Paraquat Toxicity 

Urgent Action

• Decontamination and supportive care must be initiated within hours of poisoning or there will be no beneficial effect

Interesting Facts of Paraquat Toxicity 

1. Paraquat poisoning is caused by exposure to the herbicide paraquat, almost exclusively via the ingestion route
   • Paraquat ingestion is a common method of suicide in developing countries where the herbicide is widely available
   • Mild symptoms may result from inhalational, dermal, or ocular exposure
2. Degree of toxicity is dose dependent
   • Large volume and/or high concentration of ingested solution leads to poisoning that causes death within 48 hours
     • Mortality approaches 100% with 50 mL or more of 20% solution
   • Lower-dose poisonings cause delayed death by respiratory and kidney failure within 5 weeks
3. Symptoms primarily involve the lungs, gastrointestinal tract, and kidneys
   • Symptoms manifest initially at point of contact or exposure and progress systemically as paraquat is absorbed
4. Urine dithionite testing can quickly determine systemic toxicity, but patient history is critical to differentiating paraquat toxicity from other diagnoses
5. Treatment involves decontamination (eg, washing, gastric suction with activated charcoal) and supportive care such as fluid resuscitation, hemoperfusion, and immunosuppressive therapy
   • Avoid routine provision of oxygen, as it exacerbates pulmonary toxicity
   • Corticosteroid and cyclophosphamide therapy are recommended if started within 4 hours of poisoning to reduce pulmonary fibrosis
   • Extracorporeal removal of paraquat is useful only if started within 1 to 2 hours of poisoning
6. Complications include acute renal failure, respiratory failure, and gastrointestinal tract perforation with mediastinitis, pneumomediastinum, and/or peritonitis
7. Overall mortality is high, at approximately 50% to 100%; however, patients who survive more than 3 months after exposure typically do not die of secondary effects

Pitfalls

• Avoid routine provision of oxygen, as it exacerbates pulmonary toxicity
• Avoid underestimation of potential for injury because of small volume ingested
• Failure to administer gastric decontamination early in patients with ingestion can lead to significant absorption and progression of toxicity ¹
• Failure to provide immunosuppressant therapy may result in increased pulmonary toxicity ¹

Clinical Clarification

• Paraquat toxicity results from exposure to paraquat, a nonselective herbicide that produces a superoxide radical and results in toxicity ²
  • Paraquat exposure occurs primarily through ingestion but also via inhalation or dermal, ocular, or mucous membrane contact ²³
    • After absorption, paraquat causes cellular toxicity and apoptosis and can lead to the following: ²⁴
      • Alveolitis, pneumonitis, and eventual pulmonary fibrosis ^2 4
      • Hepatotoxicity and renal injury ^2 4
  • Paraquat causes direct caustic injury to mucous membranes of gastrointestinal tract ⁵
• Clinical features are characterized by rapid progression of symptoms (hours to days) and a high mortality rate ²

Classification

• Toxicity from oral ingestion (but not dermal, ocular, or inhalational exposure) is classified by amount of paraquat ingested ¹
  • Asymptomatic or mild toxicity ¹
    • Ingestion of less than 20 mg paraquat ion per kilogram of body weight (less than 10 mL of 20%-24% concentrate) ¹
    • Associated with no symptoms or mild gastrointestinal symptoms ¹
  • Moderate to severe toxicity
    • Ingestion of 20 to 40 mg paraquat ion per kilogram of body weight (10-20 mL of 20%-24% concentrate) ¹
    • Associated with more indolent illness (developing over days to weeks) ¹
    • Predominant effects are acute alveolitis leading to secondary pulmonary fibrosis along with renal toxicity and hepatotoxicity ^1 2
  • Severe: acute fulminant toxicity ¹
    • Ingestion of more than 40 mg paraquat ion per kilogram of body weight (more than 20 mL of 20%-24% concentrate) ¹
    • Results in multiple organ failure ¹

Clinical Presentation

• Labial mucosa 4 days after the original exposure to diquat, which is a quaternary ammonium herbicide closely related to paraquat.
• 1 month after the exposure to diquat (which is a quaternary ammonium herbicide closely related to paraquat) mucosal recovery remained incomplete.
• Tongue 4 days after the original exposure to diquat, which is a quaternary ammonium herbicide closely related to paraquat.

