As this herbicide poisoning is frequent with poor outcomes so its management needs to be discussed and awareness should be raised among farmers about its use and pre-hospital treatments.
2. BACKGROUND
• Paraquat (1,1’- dimethyl-4,4’- bipyridinium) is a quaternary dipyridyl non-
specific contact herbicide
• Rapidly absorbed by the aerial plant and immediately inactivated on
contact to the clay in the soil, leaving minimal residue
• The solution is usually blue-green in color. It is present in varying
concentrations ranging from 10%-40% and requires to be diluted prior
to use.
• Paraquat, when ingested, is highly toxic. all formulations contain an
emetic to decrease absorption in case of accidental or suicidal ingestion
5. HISTORY
• First synthesized in 1882 as a redox indicator, and its herbicidal property was
recognized in the 1950s and found its way into agricultural use by 1962
• It was initially used to kill marijuana weeds in the United States and Mexico.
• Paraquat is a widely used for weed and grass control but is also a lethal poison.
In some low- and middle-income countries paraquat is commonly available and
inexpensive, making poisoning prevention difficult.
• Most of the people poisoned by paraquat have taken it as a means of self-
poisoning. its unregulated use in developing countries like India has made it a
commonly used pesticide.
6. WHY IT’S STILL IN USE ?
• Paraquat dichloride is being used for 25 crops in India, whereas it is approved
for use in only 9 crops by the Central Insecticide Board and Registration
Committee(CIBRC). This is in violation of the Indian Insecticides Act
• Syngenta, the Swiss-headquartered, Chinese-owned agrochemical giant that
inherited ICI’s pesticides business, continues to export thousands of tonnes of
Gramoxone each year from its factory - although the UK, Switzerland and China
have all banned its use on their own soil.
• Banned in 32 countries including Switzerland, where herbicide producing
company Sygenta is based.
• So far in India, only Kerala has banned the paraquat herbicide.
7. TOXICOKINETICS
• Gastrointestinal tract absorbs less than 10% of an ingested dose over 6 hours.
Presence of ulcerated mucosa or an empty stomach increases the fraction of
paraquat absorbed. peak plasma concentrations occurs within 4 hours.
• Poorly absorbed through intact human skin; however, damage to the skin by
paraquat itself or other means will permit greater systemic absorption
• It’s not actively metabolized in the body, and more than 90% is excreted
unchanged by the kidneys
• After absorption, paraquat is distributed to highly perfused organs such as the
lungs, kidneys, liver, and muscles, and remains partly in the intravascular space.
9. MECHANISMS OF TOXICITY
• The mechanism of toxicity in humans has not been clarified, but paraquat has
been shown in animals to induce complete oxidation of both NADPH and
NADH and increase peroxidation of vital lipid membranes
• Additionally, paraquat is a potent generator of acute reactive oxygen species
11. RANGE OF TOXICITY
1) MILD TOXICITY: Ingestion of less than 20 mg paraquat ion per kg body weight
(less than 7.5 mL of 20% [w/v] paraquat concentrate): No symptoms or mild GI
effects; recovery likely.
2) MODERATE to SEVERE TOXICITY: 20 to 40 mg paraquat ion per kg body weight
(7.5 to 15 mL of 20% [w/v] paraquat concentrate): Pulmonary fibroplasia develops.
Death occurs in most cases, but may be delayed 2 to 3 weeks.
3) FATAL: Greater than 40 mg paraquat ion per kg body weight (10 to 15 mL of
20% [w/v] paraquat concentrate): Multiple organ failure occurs; toxicity progresses
rapidly. Mortality is essentially 100% in 1 to 7 days
12. RANGE OF TOXICITY
• Based on the LD50 in humans (35 mg/kg), the estimated human lethal dose is
10 to 15 mL of a 20% solution.
• Mortality rates are as high as 65% in patients who ingest concentrated
formulation compared to 4% in those ingest diluted solution (25% w/v)
• Reformulation of products : Some variability may exist based on the formulation;
newer formulations may have an alginate that can increase emesis and act as a
purgative
13. CLINICAL FEATURES
• Ingestion/systemic toxicity : Nausea and vomiting, with or without diarrhoea, are
common together with a burning sensation, soreness and pain in the mouth, throat,
chest and abdomen (usually epigastric).
