Paraquat poisoning management 28.5.22.pptx

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.

1. Paraquat poisoning management Presenter : Dr. Nipa Mendapara Junior Resident Department of PHARMACOLOGY AIIMS, NEW DELHI

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. a ll formulations contain an emetic to decrease absorption in case of accidental or suicidal ingestion

3. B lue-green in color

4. 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.

5. 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. B a nned in 32 countries including Switzerland, where herbicide producing company Sygenta is based. So far in India, only Kerala has banned the paraquat herbicide.

6. TOXICOKINETICS Gastrointestinal tract absorbs less than 10% of an ingested dose over 6 hours. P resence 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.

7. Vinod et al., 2015

8. 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

9. Paraquat toxicity inside a pneumocyte and potential sites of therapy Gawarammana et al. 2011

10. 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

11. 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

12. 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

13. Clinical features Inhalation : E pistaxis and sore throat. Dermal exposures : E specially 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.

14. 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)  U rine 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

15. Nomogram : Paraquat levels and likely outcome TOXBASE.org

16. 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)

17. MANAGEMENT

18.   DECONTAMINATION Remove contaminated clothing and wash skin with soap and water. Irrigate exposed eyes. Gastric lavage not to be done due to corrosive injury. C onsider 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

19. DECONTAMINATION O ne of the following adsorbent should be given patients with an ingestion within the last 24 hours A ctivated charcoal - dose : adult - 50 to 100 g; child: 1 g/kg B entonite clay (7% solution) - dose : adult -100 to 150 g; child less than 12 years of age: : 2 g/kg F uller's earth (30% solution) – dose : adult -100 to 150 g; child less than 12 years of age: 2 g/kg IBM Micromedex

20. Activated charcoal B entonite clay F uller's earth

21. 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.

22. IMMUNOSUPPRESSIVE THERAPY C yclophosphamide, methylprednisolone and dexamethasone should be administered to treat the acute inflammatory process associated with paraquat poisoning that can lead to lung injury and death T o 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

23. 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

24. 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

25. 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 Vitamin C 100 mg 4-hourly for 14 days Vitamin E 50 mg daily for 7 days Lalloo et. al., 2008

26. 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 -   S hould 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 P atients with QT prolongation, monitor serum electrolytes including potassium, calcium and magnesium; correct any abnormalities.

27. THANK YOU