Thorax, 1979, 34, 161-165

Further clinical observations on the pulmonaryeffects of paraquat ingestionTIM HIGENBOTTAM, PETER CROME, CONSTANCE PARKINSON, AND JOHN NUNN

From Guy's Hospital, London SEJ 9RT, UK

ABSTRACT Five patients are reported who developed evidence of acute lung damage after provedingestion of paraquat. In two the lung changes resolved; in one an aspiration pneumoniaoccurred, which was successfully treated, while two developed fatal pulmonary oedema. Thesepulmonary complications after paraquat intoxication appear more common than the progressivepulmonary fibrosis previously described. It is suggested that acute pulmonary oedema is aresponse to large doses, usually of Gramoxone, that subclinical lung changes result from smalldoses, usually of Weedol, and that pulmonary fibrosis occurs after intermediate doses.Preliminary data on plasma paraquat concentrations suggest that these are of value in prognosis.

Until a few years ago the most commonly en-countered form of paraquat poisoning was that inwhich Gramoxone (a 20% w/v concentrate) wasapparently accidentally ingested. Of these patients,several suffered transient renal and hepatic dys-function, but progressive pulmonary fibrosis oftencaused death two to three weeks after ingestion.This led to the idea that paraquat ingestion associ-ated with pulmonary complications was invariablyfatal (Cooke et al, 1973).More recent experience at the London Centre

of the National Poisons Information Service isthat this form of paraquat poisoning is now un-common. Of the 188 cases of ingestion reportedto the centre from 1974 to 1976, 57 died acutelywithin seven days and only 12 died later withevidence of pulmonary fibrosis. The remaining 119patients survived without ill effects and of these,111 had swallowed the 2 5% w/v granular form ofparaquat, Weedol. A clinical difference appearedto have developed between those taking smallamounts who survived and those swallowing largeamounts of paraquat, usually in the form ofGramoxone, who developed acutely fatal compli-cations.To exemplify this present and more diverse

pattern of intoxication we have selected for re-porting five patients who developed differing pul-monary complications after swallowing paraquat.

Case reports

During 1976-7 a total of six patients were admitted

to Guy's Hospital after taking Gramoxoneand a further three after Weedol ingestion. Allthe patients who took Gramoxone died, only onesurviving for longer than seven days. On the otherhand, all those swallowing Weedol survived. Fromthese, five patients were selected to represent thedifferent pulmonary complications that may beseen after paraquat intoxication. Initially, all weresubjected to gastric aspiration and lavage, and thenreceived oral Fuller's Earth (20% w/v) andmagnesium sulphate (5% w/v) in doses of 250 mlfour-hourly for 48 hours. Intravenous fluids weregiven to produce a urine output of three litresover the first 24 hours. No additional oxygen wasadministered unless the PaO2 fell below 6 kPa, asin our two fatal cases 24 hours before death. Inaddition three patients (cases 3, 4, and 5) receivedcharcoal haemoperfusion therapy (Vale et al,1977). The urinary paraquat was detected colori-metrically (Widdop, 1976), and the plasma para-quat was estimated by radioimmunoassay (Levitt,1977). Measurements of respiratory function wereperformed upon a Vitalograph and the gas trans-fer test machine (P K Morgan Ltd). These werecompared with the predicted values for Europeans(Cotes, 1975).

CASE 1A 27-year-old man swallowed two sachets ofWeedol. The urine test for paraquat was moder-ately positive and the plasma paraquat, estimatedthree hours after ingestion, was 120 ng/ml.Initially, there were no abnormal clinical findings,

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and his chest radiograph was clear. He remainedasymptomatic over the subsequent five days,although the plasma creatinine concentration roseto 226 mmol/l and the aspartate aminotransferase(AST) to 46 u/litre. Clinical examination thenshowed bilateral basal late inspiratory crackles,and his chest radiograph showed bilateral shadow-ing scattered through the upper and mid-zones(fig 1).

