Link to 2.2.7.3.1 Paraquat Educational Resources
Link to Problems for Discussion

Paraquat

SUBSTANCES INCLUDED

Diquat
Paraquat

OVERVIEW

Paraquat is an extremely toxic herbicide which may produce multisystem organ failure and pulmonary toxicity from as little as one mouthful of 20% concentrate. There is no specific treatment and any hope of survival rests on preventing absorption. Haemoperfusion, if it can be instituted within two to four hours of ingestion, is of theoretical benefit. There are two non-randomised trials with opposite results on the value of corticosteroids and cyclophosphamide as treatment.

MECHANISM OF TOXICITY

Ingestion of paraquat leads to the generation of free oxygen radicals. These free oxygen radicals cause lipid peroxidation, damaging cell membranes and leading to cell death. Free radical scavengers such as glutathione are rapidly overwhelmed due to the efficiency of paraquat in generating free radicals. Paraquat is actively taken up into type II pneumocytes and renal tubular cells. Thus, in less severe poisonings, renal and pulmonary toxicity as well as direct gastrointestinal effects are the major clinical manifestations. In poisonings that are not fatal within days, the pulmonary fibrosis that develops is due to an acute pneumonitis that leads inevitably to generalised alveolar fibrosis. Increasing concentrations of inhaled oxygen increase pulmonary toxicity presumably by enhancing oxygen radical generation.

KINETICS IN OVERDOSE

Absorption

Paraquat is poorly absorbed. Despite this, peak plasma concentrations occur within one hour of ingestion. Absorption is decreased in the presence of food. There is little absorption through intact skin or via inhalation.

Distribution

The volume of distribution is large as it is concentrated inside cells, particularly pneumocytes. Distribution occurs rapidly with substantial distribution within the first few hours.

Metabolism - Elimination

Renal excretion is the major route of elimination for paraquat. Thus, the development of renal toxicity decreases the proportion that is eliminated. However, a substantial proportion remains bound after serum concentrations are unmeasurable, particularly within pneumocytes.

CLINICAL EFFECTS

The initial presentation is with gastrointestinal toxicity. In severe poisoning this is followed by multiorgan failure and, if patients survive this phase, by the slow development of pulmonary fibrosis leading to hypoxia and death.

Gastrointestinal effects

Concentrated paraquat (20%) is corrosive and has direct gastrointestinal toxicity leading to oesophageal and gastric erosion as well as burns in the mouth and throat. These corrosive effects are similar to that observed with alkali ingestion.

Multiorgan failure

If more than 5-10 g of paraquat has been ingested then multiorgan failure rapidly ensues. The major manifestations of this are

Acute renal failure
Hepatic necrosis
Myocardial necrosis
Acute pneumonitis
Internal haemorrhages
Pulmonary fibrosis
Death

Pulmonary effects

Ingestion of smaller quantities will lead to

Gastrointestinal symptoms followed by
Progressive development of respiratory failure

The onset of pulmonary fibrosis may be delayed for days to weeks and death may occur up to a month or more after ingestion.

INVESTIGATIONS

Blood concentrations

Plasma concentrations of paraquat are important indicators of prognosis. A plasma concentration > 5 mg/L at any time indicates an invariably fatal outcome. Nomograms have been developed which indicate the chance of survival. Paraquat blood concentrations are performed by the Princess Alexandra Hospital in Brisbane, Australia (and in some other institutions).

Paraquat Nomogram

Qualitative urine test for paraquat

This simple test, if positive, indicates exposure to paraquat.

1 mL of a 1% sodium dithionate solution (found in haematology labs) is added to 10 mL of urine.

A blue colour change indicates paraquat ingestion. If this test is negative on urine passed 2 to 6 hours after ingestion it indicates that a significant exposure is unlikely.

Other investigations

The following tests may be abnormal in paraquat overdose

Full blood count
Coagulation studies
Electrolytes
LFTs
Chest X-ray
ECG

However, the inevitable failure of supportive care in the presence of multiorgan failure and the lack of specific antidotes make the detection of these abnormalities largely unhelpful.

DETERMINATION OF SEVERITY

The following have been associated with fatal outcome

Oesophageal and gastric erosions
Renal failure
Ingestion of more than one mouthful of 20% concentrate
Multiorgan failure
Development of pulmonary opacities on chest X-ray
Decreasing lung volumes on spirometry
Paraquat concentration > 3-5 mg/L

The presence of these indicates a fatal outcome in the majority of patients.

