ToxCard: Paraquat Toxicity

Authors: Kelsey Lena, MD (Emergency Medicine Resident, Carolinas Medical Center, Charlotte, NC), Kathryn T Kopec, DO (Emergency Medicine Attending; Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: Cynthia Santos, MD (@Cynthia Santos, MD); Alex Koyfman, MD (@EMHighAK); and Brit Long, MD (@long_brit)

Case:

A 52-year-old male presents to the Emergency Department (ED) for vomiting. His wife states he has been vomiting for the past 6 hours. She noted “red spots” and slurred speech so she brought him to the ED. He works as a farmer and has a history of HTN, HLD, and depression. On initial examination, the patient appears uncomfortable, moaning as he holds his abdomen and has repeated episodes of emesis. Initial vital signs: Temp of 38.6C; HR 120 bpm; RR 26 breaths/min; BP 92/65 mmHg; and O2 saturation 90% RA. You hear the patient moan “why aren’t I dead.” Laboratory work-up demonstrates pH 7.30, HCO2 28 mmol/L, pO2 84 torr, Na+ 132 mEq/L, K+ 4.1 mEq/L, Cl- 96 mEq/L, and bicarbonate 15 mEq/L. His wife is concerned he ingested something.

What herbicide is of highest concern?
A) Malathion
B) Glyphosate
C) Paraquat
D) Pyrethroids

 

Obviously the answer is C, Paraquat – that’s why we did this toxcard 🙂


Background:

Paraquat is a fast-acting, non-selective contact herbicide responsible for significant morbidity and mortality in humans. (1) Paraquats’ mechanism of action as an herbicide on plants is the inhibition of photosynthesis and respiration by interfering with the electron transfer of Photosystem I. (1,2) Toxicity in humans can occur thru ocular or transdermal exposure, inhalation, or ingestion. (1,3) Ingestion is responsible for the majority of paraquat deaths, with an overall mortality of > 50%; however with ingestions of > 20 mL of 20% concentrated solution, mortality is nearly 100%. (1,3)

The mechanism of toxicity in paraquat ingestion is secondary to redox-cycling and subsequent generation of reactive oxygen species (ROS). Redox-cycling is the continuous oxidation and reduction of free radicals. These free radicals react with oxygen and form hydroxyl free radicals and superoxide oxygen. (1,2,3) These ROS cause lipid peroxidation and activation of nuclear factor kappa B (NF-kB), which compromises cellular membranes, triggers apoptosis, attracts inflammatory cells and enhances platelet aggregation. (3)

Paraquat has a multi-organ distribution and can cause toxicity in the GI, renal, cardiac, respiratory and CNS systems. The highest concentration is found in the alveolar epithelium of the lungs. The generation of ROS within the lungs, leads to acute alveolitis, diffuse alveolar collapse, vascular congestion, and adherence of activated platelets and leukocytes to the vascular endothelium. (3) Pulmonary injury occurs in two phases:

  • Destructive Phase: Loss of type I and type II alveolar cells with infiltration of inflammatory cells, pulmonary edema, and sloughing of the alveoli. (1,3)
    • Occurs within hours to 5 days post ingestion
  • Proliferative Phase: Alveolar space fills with mononuclear pro-fibroblasts, which will eventually mature to fibrosis in the interstitium and alveolar spaces. (1,3)
    • Occurs 5 days to weeks post ingestion

Diagnosis:

The diagnosis is often made by the history. It is important to inquire about the exposure type (accidental or intentional), route of exposure, concentration of the product, time of occurrence, and estimated amount ingested.

Table 1 is a guideline on clinical effects and severity based on ingestion amount.

Clinical Presentation:

There is a wide range of potential symptomatic findings:

  • CNS: somnolence, seizures, coma
  • EENT: conjunctival irritation, blurry vision, mucosal erythema with ulcerations, excessive drooling, epistaxis
  • GI: nausea, vomiting, abdominal pain, hematemesis, peritonitis
  • Pulmonary: dyspnea, cough, hemoptysis, acute respiratory failure
  • Genitourinary: decreased urinary output, renal dysfunction

 

Patients who ingest 20-40 mg/kg (7.5-15 mL) of paraquat and survive the initial phase of toxicity typically return to the hospital within 1-3 weeks for significant dyspnea secondary to the development of pulmonary fibrosis. (1)


Laboratory Testing:

  • BMP, lipase, LFTs, PT/INR, lactate, and ABG including alveolar-arterial gradient
  • Paraquat levels in the urine and blood are often send out tests limiting acutely available results. (3,4)
  • Nomogram:
    • Based on plasma paraquat concentration and time of ingestion at 4-24 hours (5)
    • Better at predicting death than survival but tends to underestimate mortality (5)
    • Not commonly used
  • Urine Testing: Sodium Dithionite Test (4)
    • Take 1 gm of sodium dithionite and 1 gm of sodium bicarbonate mixed with 10ml of patient urine
    • Positive = Blue coloration
    • The higher the concentration the darker the color
    • If a colorimetric test is negative at 6 hours, paraquat toxicity is less likely