• Ulceration in the mouth (which may be severe), sloughing of the oropharyngeal
mucosae, an inability to swallow, dysphagia and aphonia ensue.
• Within hours generalised weakness, myalgia, giddiness, headache, anorexia and
fever develop.
• Oliguria or non-oliguric renal failure may supervene due to acute tubular necrosis.
• Most patients develop a cough which may be productive and blood stained.
Dyspnoea is a prominent feature in substantial amount of paraquat due to acute
respiratory distress syndrome (ARDS). In less severe cases, the onset of dyspnoea is
due to pulmonary fibrosis
14. CLINICAL FEATURES
• Inhalation : Epistaxis and sore throat.
• Dermal exposures : Especially in concentrated formulations, has a strong irritant
action on various types of epithelia. It will cause erythema, blistering, irritation
and ulceration of the skin and eczematous dermatitis.
• Eye exposure : Severe inflammation of the cornea and conjunctiva and may lead
to ulceration of the conjunctiva and cornea
• Intravenous or intramuscular injection : may lead to systemic toxicity.
15. LABORATORY MONITORING
A) Full laboratory analysis, including liver and renal function tests, basic metabolic
panel, complete blood count, chest x-ray and urinalysis, should be performed on
anyone ingesting paraquat. Arterial blood gas analysis should be performed on
those with a late presentation or those with hypoxia.
B) Urine dithionite test(UDT) : Bedside testing can be performed using a 1%
aqueous sodium dithionite in 0.1 normal sodium hydroxide to form a stable blue
radical in the urine. If paraquat is present, the urine will appear blue compared
with the control urine.
C) Serum paraquat concentrations can be useful for prognosis
17. LABORATORY TESTING
• If paraquat concentration is more than 1 mg/ml,
the urine will appear blue and this finding alone
indicates a very poor prognosis
• Urine testing that detects paraquat concentrations
of 1 mg/mL or above, gas chromatography (1
microgram/mL) and radioimmunoassay (< 0.1
microgram/mL)
19. DECONTAMINATION
• Remove contaminated clothing and wash skin with soap and water. Irrigate
exposed eyes.
• Gastric lavage not to be done due to corrosive injury.
• Consider gastric aspiration or lavage in adults who have ingested a potentially
lethal dose within 1 hour of ingestion.
• Gastric lavage followed by administration of 1 g/kg of activated charcoal in 250
mL of magnesium citrate or saline in patients presenting within 24 hrs.
• Activated charcoal's absorbing capacity for paraquat is increases when it is
suspended in magnesium citrate and is maximal at pH 7.8 (Intestine pH~7.0).
Also as cathartic it’s frequently administered to increase gastrointestinal transit
and decrease absorption of ingested toxins.
Gaudreault et al. Efficacy of activated charcoal and magnesium citrate in the treatment of oral paraquat intoxication. Ann Emerg
Med. 1985
20. DECONTAMINATION
• One of the following adsorbent should be given patients with an ingestion within the last
24 hours
I. Activated charcoal - dose : adult - 50 to 100 g; child: 1 g/kg
II. Bentonite clay (7% solution) - dose : adult -100 to 150 g; child less than 12 years of
age: : 2 g/kg
III.Fuller's earth (30% solution) – dose : adult -100 to 150 g; child less than 12 years of
age: 2 g/kg
IBM Micromedex
22. HEMOPERFUSION
• The first and the earliest modality of treatment of removal of paraquat. Ideally, it
should be started within 4 hours of exposure or ingestion. As early
hemoperfusion may reduce mortality.
• Two 8 hours courses of activated charcoal hemoperfusion within 24 hrs of
paraquat ingestion
• If the patient develops AKI, then standard indications for hemodialysis are
applicable but it is always useful to start hemofiltration at the earliest to avoid
subsequent development of acute kidney injury due to paraquat.