70]o 90-

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4- 9 70-

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0 2 4 6 8 10 12 14Tine after ingestion ( days)

Fig 1 Chest radiograph of case I five days afterparaquat ingestion showing peripheral bilateralshadowing of upper and mid-zones.

The forced expired volume in one second(FEV1) and vital capacity (VC) had not alteredduring this time, which remained at 100% of thepredicted values. However, the transfer factor forcarbon monoxide fell (fig 2). Two weeks afteradmission his chest signs had receded, the gas

transfer factor had begun to return to the pre-

dicted value, and his plasma creatinine concentra-tion and AST were normal.A follow-up one year later showed further im-

provement in respiratory function (fig 2) and a

clear chest film.

CASE 2

Another 27-year-old man stated that he had swal-lowed 30-60 ml of Gramoxone but vomited im-mediately afterwards. The urine test for paraquatwas only weakly positive, and the initial plasmaparaquat concentration eight hours after ingestionwas 50 ng/ml. He had oral and pharyngeal ulcer-ation but no other abnormal physical signs. In-

Fig 2 Change observed in gas transfer factor forcarbon monoxide in case I after swallow.ng paraquat.Gas transfer factor is shown as percentage ofpredicted value.

itially, the AST rose to 60 u/l, falling to withinthe normal range within two weeks. Throughouthis admission his chest radiograph remained clear,and neither his FEV1 nor VC fell. However, 11and 13 days after ingestion the gas transfer factorfor carbon monoxide was 64% of the predictedvalue, rising to 81% of the predicted level twomonths later. He remained well with no respir-atory complications some two years after takingthe paraquat.

CASE 3

A 47-year-old man drank the contents of a sachetof Weedol and was subjected to gastric lavage.The four hour plasma paraquat concentration was

115 ng/ml. Initially he was asymptomatic and hadminimal radiographic shadowing at the right base(fig 3). Two days after admission a fever andleucocytosis developed. The chest film now

showed, predominantly, right lower lobe shadow-ing (fig 4). Aspiration pneumonia was diagnosed,and antibiotic treatment begun. Within the nextfive days he improved clinically and there was

considerable clearing of the lungs on the chestfilm. From the time of admission to the resolutionof chest signs the FEV1 and VC remained un-

changed, and the gas transfer factor for carbonmonoxide, although initially 68%, rose only to72% of predicted. At no time during his admissiondid either the AST or the blood urea rise.

CASE 4

A 56-year-old woman drank an undeterminedamount of Gramoxone. Three hours later theinitial plasma paraquat concentration was 940 ng/ml. Although showing oral and pharyngeal ulcer-

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Further clinical observations on the pulmonary effects of paraquat ingestion

were greater than their predicted values, the gastransfer factor was only 35% of the predictedvalue. The plasma creatinine concentration wasraised to 240 mmol/l and the AST was raised at80 u/I. Despite assisted ventilation her clinicalcondition progressively deteriorated, and she diedin respiratory failure six days after takingparaquat.

Fig 3 Admission chest radiograph of case 3.

Fig 5 Chest radiograph four days after paraquatingestion in case 4 showing widespread bilateral lungshadowing.

Fig 4 Chest radiograph of case 3 two days afterswallowing paraquat showing basal shadowingpredominantly in right lower zone.

ation, there were no abnormal physical signs on

examination of her chest. Within four days shebecame severely dyspnoeic and had begun to pro-

duce copious quantities of clear sputum. The chestradiograph at this time showed bilateral shadow-ing (fig 5) and, although the dynamic lung volumes

At necropsy the major pathological changeswere confined to the lungs, liver, and kidneys.Copious clear mucus was present throughout thetrachea and bronchi. The lungs were oedematousand congested; the right lung weighed 1025 g andthe left lung 900 g. In addition to these changes,light microscope examination showed widespreadintra-alveolar haemorrhage and hyaline membraneformation within respiratory bronchioles andalveoli. Mononuclear cells with oval nuclei andprominent nucleoli were present in both alveolarwalls and spaces. These cells resembled the"profibroblasts" described by Smith and Heath(1975) in the lungs of rats exposed to paraquat.Foci of bronchiolar epithelial cell proliferationwere present extending into adjacent alveoli. Theliver showed necrosis of centrilobular cells associ-ated with a mixed polymorphonuclear and mono-nuclear cell infiltrate. Renal tubular necrosis waspresent, as defined by cellular and hyaline castsand tubular epithelial regeneration.