History ^4 6

• Symptoms are primarily related to 2 organ systems, lungs and kidneys, although gastrointestinal system is directly affected via caustic injury ^2 6
• Symptoms are directly related to amount of paraquat ingested (eg, volume and concentration of solution) and route of exposure ¹
  • Small volume and/or low concentration of ingested solution (eg, less than 20 mL of 20% solution) ¹
    • Ingestion has direct irritant effects on mucous membranes within 12 hours of exposure ²
      • Irritation and numbness of tongue and mouth are typically the only symptoms in the first few days after paraquat ingestion ⁴
      • Nausea, vomiting, or both may be immediate because some paraquat formulations contain an emetic ⁶
      • Diarrhea and abdominal pain ⁶
      • Oliguria ¹
      • Dyspnea and tachypnea ⁴
        • Typically appear 3 to 4 days after ingestion ⁴
      • Acute respiratory impairment ²⁴⁶
        • May occur days to weeks after ingestion ^2 6
  • Large volume and/or high concentration of ingested solution (eg, more than 50 mL of 20% solution) ¹
    • Oral mucosal and pharyngeal pain and burns, with chest pain due to esophageal caustic injury and possible esophageal rupture ^2 6
    • Agitation and confusion, secondary to pain and hypoxia ²
    • Burning skin sensation (indicative of poor prognosis) ^2 7
    • Decreased urine flow progressing to anuria over 2 to 3 days ^2 4
    • Diffuse abdominal pain progressing to frank peritonitis ^2 6
  • Inhalation results in symptoms generally limited to respiratory system (eg, nasal cavity, pharynx, trachea, bronchi) ¹
    • Oropharyngeal pain, irritation, or swelling ¹
    • Cough ¹
    • Nosebleed ¹
    • Confusion or disorientation ⁴
    • Systemic poisoning through inhalation has not been recorded ¹
  • Severity and type of symptoms with dermal or ocular exposure are proportional to dosage and duration of exposure ¹
    • Paraquat is irritating to the skin; skin damage may occur in cases of prolonged contact ¹
      • Systemic poisoning can occur through broken skin with prolonged exposure, such as with leaking from a knapsack type of sprayer; it causes symptoms of mild to severe toxicity, depending on volume absorbed ¹
    • Direct ocular exposure results in burning pain and visual impairment ²

Physical examination ^2 6

• Small volume or low concentration of ingested solution (eg, less than 20 mL of 20% solution) ²⁶
  • Initial signs may be mild but become more pronounced as poisoning progresses over several days ^2 6
  • Increased dyspnea, with hypoxia and central cyanosis, presents 5 to 7 days after ingestion, progressing to gradual respiratory failure over 5 weeks ^2 6
• Large volume and/or high concentration of ingested solution (eg, more than 50 mL of 20% solution) ²⁶
  • Mucosal lesions of mouth and tongue (“paraquat tongue”) ²⁸
    • Ulceration has yellow necrotic base and deep fissures; raw areas with bleeding are interposed between areas of necrosis ⁸
  • Tachycardia, hypotension, and cardiovascular collapse ^2 6
  • Pulmonary edema with respiratory distress and rapid respiratory failure within 48 hours ^2 6
• Cyanosis, dyspnea, and tachypnea also appear to varying degrees after paraquat inhalation; degree depends on dose and acute versus chronic exposure ¹
• Ulceration and/or blistering of skin can occur after hours of acute dermal contact or after chronic low-level dermal exposure ¹
  • Nail atrophy can occur secondary to hours of acute dermal contact or chronic low-level exposure ¹
    • However, observable nail damage is delayed from time of exposure, owing to time needed for damaged nail bed to grow out and be seen ⁹
  • Transverse cracking dermatitis can occur with chronic occupational exposure ¹
• With severe ocular exposure, paraquat may cause significant corrosive injury to the cornea, resulting in protracted opacification ¹
  • Corneal injury is typified by irregular, opaque, hazy, leathery, and edematous epithelial defect over cornea ¹⁰
    • Conjunctiva is hyperemic and chemotic, with congestion of limbal vasculature ¹⁰
  • Ocular injury may progress for up to 24 hours after exposure ¹
  • Ocular exposure rarely leads to systemic toxicity ¹

Dermal, ocular, and inhalational exposures to paraquat rarely lead to systemic toxicity, although they do cause significant irritation to contact surfaces and symptoms associated with route of exposure ¹