23. IMMUNOSUPPRESSIVE THERAPY
• Cyclophosphamide, methylprednisolone and dexamethasone should be
administered to treat the acute inflammatory process associated with paraquat
poisoning that can lead to lung injury and death
• To a patient at risk of moderate or severe pulmonary toxicity and those with
symptoms consistent with moderate to severe toxicity
• Several small studies suggest that it can reduce the mortality rate of severe
paraquat poisoning
24. PULSE THERAPY
• After hemoperfusion, IV cyclophosphamide 15 mg/kg/day in 200 mL D5NS infused over
2 hrs for 2 consecutive days and 1 g methylprednisolone in 200 mL D5NS infused over 2
hrs daily for 3 consecutive days.
• After the initial pulse therapy, administer dexamethasone 5 mg IV every 6 hrs until PaO2
is 80 mmHg (11.5 kPa) or greater.
• If PaO2 is less than 60 mmHg (8.64 kPa), repeat IV methylprednisolone 1 g in 200 mL
D5NS infused over 2 hours daily for 3 consecutive days.
• If WBC is greater than 3000/m3 and it has been 2 weeks since the initial pulse of
cyclophosphamide, repeat IV infusion of cyclophosphamide 15 mg/kg in 200 mL D5NS
infused over 2 hrs as a single dose.
• Then continue IV dexamethasone 5 mg every 6 hrs until PaO2 is 80 mmHg or greater.
Then reduce dexamethasone dose gradually.
IBM Micromedex
25. ALTERNATIVE THERAPIES
• High-dose therapy includes the same initial treatment (activated charcoal and
hemoperfusion) as pulse therapy along with high-dose cyclophosphamide (5
mg/kg/d) and dexamethasone 24 mg/d for 14 days.
• Another method includes early decontamination and 15 mg/kg of
cyclophosphamide in D5NS in 200 mL infused over 2 hrs for 2 days and
methylprednisolone 1 g in 200 mL D5NS IV infused over 4 hrs and repeated for
3 consecutive days. Mesna (15 mg/kg) was also administered over 4 days to
avoid side effects to cyclophosphamide.
IBM Micromedex
26.
27. OTHER THERAPIES
Antioxidants
• High-dose long-term antioxidants could potentially be a critical component
improving the survival rate in severe paraquat poisoning
(1) N-Acetylcysteine is renally protective with a low adverse reaction profile
• An infusion of N-acetylcysteine at 150 mg/kg for 1 hour, 50 mg/kg over the next
4 hours, then 100 mg/kg daily for 4 days
(2) Vitamin C 100 mg 4-hourly for 14 days
(3) Vitamin E 50 mg daily for 7 days
Lalloo et. al., 2008
28. SUPPORTIVE CARE
• ANTIDOTE - NO antidote available
• NAUSEA AND VOMITING - Antiemetics should be provided liberally. Stress ulcer
prophylaxis should be provided
• HYPOTENSION - Treat hypotension with isotonic fluid resuscitation, followed by addition of
vasopressors
• ACUTE TUBULAR NECROSIS - Adequate fluid resuscitation is key to limiting secondary
renal injury. Hemodialysis for oliguric renal failure is occasionally necessary as a
temporizing measure until renal function improves
• OXYGEN THERAPY - Should be withheld until the PaO2 is below 50 mmHg, because
supplemental O2 may lead to increased production of oxygen free radicals and increased
pulmonary toxicity
• Patients with QT prolongation, monitor serum electrolytes including potassium, calcium
and magnesium; correct any abnormalities.
Paraquat is available in commercial 20% concentrate form, as 2.5% granules, and 0.2% aerosol.
Paraquat is available in commercial 20% concentrate form, as 2.5% granules, and 0.2% aerosol.
*Paraquat is stopped (distribution, sale and use) in the State of Kerala since 2011, as per the Kerala Government order dated 07.05.2011
SOD, superoxide dismutase; CAT, catalase; Gred, glutathione reductase; Gpx, glutathione peroxidase; FR, Fenton reaction; HWR, Haber-Weiss reaction.
1–8: potential sites of action by available treatment options. 1: activated charcoal and Fuller’s earth; 2: dialysis; 3, 4, 6 and 8: salicylates; 5 and 8: N-acetylcysteine; 7 (P-glycoprotein induction): dexamethasone; 4: immunosuppression
Diluted paraquat is unlikely to irritate skin unless clothing soaked with spray is worn for prolonged periods.
Efficacy of activated charcoal declines rapidly with time since ingestion but there may be some potential benefit from later use, especially following ingestion of highly toxic substances.