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CASE 5

A 28-year-old man swallowed an eggcupful ofGramoxone. Four hours later the plasma paraquatconcentration was 420 ng/ml. Initial examinationshowed oral and pharyngeal ulceration, and hecomplained of breathlessness. Over the next threedays he became progressively more breathless andbegan to produce large quantities of clear frothysputum. The chest radiograph at this stage showedbilateral diffuse shadowing (fig 6). He was unable,due to severe breathlessness, to perform the car-

bon monoxide gas transfer test. The FEV1 was

20% of the predicted value, and the VC was only30%. The arterial gas tension was PaO2 9-7 kPa(73 mmHg) and Paco2 50 kPa (38 mmHg). Hedied of respiratory failure seven days after takingparaquat despite assisted ventilation. Terminally,his blood urea had risen only to 13 mmol/l and hisAST to 80 u/1.

Fig 6 Chest radiograph showing bilateral widespreadshadowing in case 5 three days after paraquatingestion.

At necropsy the trachea and bronchi containedblood-stained mucus. The lungs were firm anddeep purple in colour; scattered petechial haemor-rhages were present in the visceral pleura. Theright lung weighed 900 g and the left lung 820 g.

On microscopical examination the lungs showedoedema, congestion, intra-alveolar haemorrhage,and intra-alveolar hyaline membranes. Well-defined spindle-shaped fibroblasts were present,both within the alveolar walls and spaces, associ-

ated with collagen formation producing a finefibrosis as defined by van Gieson's stain and asilver impregnation technique. Foci of hyperplasticbronchiolar epithelium were seen extending intoand lining adjacent alveolar spaces. The heartshowed toxic myocarditis, and centrilobularhepatic necrosis was present associated with aminimal inflammatory cell response. The kidneysshowed tubular necrosis as in case 4.

Discussion

These five case histories show a variety of pul-monary complications that may ensue and thatare quite distinct from the more commonly des-cribed progressive pulmonary fibrosis (Matthewet al, 1968; Toner et al, 1970; Smith and Heath,1974; Thurlbeck and Thurlbeck, 1976). The firstpatients (cases 1 and 2) showed on serial examin-ation a reduction in the gas transfer factor forcarbon monoxide and in one of these (case 1)basal late inspiratory crackles and bilateral radio-graphic shadowing developed. In both patientsthese pulmonary abnormalities resolved on sup-portive measures alone and were associated withlaboratory evidence of transient minor dysfunctionof either the kidneys or the liver. It appearedlikely to us that these reversible pulmonarychanges could be attributed to the paraquat. Incase 1 there are similarities with the case of pul-monary oedema in paraquat poisoning reportedby Gardiner (1972).

In contrast, case 3, who developed predomin-antly unilateral pulmonary radiographic changestogether with clinical evidence of pneumonia, can-not be considered as having directly paraquat-damaged lungs. The pulmonary changes werethought to result from aspiration after the admin-istration of the Fuller's Earth or the initial gastriclavage.These findings have some interesting implica-

tions in relation to the claims made about treat-ments reversing paraquat-induced lung damage.Firstly, the pulmonary complications may not infact be directly attributable to paraquat but,rather, may have been due to pneumonia after thetreatment. Alternatively, as in our first twopatients, the lung changes may have been inducedby paraquat, but then resolved on supportivemeasures alone.

