Poisoning Management
Drug Safety 5 (4): 243-251, 1990 0114-5916/ 90/ 0007-0243/$04.50/0 © Adis International Limited All rights reserved. MEDT03296
Paraquat Poisoning
An Overview of the Current Status C. Bismuth, R. Garnier, F.J. Baud, J. Muszynski and C. Keyes Clinique Toxicologique, Hopital Fernand Widal, Paris, France and Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, USA
Contents
Summary ............................ ........................................................................................................ 243 1. Mechanism of Lung Toxicity ...............................................................................................244 2. Prognostic Factors .................................................................................................................244 3. Treatment ............................................................................................................................... 245 3.1 Modification of the Toxicokinetics ............................................................................... 245 3.2 Modification of the Toxicodynamics ..........................................................................:.247 3.2.1 Prevention of Lipid Peroxidation ......................................................................... 247 3.2.2 Prevention of NADPH Depletion ........................................................................ 248 3.2.3 Prevention of Lung Fibrosis ................................................................................. 248 3.2.4 Lung Transplantation ............................................................................................ 249 4. Conclusions .................................................................................... ........................................249
Summary
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.
244
Drug Safety 5 (4) 1990
The bipyridyl compound paraquat, a contact herbicide, is marketed in more than 130 countries. In Japan, the country with the highest incidence of paraquat poisoning, 1200 to 1500 deaths, predominantly from suicides, are attributed to the compound each y~ar .. The substance has 4 major characteristics"ofinterest to toxicologists. First, it is inactivated by the natural components of the soil. Thus, the herbicide leaves no biologically active residues. Secondly, no toxicity from chronic exposure has been described. However, mutagenic effects have been demonstrated in several studies (Vaishampayan 1984; Yonei et al. 1986). Thirdly, when inhaled, paraquat is poorly absorbed. Most aero soli sed paraquat particles have a diameter greater than S~m and therefore do not reach the alveolar barrier (Chester & Ward 1984; Hart 1987). Finally, the ingestion of paraquat and, to a lesser extent, cutaneous exposure to the drug can result in a severe clinical course: of 92 patients treated for paraquat intoxication at our institution, 80% died. 55% of the deaths were due to cardiac and multiorgan failure within 72 hours of ingestion, 45% occurred between the fourth and twenty-third days due to the development of intractable pulmonary fibrosis with or without septic complications (Bismuth 1988).
1. Mechanism
0/ Lung Toxicity
The pulmonary toxicity of paraquat can be explained in part by the selective accumulation of the toxin in the lungs. Accumulation is energydependent (Rose et al. 1974), obeys saturable kinetics and is apparently confined to the alveolar epithelial type I and type II cells and Clara cells in the ·Iung. Paraquat accumulates by an uptake system that is able to transport a variety of polyamine compounds (Smith 1982). The toxin undergoes a I-electron reduction to form a free radical, which then reacts with molecular oxygen to reform the cation and a superoxide anion (02-') [fig. I]. This oxygen radical may then dismutate to form H202, which in the presence of FE++ will form highly reactive and toxic radicals such as OH· (Smith 1977; Smith & Rose 1977) which is capable of inducing
lipid peroxidation. The redox cycling of paraquat and the detoxification of H202 and lipid hydroperoxides consume NADPH. The inability to maintain physiological levels of NADPH for prolonged periods may in itself cause cell damage and render the cell more susceptible to free radical attack and peroxidation of vital cellular constituents. Following destruction of the alveolar epithelial cells, acute alveolitis develops. If the damage to the alveolar architecture is extensive, widespread fibrosis occurs causing severe and fatal hypoxia. Whether the initial fibrotic changes are interstitial or intraalveolar remains uncertain.
2. Prognostic Factors Prognostic factors in paraquat poisoning have been described, and may be noted within 24 hours of the ingestion (Bismuth et al. 1982). The most important of these is the plasma concentration of paraquat determined by radioimmunoassay, which correlates well with outcome, both in samples taken during the first 24 hours (Proudfoot et al. 1979) [concentrations above 2 mg/L at 4 hours, 1.6 mg/ L at 12 hours, 0.6 mg/L at 16 hours, and 0.16 mg/ L at 24 hours are lethal] and over the ensuing 10 or II days (Scherrmann et al. 1983, 1987). The quantity of paraquat in the specific herbicidal preparation and the volume ingested (I mouthful of a 20% solution is potentially lifethreatening) determined by history, or ideally by actual examination of the container and its contents, are paramount information (Bismuth et al. 1982). The time between ingestion of paraquat and the last meal may also be significant because of the propensity for paraquat to be absorbed and partially neutralised by food particles (Bismuth et al. 1982). The presence of oesophageal and stomach ulceration within 24 hours of paraquat ingestion confirms severe intoxication whereas the absence of such frank ulceration indicates a good prognosis. While renal failure will develop in the majority of patients who eventually die, it may not, if the sole prognostic factor, indicate a fatal outcome. Excretion of paraquat is almost exclusively renal (Bismuth et al. 1982); the kidney is able to excrete up
245
Paraquat Poisoning: An Overview
Hexose monophosphate shunt Superoxide - ' - - - _ , H202 ' H20 dismutase Catalase - - - -.. , OHo Fe+++. Fe H
1
+ '/2
02
+ OW + 02
Lipid peroxidation
NADP'\ ( Hexose monophosphate shunt
I I
GSH
+ Lipid ...-_ _ _,,,hydroperoxide
Glutathione reductase
NADPH)
~
GSSG-":::::::::="'--~
Lipid alcohol
Fig. 1. Biochemical pathway showing the metabolism of paraquat. Key: PQ+ = paraquat radical; PQ++ = paraquat; 02-' = superoxide anion; H202 = hydrogen peroxide; OHo = hydroxyl radical; OH- = hydroxyl ion; GSH = reduced glutathione; GSSG = oxidised glutathione.
