442
Proc. roy. Soc. Med. Volume 68 July 1975
Dr D S Davies and Dr M E Conolly (Royal Postgraduate Medical School, London W12 OHS) Paraquat Poisoning - Possible Therapeutic Approach
The treatment of paraquat poisoning is governed by our understanding of its disposition in the body and of the mechanism of its toxic effects. Studies in the rat indicate that much of an oral dose is unabsorbed and can be recovered from the fieces. Paraquat absorbed into the systemic circulation is quantitatively and rapidly excreted in the urine. Thus the first line of treatment of cases seen soon after ingestion is to prevent further absorption. Gastric lavage should be followed by copious doses of fuller's earth which adsorbs paraquat. With normal renal function, paraquat clearance through the kidneys is rapid and is not apparently enhanced by forced diuresis. In any case this is liable to be dangerous after ingestion of a poison known to be able to cause pulmonary cedema. For these reasons we advise against the use of forced diuresis. Hxemodialysis is a less clear-cut issue. Since paraquat is not heavily protein bound it should be readily dialysable; however, there are as yet no published data on this. Our present policy is to recommend it in cases seen soon after a large dose has been taken, if renal function is inadequate. Specific treatment for paraquat poisoning is based on a consideration of the possible toxic mechanism in the lung. Paraquat's herbicidal activity appears to depend upon its ability to generate superoxide (O), a reactive form of oxygen (Fletcher 1974). We have shown that enzymes in rat lung (Davies & Davies 1974) are able to reduce paraquat to its radical ion which, in the presence of oxygen, generates superoxide. As in plants, this may be the toxic agent in the lung. Superoxide is a ubiquitous, naturally occurring radical ion which is normally inactivated by the enzyme superoxide dismutase (Saltzman & Fridovich 1973). However, the lung, which is exposed to higher concentrations of oxygen than any other tissue, also achieves high levels of paraquat, and it may be that these conditions favour abnormally rapid formation of superoxide, thereby swamping the endogenous enzyme. With this in mind we have administered superoxide dismutase. We have chosen to give it both intravenously and by nebulized aerosol, since there was no information on the relative effectiveness of either route in reaching the alveolar epithelium. Apart from troublesome thrombophlebitis at the site of the infusion, we
22
have experienced no untoward reactions in giving it for periods of up to one month. We also use two other drugs, beclomethasone and D-propranolol. Beclomethasone is given in the hope of reducing inflammatory reaction in the lung. D-propranolol was given in an attempt to displace paraquat from the lungs. Subsequent experiments have shown that this does not occur but it may be able to prevent paraquat entering lung tissue. Conclusion At the present time it is not possible to make any claim for the efficacy of this approach to paraquat poisoning. We offer it rather as a basis for ongoing research and debate into what remains a difficult and distressing problem. REFERENCES Davies D S & Davies D L (1974) Federation Proceedings 33, 228 Fletcher K (1974) In: Forensic Toxicology. Ed. B Ballantyne. John Wright, Bristol; pp 86-98 Saltzman H A & Fridovich) (1973) Circulation 48, 921
The following papers were also presented:
Changes in Lung Induced by the Anorexigens, Chlorphentermine and Aminorex Professor Donald Heath (Department ofPathology, University of Liverpool, Liverpool, L69 3BX) REFERENCES Heath D, Smith P & Hasdeton P S (1973) Thorax 28, 551 Kay J M, Snmith P & Heath D (1971) Thorax 26, 262 Smith P & Heath D (1974) Arzneimittel-Forschung 9, 1277 Smith P, Heath D & Hasleton P S (1973) Thorax 28, 559 Smith P, Heath D, Kay J M, Wright J S & McKendrick C S (1973) Cardiovascular Research 7, 30
Paraquat Lung: Clinical and Radiological Features Dr Maurice Raphael (Hammersmith Hospital, London W12) Paraquat Lung: Pathology in Human Lung Dr William Thurlbeck (Midhurst Medical Research Institute, Midhurst, Sussex, GU29 OBL)
Busulphan Lung Dr Hugh Stctt (Brompton Hospital, Fulham Road, London S W3)
Proc. roy. Soc. Med. Volume 68 July 1975
