• Diquat
• Paraquat

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. There is a suggestion that early haemoperfusion with continuous veno-venous haemofiltration may improve survival. Immunosuppression with dexamethasone, cyclophosphamide and methylprednisolone is widely practised, but evidence for efficacy is very weak. Antioxidants such as acetylcysteine and salicylate might be beneficial through free radical scavenging, anti-inflammatory and NF-κB inhibitory actions. However, there are no published human trials.

Ingestion of paraquat leads to the generation of highly reactive oxygen and nitrite species resulting in toxicity in most organs but the toxicity is particularly severe in the lungs as paraquat is taken up against a concentration gradient in to the lung (Xu, 2014). Paraquat can induce apoptosis by production of ROS and activation of NF-κB. This leads to nuclear condensation and DNA fragmentation. These free oxygen radicals cause lipid peroxidation, damaging cell membranes and leading to cell death. Lipid peroxidation is considered by some to be a key initial pathophysiological process in the cascade of events following paraquat poisoning, although the primary importance of this mechanism is not universally accepted, with others postulating these effects follow other pathological processes. 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. About half of those patients who survive long enough (6–9 days) will develop a mild hepatitis (Yang, 2012).

Paraquat is rapidly but incompletely absorbed. It is primarily absorbed in the small intestine (poorly from the stomach) and its absorption rate is estimated to be 1–5% in humans over 1–6 hours, and the rest is eliminated through defecation. Absorption is decreased in the presence of food. Plasma peak concentrations in humans are attained within 30 minutes to 4 hours; concentrations decline rapidly over the first 15 hours in humans to much lower levels and more slowly than those described in rats as a result of tissue distribution. There is little absorption through intact skin or via inhalation.

Paraquat is rapidly distributed to lung, liver, kidney and muscle. It has a volume of distribution of 1.2–1.6 L/kg (Wunnapuk, 2014). 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. During this period, concentrations of paraquat in lung tissue rise progressively to several times that of the plasma concentration.

Paraquat is rapidly distributed to lung, liver, kidney and muscle. It has a volume of distribution of 1.2–1.6 L/kg (Wunnapuk, 2014). 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. During this period, concentrations of paraquat in lung tissue rise progressively to several times that of the plasma concentration.

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.

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.
Paraquat is rapidly distributed to lung, liver, kidney and muscle. It has a volume of distribution of 1.2–1.6 L/kg (Wunnapuk, 2014). 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. During this period, concentrations of paraquat in lung tissue rise progressively to several times that of the plasma concentration.

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

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.

CXR at Day 5

Chest CT at 1 year

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).

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.

The following tests may be abnormal in paraquat overdose:

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

A new formulation with an increased emetic concentration, an alginate and a purgative (INTEON®) was initially associated with an improvement in mortality in Sri Lanka that was not sustained.
A formulation of paraquat with lysine acetylsalicylate was shown to have low mammalian toxicity and effective herbicidal activity in a rat model.

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).

The time course of the rise in blood lactate can also help in predicting outcome in the absence of paraquat concentrations (Sun, 2014)

Patients in extremis have no realistic hope of recovery with current treatments. Treatment of such patients should be palliative once the diagnosis is established. Otherwise, the standard principles of resuscitation (assessment and management of airway, breathing and circulation) should generally be followed as per routine guidelines.

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.

Patients with moderate poisoning may benefit from good supportive care. Mild to moderate hypoxia should not be routinely treated with oxygen as it will worsen oxidative stress and it greatly increases lethality in animal models. 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.

Corticosteroids and cyclophosphamide have been suggested as treatment. There are two non-randomised trials with opposite results (Buckley, 2001) and a randomised trial which did not show benefit (Gawarammana, 2012). 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.

Patients with borderline paraquat concentrations or ingestions around the potentially lethal dose (i.e. 5 g), may benefit from early charcoal haemoperfusion with CVVHD (Gao, 2014). 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).

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.

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