• In cases of extreme contact or inhalational exposure or chronic occupational exposure, mild to severe systemic toxicity is possible ¹

Causes and Risk Factors

What causes Paraquat Toxicity? ^6 11

• Ingestion of paraquat
  • Oral ingestion is the most common route of exposure
    • Usually intentional (suicide)
• Less common routes of exposure include:
  • Inhalation
  • Dermal or ocular contact exposure
  • IV injection

What are the Risk factors and/or associations

Other risk factors/associations

• Location
  • Widely used suicide agent in developing countries, owing to widespread availability, low toxic dose, and low cost ⁴
  • Available only to commercially licensed professionals in the United States ³

Diagnostic Procedures

• The prognostic nomogram for use in cases of poisoning with paraquat; prognosis is guarded in the shaded area.

Primary diagnostic tools ⁴

• History of paraquat ingestion or of activities that may involve paraquat exposure (eg, farming, landscaping) ¹
• Qualitative detection of paraquat in urine, plasma, and/or serum is both necessary and sufficient for diagnosis of systemic paraquat poisoning in appropriate clinical circumstances ²⁴
  • Qualitative testing is indicated regardless of route of exposure
    • Urine dithionite test is the most common method ^2 4
  • Plasma analysis is preferable to serum analysis: serum paraquat concentrations are approximately lower than those in plasma prepared from the same blood sample
    • If only serum is available, interpret results with caution in relation to survival curves
• Important prognostic measures include plasma paraquat concentrations, extent of lung injury, and degree of renal impairment ⁴
  • Measure plasma paraquat concentration to evaluate peak levels and monitor clearance over time
    • Measure plasma paraquat concentration no more often than every 24 hours for the first 72 hours
  • Perform pulmonary function testing to evaluate paraquat-induced lung injury in patients presenting with paraquat poisoning or to monitor survivors ⁴
  • Measure serum creatinine concentration to evaluate renal function in patients presenting with paraquat poisoning or to monitor survivors

• Measure serum creatinine concentration to evaluate renal function in patients presenting with paraquat poisoning or to monitor survivors

Laboratory

• Urine dithionite test ²⁴
  • Colorimetric, qualitative test for paraquat ⁴
  • Provides rapid bedside detection ⁴
  • Detection sensitivity: 1 mg/L ⁴
  • Can detect paraquat a few hours after ingestion ⁴
  • Availability may be limited
• Plasma analysis ¹²
  • Can be qualitative or quantitative
    • Qualitative: dithionite plasma test identical to urine test ²
      • Colorimetric qualitative test for paraquat in plasma sample ²
      • Detection sensitivity: 1 mg/L ²
    • Quantitative: limited availability in specialized laboratories only ²
      • Quantitative analysis can be performed on either plasma or serum
      • Important to use a plasma sample and not a serum sample because paraquat levels are 3 times higher in plasma than in serum ^12 13
  • 5 nomograms are available with plasma paraquat concentration plotted against time to predict mortality ^2121314
    • All published nomograms have comparable accuracy in predicting mortality ¹⁵
• Serum creatinine ²¹⁶
  • Rate of increase of serum creatinine level is used as a nonspecific predictor of mortality ^2 16
  • Rate of increase of 3 μmol/L/h or less over 5 hours predicts survival ^2 16
  • Rate of increase of 5.4 μmol/L/h or greater over 5 hours predicts death ^2 16

Imaging

• High-resolution CT of lungs ⁴
  • Perform at least 7 days after paraquat ingestion to evaluate lung injury ¹⁷
    • Lung abnormalities may not present for up to 7 days; therefore, do not use them as a primary diagnostic tool
  • Subpleural ground-glass opacities indicate alveolar inflammation ⁴
  • Ground-glass opacity area more than 50% of total lung volume is usually fatal ⁴
  • Lesions typically progress to fibrosis after 2 to 3 weeks ⁴
  • Ground-glass opacity area less than 20% of total lung volume on high-resolution CT is survivable ⁴

Functional testing

• Pulmonary function testing ⁴
  • Performed at presentation and every 2 to 3 days thereafter to monitor for pulmonary toxicity
  • Restrictive lung disease is typically present ⁴
  • Significant rise in mortality is seen when PaO₂ cannot be maintained at 60 mm Hg or more ⁴