to approximately Ig ofparaquatjL of urine formed before the onset of renal failure, measured by the dithionite test (Scherrmann 1983). Urine containing more than 70 mgjL 8 hours after the ingestion, or I mg/L after 16 hours is associated with virtually 100% mortality (Scherrmann et al. 1987). A strong negative correlation exists between the amount of paraquat removed by haemodialysis and/or haemoperfusion between the sixth and twenty-fourth hours, and the number of days that the patient survives (Bismuth et al. 1987). The larger the amount of paraquat removed from the blood the greater the body load of the compound and thus the greater probability of early death (fig. 2).
3. Treatment The treatment of paraquat intoxication remains largely ineffective. After gastric lavage and other general supportive measures are undertaken, inter-
ventions are directed towards: (a) preventing the accumulation of paraquat in cells and modification of the toxicokinetics of the herbicide; and (b) decreasing the subsequent damage caused by tissue exposure to the poison. 3.1 Modification of the Toxicokinetics The toxicokinetics of paraquat can be primarily modified by either decreasing the absorption (Meredith & Vale 1987), or by enhancing elimination (table I). The herbicide is poorly absorbed in humans, with only I to 5% of the ingested amount reaching the bloodstream (Conning et al. 1969). It has been recommended that Fuller's earth, resins (Nokata et al. 1984; Yamashita et al. 1987) or activated charcoal be administered within the first few minutes after an ingestion, if possible. A recent meal may similarly absorb toxin, with subsequent 'trapping' within the gastrointestinal lumen. The
246
Drug Safety 5 (4) 1990
800
•
Ci 700
.Sal> 0
E
600
~
10 500 :> C"
~
Q.
'0
C :>
0
E
400
•
300
O!
~
s
200
•
Drug Safety 5 (4): 243-251, 1990 0114-5916/ 90/ 0007-0243/$04.50/0 © Adis International Limited All rights reserved. MEDT03296
Paraquat Poisoning
An Overview of the Current Status C. Bismuth, R. Garnier, F.J. Baud, J. Muszynski and C. Keyes Clinique Toxicologique, Hopital Fernand Widal, Paris, France and Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, USA
Contents
Summary ............................ ........................................................................................................ 243 1. Mechanism of Lung Toxicity ...............................................................................................244 2. Prognostic Factors .................................................................................................................244 3. Treatment ............................................................................................................................... 245 3.1 Modification of the Toxicokinetics ............................................................................... 245 3.2 Modification of the Toxicodynamics ..........................................................................:.247 3.2.1 Prevention of Lipid Peroxidation ......................................................................... 247 3.2.2 Prevention of NADPH Depletion ........................................................................ 248 3.2.3 Prevention of Lung Fibrosis ................................................................................. 248 3.2.4 Lung Transplantation ............................................................................................ 249 4. Conclusions .................................................................................... ........................................249
Summary
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.
244
Drug Safety 5 (4) 1990
The bipyridyl compound paraquat, a contact herbicide, is marketed in more than 130 countries. In Japan, the country with the highest incidence of paraquat poisoning, 1200 to 1500 deaths, predominantly from suicides, are attributed to the compound each y~ar .. The substance has 4 major characteristics"ofinterest to toxicologists. First, it is inactivated by the natural components of the soil. Thus, the herbicide leaves no biologically active residues. Secondly, no toxicity from chronic exposure has been described. However, mutagenic effects have been demonstrated in several studies (Vaishampayan 1984; Yonei et al. 1986). Thirdly, when inhaled, paraquat is poorly absorbed. Most aero soli sed paraquat particles have a diameter greater than S~m and therefore do not reach the alveolar barrier (Chester & Ward 1984; Hart 1987). Finally, the ingestion of paraquat and, to a lesser extent, cutaneous exposure to the drug can result in a severe clinical course: of 92 patients treated for paraquat intoxication at our institution, 80% died. 55% of the deaths were due to cardiac and multiorgan failure within 72 hours of ingestion, 45% occurred between the fourth and twenty-third days due to the development of intractable pulmonary fibrosis with or without septic complications (Bismuth 1988).