Dr D S Davies and Dr M E Conolly (Royal Postgraduate Medical School, London W12 OHS) Paraquat Poisoning - Possible Therapeutic Approach
The treatment of paraquat poisoning is governed by our understanding of its disposition in the body and of the mechanism of its toxic effects. Studies in the rat indicate that much of an oral dose is unabsorbed and can be recovered from the fieces. Paraquat absorbed into the systemic circulation is quantitatively and rapidly excreted in the urine. Thus the first line of treatment of cases seen soon after ingestion is to prevent further absorption. Gastric lavage should be followed by copious doses of fuller's earth which adsorbs paraquat. With normal renal function, paraquat clearance through the kidneys is rapid and is not apparently enhanced by forced diuresis. In any case this is liable to be dangerous after ingestion of a poison known to be able to cause pulmonary cedema. For these reasons we advise against the use of forced diuresis. Hxemodialysis is a less clear-cut issue. Since paraquat is not heavily protein bound it should be readily dialysable; however, there are as yet no published data on this. Our present policy is to recommend it in cases seen soon after a large dose has been taken, if renal function is inadequate. Specific treatment for paraquat poisoning is based on a consideration of the possible toxic mechanism in the lung. Paraquat's herbicidal activity appears to depend upon its ability to generate superoxide (O), a reactive form of oxygen (Fletcher 1974). We have shown that enzymes in rat lung (Davies & Davies 1974) are able to reduce paraquat to its radical ion which, in the presence of oxygen, generates superoxide. As in plants, this may be the toxic agent in the lung. Superoxide is a ubiquitous, naturally occurring radical ion which is normally inactivated by the enzyme superoxide dismutase (Saltzman & Fridovich 1973). However, the lung, which is exposed to higher concentrations of oxygen than any other tissue, also achieves high levels of paraquat, and it may be that these conditions favour abnormally rapid formation of superoxide, thereby swamping the endogenous enzyme. With this in mind we have administered superoxide dismutase. We have chosen to give it both intravenously and by nebulized aerosol, since there was no information on the relative effectiveness of either route in reaching the alveolar epithelium. Apart from troublesome thrombophlebitis at the site of the infusion, we
22
have experienced no untoward reactions in giving it for periods of up to one month. We also use two other drugs, beclomethasone and D-propranolol. Beclomethasone is given in the hope of reducing inflammatory reaction in the lung. D-propranolol was given in an attempt to displace paraquat from the lungs. Subsequent experiments have shown that this does not occur but it may be able to prevent paraquat entering lung tissue. Conclusion At the present time it is not possible to make any claim for the efficacy of this approach to paraquat poisoning. We offer it rather as a basis for ongoing research and debate into what remains a difficult and distressing problem. REFERENCES Davies D S & Davies D L (1974) Federation Proceedings 33, 228 Fletcher K (1974) In: Forensic Toxicology. Ed. B Ballantyne. John Wright, Bristol; pp 86-98 Saltzman H A & Fridovich) (1973) Circulation 48, 921
The following papers were also presented:
Changes in Lung Induced by the Anorexigens, Chlorphentermine and Aminorex Professor Donald Heath (Department ofPathology, University of Liverpool, Liverpool, L69 3BX) REFERENCES Heath D, Smith P & Hasdeton P S (1973) Thorax 28, 551 Kay J M, Snmith P & Heath D (1971) Thorax 26, 262 Smith P & Heath D (1974) Arzneimittel-Forschung 9, 1277 Smith P, Heath D & Hasleton P S (1973) Thorax 28, 559 Smith P, Heath D, Kay J M, Wright J S & McKendrick C S (1973) Cardiovascular Research 7, 30
Paraquat Lung: Clinical and Radiological Features Dr Maurice Raphael (Hammersmith Hospital, London W12) Paraquat Lung: Pathology in Human Lung Dr William Thurlbeck (Midhurst Medical Research Institute, Midhurst, Sussex, GU29 OBL)
Busulphan Lung Dr Hugh Stctt (Brompton Hospital, Fulham Road, London S W3)
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