Patients nos 4 and 5 showed many of the typicalfeatures of severe paraquat poisoning; evidence ofrenal and hepatic damage, together with severedyspnoea and bilateral pulmonary shadowing onthe chest radiograph, which developed a few daysafter ingestion. They both died within seven days

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Further clinical observations on the pulmonary effects of paraquat ingestion

of ingestion. At necropsy the predominant lightmicroscopic findings in the lungs included capillarycongestion, alveolar oedema and haemorrhage,hyaline membranes, and early fibrosis in case 5.These changes were sufficient to result in deathbefore the development of the dense fibrosis,associated in some instances with obliteration ofpulmonary architecture, reported in man 9-22days after swallowing paraquat (Smith and Heath,1974; Thurlbeck and Thurlbeck, 1976).

Clinically, the two patients who succumbedwere distinguished from the others by the rapidonset of severe breathlessness and cough produc-ing copious quantities of sputum, the latter pre-sumably associated with the underlying pulmonaryoedema. To judge from their individual plasmaparaquat concentrations, we believe that theseestimations may also aid in predicting the out-come of paraquat poisoning. This is supported byour preliminary analysis of the prognostic signifi-cance of plasma paraquat concentrations. Suchdeterminations have become only recently avail-able after the development by Levitt (1977) of arapid and reproducible radioimmunoassay. Thereis a pronounced difference between concentrationsfound in fatal and non-fatal cases (see table).

Plasma paraquat concentrations in 40 patients(1977-8)

No of Plasma paraquat Mean timepatients concentrations after ingestion

mean (SEM) (hours)(Gg/i)

Fatal cases 14 1263 (278) 8-3Non-fatal cases 26 214 (76) 8-6

We propose that in man the paraquat-inducedlung damage may be dose related. When smallamounts of this chemical are swallowed and theinitial plasma paraquat concentrations are low,there may either be no pulmonary damage orminimal changes associated with only a reductionin gas transfer factor, as in case 2, or with both areduction in gas transfer factor and apparent pul-monary oedema as in case 1. This minimal para-quat "injury" may well be reversible. With theingestion of larger amounts of this chemical, suf-ficient lung damage may occur to cause death from

a pronounced alveolar oedema before the develop-ment of pulmonary fibrosis, as in case 5. Probablythe latter complication requires survival beyonda period of six days and occurs after intermediateamounts of paraquat have been taken. This typeof poisoning appears to be rare in that mostpatients take either small quantities (in the formof Weedol) or very large amounts, as the liquidconcentrate, usually in the form of Gramoxone.

We would like to thank Dr R Goulding for hisadvice in the preparation of this report and DrT Levitt who performed the plasma paraquatdeterminations.

References

Cooke, N J, Flenley, C D, and Matthew, H (1973).Paraquat poisoning. Quarterly Journal of Medicine,42, 683-692.

Cotes, J (1975). Lung function. Assessment andApplication in Medicine. 3rd edn. Blackwell, Oxford.

Gardiner, A J S (1972). Pulmonary oedema in para-quat poisoning. Thorax, 27, 132-135.

Levitt, T (1977). Radio-immunoassay for paraquat.Lancet, 2, 358-359.

Matthew, H, Logan, A, Woodruff, M F A, and Heard,B (1968). Paraquat poisoning-lung transplantations.British Medical Journal, 3, 759-762.

Smith, P, and Heath, D (1974). Paraquat lung: A re-appraisal. Thorax, 29, 643-653.

Smith, P, and Heath, D (1975). The pathology ofthe lung in paraquat poisoning. Journal of ClinicalPathology, 28, suppl 9, 81-93.

Thurlbeck, W M, and Thurlbeck, S M (1976). Pul-monary effects of paraquat poisoning. Chest, 69,276-280.

Toner, P G, Vetters, J M, Spilg, W G S, and Harland,W A (1970). Fine structure of the lung lesion in acase of paraquat poisoning. Journal of Pathology,102, 182-185.

Vale, J A, Crome, P, Volans, G N, Widdop, B, andGoulding, R (1977). Treatment of paraquat poison-ing using oral sorbents and charcoal haemoper-fusion. A cta pharmacologica et toxicologica, 41,suppl II, 109-117.

Widdop, B (1976). Detection of paraquat in urine.British Medical Journal, 2, 1135.

Requests for reprints to: Dr T Higenbottam, Guy'sHospital, London SEI 9RT.

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