Differential Diagnosis

Most common

• Ingestion of other herbicide products (eg, glyphosate)
  • Patient may present with cardiovascular toxicity similar to that seen with large-volume paraquat ingestion
    • Hypotension and tachycardia with cardiovascular collapse
  • Differentiated from paraquat toxicity by absence of pulmonary and renal impairment and negative qualitative paraquat urine or plasma assay results
• Inhalational exposure to other substances
  • Inhalation of other chemicals or irritants leading to pneumonitis
  • Patients may present with respiratory symptoms similar to those seen with paraquat exposure
  • Differentiated via absence of history of exposure to paraquat
• Idiopathic pulmonary fibrosis
  • Chronic, progressive fibroproliferative disease of unknown cause
  • Fibrosis is a common complication of paraquat toxicity
  • Differentiated via absence of history of exposure to paraquat and absence of involvement of other organ systems (eg, renal and gastrointestinal)

Treatment Goals

• Early decontamination
• Early initiation of supportive treatment ⁴
• Prevention of further paraquat absorption after ingestion
• Prevention of organ-specific toxicity (eg, renal and pulmonary damage) ⁴
• Palliative care for severe poisoning

Disposition

Admission criteria

Admit any patient with history of having ingested any amount of paraquat

• Mandatory observation for at least 6 hours or until a urine dithionite test can be performed

For any patient with corrosive injury of the eye, gastrointestinal or respiratory toxicity, or systemic toxicity, admit for immediate decontamination ²

Criteria for ICU admission

• Admit to ICU all patients with abnormal vital signs (eg, tachycardia, hypotension, hypoxia) or severe abdominal pain
  • Expectation is that without proper care, symptoms will progress rapidly

Recommendations for specialist referral

• If patient is recovering from attempted suicide, refer to psychiatrist or psychologist
• Refer patients with ocular exposure to ophthalmologist
• Consult a toxicologist for all paraquat ingestions and for dermal exposures involving more than minimal body surface area
• For patients with specific organ dysfunction, refer to appropriate subspecialist for support (eg, pulmonologist, urologist)

Treatment Options ²

Currently, there are no widely accepted treatment guidelines and no known antidote to paraquat ²

Treatment of paraquat poisoning involves prevention of further absorption and administration of supportive care ¹

• Accomplish topical decontamination of eyes and skin by undressing patient and irrigating with water and mild soap
• Perform gastric decontamination using 1 oral dose of activated charcoal or Fuller’s earth in all cases of paraquat ingestion involving consenting patients with a protected airway
  • Failure to administer gastric decontamination early in patients with ingestion can lead to significant absorption and progression of toxicity ¹
• Early extracorporeal elimination to limit uptake of paraquat into pulmonary tissues is indicated only if it can be started within 1 to 2 hours of paraquat exposure
  • Charcoal hemoperfusion is more effective than hemodialysis but is less available
  • Hemoperfusion followed by continuous venovenous hemofiltration may prolong the time to death ¹⁸
• Administer immunosuppressive therapy to reduce severity of paraquat-induced pulmonary fibrosis ¹⁹
  • Mild to moderate exposure: glucocorticoids and cyclophosphamide ²⁰
  • Severe exposure: combination of methylprednisolone (to reduce inflammation), dexamethasone, and cyclophosphamide ²²¹²²
    • Several small studies suggest that immunosuppressive therapy may reduce mortality rates of severe paraquat poisoning ¹
      • Effective only if begun within a few hours after exposure (more than 4 hours is too long) ⁴
    • More recent study has shown no benefit from high-dose immunosuppression in acute self-poisoning with paraquat ²³
• Provide supportive care ¹
  • Fluid resuscitation as deemed appropriate based on renal function
  • Oxygen therapy only for hypoxic patients expected to die
    • Avoid routine provision of oxygen as it exacerbates pulmonary toxicity

Decontamination and supportive care must be initiated within hours of poisoning or there will be no beneficial effect