Imaging: (3,6)

  • CXR at time of presentation to assess for pneumothorax, pneumomediastinum, or pulmonary edema
  • Consider early upper GI Endoscopy if concern for corrosive injury
  • Can consider a CT chest 7-14 days after ingestion to assess for early pulmonary fibrosis

Clinical Management:

  • Any exposure to paraquat is a potential medical emergency and often requires hospitalization.
  • Early treatment is mainly supportive
  • Decontamination:
    • Remove clothing and decontaminate skin with mild detergent and water
    • If a patient presents within 4 hours post ingestion, can attempt GI decontamination with absorbents that bind paraquat. (1,3)
  • Single dose of activated charcoal (1-2 g/kg)
  • Diatomaceous Fuller’s Earth (1-2 g/kg in 15% aqueous suspension)
  • Airway protection / Intubation if indicated
  • Do NOT administer supplemental oxygen unless the patient is severely hypoxic
    • Oxygen stimulates superoxide radical formation and promotes oxidative stress (7)
    • Allow permissive hypoxia
  • IVF resuscitation
  • Maintain good urine output (3)
  • Pain control
  • Evaluate for caustic injuries and potential need for endoscopy
  • Hemodialysis:
    • Has not shown to improve prognosis
    • Can be considered for severe acid-base dysfunction and/or acute renal failure (3,8)
  • Pulmonary fibrosis treatment is primarily supportive care as well
    • Investigational/Experimental Treatments (3,4,9)
      • Glucocorticoids
      • Cyclophosphamide
      • Lung Transplant

Case Conclusion:

The patient became acutely hypoxic with oxygen saturations in the 70’s. He was placed on nasal cannula then intubated. Over the course of 72 hours, he developed severe metabolic acidosis, refractory hypotension, and multi-organ failure. The patient expired on day 4 of hospitalization.


Key Points:

  • Paraquat is a herbicide that is rapidly absorbed and undergoes redox-cycling with generation of ROS causing cellular dysfunction and death.
  • 15-20 mL of ingested paraquat can lead to fulminant multi-organ failure with mortality rates close to 100%.
  • The pulmonary system is most commonly and severely affected with hypoxia, dyspnea, cough, hemoptysis, and subsequent development of pulmonary fibrosis.
  • History is key to the diagnosis.
  • Paraquat levels are of little use as they are often unavailable.
  • Sodium Dithionite Test: bedside urine testing can assist in diagnosis.
  • Treatment gold standard is supportive care.
  • Can consider decontamination with AC or Fuller’s Earth.
  • Tolerate hypoxia and avoid oxygen as it can promote oxidative stress and causes further tissue damage.

References:

  1. Pesticides. Chapter 201 In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank’s Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015.
  2. Dodge AD. The mode of action of the bipyridylium herbicides, paraquat and diquat. Endeavour. 1971;30(111):130‐135. doi:10.1016/0160-9327(71)90039-1
  3. Gawarammana I, Buckley N. Medical management of paraquat ingestion. British Journal of Clinical Pharmacology. 23 May 2011. DOI:10.1111/j.1365-2125.2011.04026.
  4. Liu, X., Ma, T., & Liu, Z. (2018). Prognostic significance of urine paraquat concentrations of patients with acute paraquat poisoning on admission at the emergency department. Hong Kong Journal of Emergency Medicine, 25(1), 3–11.
  5. Senarathna L, Eddleston M, Wilks MF, Woollen BH, Tomenson JA, Roberts DM, Buckley NA. Prediction of outcome after paraquat poisoning by measurement of the plasma paraquat concentration. QJM 2009; 102: 251–9.
  6. Zhang Q, Wu W, Lu Y, Wang J, Shang A, Yao F, Chen Y. Case Report: Successful treatment of patients with paraquat intoxication: three case reports and review of the literature. Journal of Zheijang University-Science B (Biomedicine and Biotechnology). 2012 13(5):413-418.
  7. Yamamoto I, Saito T, Harunari N, Sato Y, Kato H, Nakagawa Y, Inokuchi S, Sawada Y, Makuuchi H. Correlating the severity of paraquat poisoning with specific hemodynamic and oxygen metabolism variables. Crit Care Med 2000; 28: 1877–83.
  8. Shi Y, Bai Y, Zou Y, et al. The value of plasma paraquat concentration in predicting therapeutic effects of haemoperfusion in patients with acute paraquat poisoning. PLoS One. 2012;7(7):e40911. doi:10.1371/journal.pone.0040911
  9. Walder, Bernhard1,2; Bründler, Marie-Anne3; Spiliopoulos, Anastase4; Romand, Jacques A.1 Successful Single Lung Transplantation after Paraquat Intoxication, Transplantation: September 15th, 1997 – Volume 64 – Issue 5 – p 789-791.

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