The rate of increase in plasma creatinine over time (5 hours) is also correlated with outcome and can give prognostic information (Ragoucy-Sengler C and Pileire B, 1996).
It is also possible to predict the probability of survival for any specified time and concentration after ingestion of paraquat up to at least
200 h after ingestion (Jones AL et al, 1999).

TREATMENT

GI Decontamination

Activated charcoal and/or Fuller's Earth (if available) should be given immediately. Emesis and lavage are contraindicated due to the corrosive nature of paraquat. Fuller's Earth and activated charcoal should be repeated 4th hourly if tolerated.

Supportive

Patients with moderate poisoning may benefit from good supportive care. Oxygen should only be administered if the arterial oxygen saturation falls below 90%. In patients with high paraquat concentrations and/or multiorgan failure it can be argued that palliative care is the most rational treatment due to the extremely poor prognosis.

Antidotes

Corticosteroids and cyclophosphamide have been suggested as treatment. There are two non-randomised trials with opposite results (Buckley, 2001). There are a large number of other theoretically appealing treatments including N-acetylcysteine, lung transplantation and superoxide dismutase, however, there is insufficient animal or human work to support their use.

Elimination enhancement

Patients with borderline paraquat concentrations or ingestions around the potentially lethal dose (i.e. 5 g), may benefit from early charcoal haemoperfusion. This will only be useful if it can be given prior to the distribution of the majority of paraquat into pneumocytes (i.e. within 2 to 4 hours).

LATE COMPLICATIONS, PROGNOSIS

Patients who do not develop multiorgan failure and therefore do not die within the first week may still develop progressive pulmonary fibrosis. This may slowly develop up to six weeks later. Patients in this situation who had confirmed exposure to paraquat should have regular clinical follow up and chest X-rays. Paraquat has only occasionally been reported to cause chronic non fatal pulmonary fibrosis, i.e. the development of pulmonary fibrosis appears to lead almost inevitably to death.

REFERENCES

Hart TB, Nevill A, Whitehead A. A statistical approach to the prognostic significance of plasma paraquat concentrations. Lancet 1984;2:1222-1223.
Pond SM. Manifestations and management of paraquat poisoning. Medical Journal of Australia 1990;152:256-259.
Ragoucy-Sengler C, Pileire B. A biological index to predict patient outcome in paraquat poisoning. Hum Exp Toxicol 1996; 15: 265-268
Jones AL, Elton R, Flanagan R. Multiple logistic regression analysis of plasma paraquat concentrations as a predictor of outcome in 375 cases of paraquat poisoning. QJM 1999; 92: 573-578
Lin JL, Leu ML, Liu YC, Chen GH. A prospective clinical trial of pulse therapy with glucocorticoid and cyclophosphamide in moderate to severe paraquat-poisoned patients. Am J Respir Crit Care Med 1999; 159: 357-360
Buckley,N.A. Pulse corticosteroids and cyclophosphamide in paraquat poisoning. Am J Respir Crit Care Med 2001 Feb;163(2):585

Eisenman A, Armali Z, Raikhlin-Eisenkraft B et al. Nitric oxide inhalation for paraquat-induced lung injury.J Toxicol Clin Toxicol. 1998;36:575-84.
Jones GM. Vale JA. Mechanisms of toxicity, clinical features, and management of diquat poisoning: a review. J Toxicol Clin Toxicol. 2000;38:123-8.
Lin JL, Leu ML, Liu YC, Chen GH. A prospective clinical trial of pulse therapy with glucocorticoid and cyclophosphamide in moderate to severe paraquat poisoned patients. Am J Respir Crit Care Med 1999; 59:357–60.
Duenas-Laita A,. Nogue S. Erratum: cyclophosphamide in paraquat poisoning.[letter] Am J Respir Crit Care Med. 2001;163(1):292
Buckley NA. Pulse corticosteroids and cyclophosphamide in paraquat poisoning. [letter] Am J Respir Crit Care Med. 2001;163(2):585.
Eddleston M, Wilks MF, Buckley NA.Prospects for treatment of paraquat induced lung fibrosis with immunosuppressive drugs and the need for better prediction of outcome: a systematic review. QJM. 2003;96:809-24.
Agarwal R, Srinivas R, Aggarwal A N, Gupta D. Immunosuppressive therapy in lung injury due to paraquat poisoning: a meta-analysis. Singapore Med J 2007;48 1000-5