1. Mechanism
0/ Lung Toxicity
The pulmonary toxicity of paraquat can be explained in part by the selective accumulation of the toxin in the lungs. Accumulation is energydependent (Rose et al. 1974), obeys saturable kinetics and is apparently confined to the alveolar epithelial type I and type II cells and Clara cells in the ·Iung. Paraquat accumulates by an uptake system that is able to transport a variety of polyamine compounds (Smith 1982). The toxin undergoes a I-electron reduction to form a free radical, which then reacts with molecular oxygen to reform the cation and a superoxide anion (02-') [fig. I]. This oxygen radical may then dismutate to form H202, which in the presence of FE++ will form highly reactive and toxic radicals such as OH· (Smith 1977; Smith & Rose 1977) which is capable of inducing
lipid peroxidation. The redox cycling of paraquat and the detoxification of H202 and lipid hydroperoxides consume NADPH. The inability to maintain physiological levels of NADPH for prolonged periods may in itself cause cell damage and render the cell more susceptible to free radical attack and peroxidation of vital cellular constituents. Following destruction of the alveolar epithelial cells, acute alveolitis develops. If the damage to the alveolar architecture is extensive, widespread fibrosis occurs causing severe and fatal hypoxia. Whether the initial fibrotic changes are interstitial or intraalveolar remains uncertain.
2. Prognostic Factors Prognostic factors in paraquat poisoning have been described, and may be noted within 24 hours of the ingestion (Bismuth et al. 1982). The most important of these is the plasma concentration of paraquat determined by radioimmunoassay, which correlates well with outcome, both in samples taken during the first 24 hours (Proudfoot et al. 1979) [concentrations above 2 mg/L at 4 hours, 1.6 mg/ L at 12 hours, 0.6 mg/L at 16 hours, and 0.16 mg/ L at 24 hours are lethal] and over the ensuing 10 or II days (Scherrmann et al. 1983, 1987). The quantity of paraquat in the specific herbicidal preparation and the volume ingested (I mouthful of a 20% solution is potentially lifethreatening) determined by history, or ideally by actual examination of the container and its contents, are paramount information (Bismuth et al. 1982). The time between ingestion of paraquat and the last meal may also be significant because of the propensity for paraquat to be absorbed and partially neutralised by food particles (Bismuth et al. 1982). The presence of oesophageal and stomach ulceration within 24 hours of paraquat ingestion confirms severe intoxication whereas the absence of such frank ulceration indicates a good prognosis. While renal failure will develop in the majority of patients who eventually die, it may not, if the sole prognostic factor, indicate a fatal outcome. Excretion of paraquat is almost exclusively renal (Bismuth et al. 1982); the kidney is able to excrete up
245
Paraquat Poisoning: An Overview
Hexose monophosphate shunt Superoxide - ' - - - _ , H202 ' H20 dismutase Catalase - - - -.. , OHo Fe+++. Fe H
1
+ '/2
02
+ OW + 02
Lipid peroxidation
NADP'\ ( Hexose monophosphate shunt
I I
GSH
+ Lipid ...-_ _ _,,,hydroperoxide
Glutathione reductase
NADPH)
~
GSSG-":::::::::="'--~
Lipid alcohol
Fig. 1. Biochemical pathway showing the metabolism of paraquat. Key: PQ+ = paraquat radical; PQ++ = paraquat; 02-' = superoxide anion; H202 = hydrogen peroxide; OHo = hydroxyl radical; OH- = hydroxyl ion; GSH = reduced glutathione; GSSG = oxidised glutathione.
to approximately Ig ofparaquatjL of urine formed before the onset of renal failure, measured by the dithionite test (Scherrmann 1983). Urine containing more than 70 mgjL 8 hours after the ingestion, or I mg/L after 16 hours is associated with virtually 100% mortality (Scherrmann et al. 1987). A strong negative correlation exists between the amount of paraquat removed by haemodialysis and/or haemoperfusion between the sixth and twenty-fourth hours, and the number of days that the patient survives (Bismuth et al. 1987). The larger the amount of paraquat removed from the blood the greater the body load of the compound and thus the greater probability of early death (fig. 2).
3. Treatment The treatment of paraquat intoxication remains largely ineffective. After gastric lavage and other general supportive measures are undertaken, inter-
ventions are directed towards: (a) preventing the accumulation of paraquat in cells and modification of the toxicokinetics of the herbicide; and (b) decreasing the subsequent damage caused by tissue exposure to the poison. 3.1 Modification of the Toxicokinetics The toxicokinetics of paraquat can be primarily modified by either decreasing the absorption (Meredith & Vale 1987), or by enhancing elimination (table I). The herbicide is poorly absorbed in humans, with only I to 5% of the ingested amount reaching the bloodstream (Conning et al. 1969). It has been recommended that Fuller's earth, resins (Nokata et al. 1984; Yamashita et al. 1987) or activated charcoal be administered within the first few minutes after an ingestion, if possible. A recent meal may similarly absorb toxin, with subsequent 'trapping' within the gastrointestinal lumen. The
246
Drug Safety 5 (4) 1990
800
•
Ci 700
.Sal> 0
E
600
~
10 500 :> C"
~
Q.
'0
C :>
0
E
400
•
300
O!
~
s
200
•
