severe illness when ingested orally, death usually occurring within 2 days of ingestion of 50 mg/kg. At lower doses death may be delayed for several weeks. The toxic compound accumulates in lung tissue where free radicals are formed, lipid peroxidation is induced and nicotinamide adenine dinucleotide phosphate (NADPH) is depleted. This produces diffuse alveolitis followed by extensive pulmonary fibrosis. The most important prognostic indicator is the quantity of paraquat absorbed, as shown by the plasma paraquat concentration. While renal failure will develop in the majority of those patients who eventually die, it may not, if present alone, indicate a fatal outcome. The absence of caustic burns in the upper digestive tract indicates a good prognosis. Treatment of paraquat poisoning remains ineffective, but Fuller's earth, activated charcoal and resins may prevent some absorption of the toxin. When tubular necrosis occurs, renal excretion of the compound decreases rapidly. A 3-compartment pharmacokinetic model has been described following ingestion of tracer doses including a 'deep' compartment for active pulmonary accumulation. Haemodialysis, haemoperfusion and forced dialysis have been attempted, with no clear improvement in survival rates. Superoxide dismutase, glutathione peroxidase, N-acetylcysteine and other 'free radical scavengers' have failed to alter the outcome in poisoned patients. Other theoretical treatments, such as deferoxamine, immunotherapy, NADPH repletion and lung transplantation still require clinical validation.

Toxicokinetics of Paraquat in Humans

1. The toxicokinetics of paraquat were studied in 18 cases of acute human poisoning using a specific radioimmunoassay. Plasma paraquat concentration exhibited a mean distribution half-life (t1/2 alpha) of 5 h and a mean elimination half-life (t1/2 beta) of 84 h. Cardiovascular collapse supervened early during the course of the intoxication and was associated with the distribution phase. Death related to pulmonary fibrosis occurred late and was associated with the elimination phase. 2. Pharmacokinetic analysis of urine paraquat excretion confirmed the biphasic decline of paraquat. Moreover, renal paraquat and creatinine clearances were not correlated but renal paraquat clearance was never higher than the renal creatinine clearance. 3. Tissue paraquat distribution was ubiquitous with an apparent volume of distribution ranging from 1.2 to 1.6 l/kg. Muscle could represent an important reservoir explaining the long persistence of paraquat in plasma and urine for several weeks or months after poisoning.