Drug therapy

• NOTE: in order to see any potential benefits from these treatments, therapy must be initiated within a few hours of exposure ⁴
• Antineoplastic agent
  • Cyclophosphamide
    • Indicated in patients with risk of, and symptoms consistent with, moderate to severe toxicity ²⁰²¹
      • Cyclophosphamide Solution for injection; Adults: 15 mg/kg IV daily for 2 days has been reported. (Max: 1000 mg/dose) ²³
• Corticosteroids ²⁰²¹
  • Glucocorticoids
    • Methylprednisolone
      • Indicated in patients with risk of, and symptoms consistent with, moderate to severe toxicity ¹
      • Methylprednisolone Sodium Succinate Solution for injection; Adults: 1000 mg IV daily for 3 days. ^20 23
    • Dexamethasone
      • Indicated in patients with risk of, and symptoms consistent with, moderate to severe toxicity ¹
      • Dexamethasone Oral tablet; Adults: 8 mg PO three times daily for 14 days (begin after methylprednisolone administration is complete)

Nondrug and supportive care

Oxygen therapy

• Administer oxygen only for palliative purposes in hypoxic patients who are expected to die ²
• Supplemental oxygen can cause progression of pulmonary fibrosis; therefore, do not administer it to patients who may survive the acute exposure ¹

Fluid resuscitation ²

• IV administration of isotonic fluid for cardiovascular support, to prevent acute kidney injury, and to augment toxin elimination
• 15 to 20 mL/kg over 15 to 30 minutes repeated as necessary until a high urine output is obtained

Procedures

Hemoperfusion, hemofiltration, or hemodialysis

General explanation

• Hemoperfusion involves extracorporeal elimination of paraquat by circulating blood through activated charcoal filter cartridges to limit pulmonary uptake ²²⁴
  • Reduces circulating paraquat concentrations
  • Ineffective if serum concentration is 3 mg/L or higher ¹⁸
  • Only effective when initiated in the first 1 to 2 hours, when peak plasma concentrations occur
  • Perform two 8-hour courses of activated charcoal hemoperfusion within 24 hours of paraquat ingestion ¹
• Continuous venovenous hemofiltration may prolong survival of patients and improve stability of circulatory system, allowing further treatment ²⁵
• Treatment with combined continuous venovenous hemofiltration and hemoperfusion may significantly improve 90-day survival rates ²⁶

Indication

• Indicated in patients presenting with severe toxicity from paraquat ingestion if treatment can start within 1 to 2 hours of ingestion ²⁷

Contraindications

• Hemodynamic instability

Decontamination (gastric, ocular, or dermal)

General explanation

• Gastric decontamination
  • Nasogastric suction with a soft, small-gauge tube ¹
  • Administer an antiemetic before administration of an adsorbent agent
    • Ondansetron (antiemetic) ¹
      • Adult dose: 4 to 8 mg IV ¹
      • Pediatric dose: 0.15 mg/kg IV ¹
  • Administer an adsorbent agent
    • Activated charcoal ¹
      • Adult dose: 50 to 100 g ¹
      • Pediatric dose: 1 g/kg ¹
• Ocular decontamination
  • Remove contact lenses
  • Irrigation with saline or sterile water ¹
    • Ocular irrigation typically is only necessary for 10 to 15 minutes
      • If burning sensation is present after 15 minutes of irrigation, continued irrigation is necessary until burning has resolved
      • Mandatory ophthalmologic evaluation determines if corrosive injury requires additional irrigation
• Dermal decontamination
  • Remove contaminated clothing and wash the contact area thoroughly with soap and water ¹

Indication

• All patients presenting with paraquat toxicity or with history of paraquat ingestion or exposure (whether inhalational, dermal, or ocular)

Monitoring

• If available, use thoracic high-resolution CT to evaluate paraquat-induced lung injury in patients presenting with paraquat poisoning who survive for 1 week ²⁴
  • CT may be useful in detecting early lung fibrosis or assessing long-term damage in survivors
• Measuring pulmonary function and serum creatinine level allows monitoring of progression of lung and kidney injury and recovery. Measuring more frequently than every 2 to 3 days is not helpful

What are the Complications of Paraquat Toxicity?

• Acute renal failure
  • Acute tubular injury resulting in necrosis ¹
    • Largely reversible with fluid resuscitation ¹
    • Hemodialysis for oliguric renal failure is only occasionally necessary ¹
• Respiratory failure ²¹
  • In patients with pulmonary involvement, acute alveolitis may progress over the course of 1 to 3 days, followed by secondary, rapidly progressing fibrosis ²
  • Fibrotic lesions, once established, prevent gas exchange, resulting in severe hypoxia and anoxia ²
• Perforation and mediastinitis and/or pneumomediastinum ²
  • May result as complication of mucosal lesions in pharynx, esophagus, and stomach ²
    • Lesions may also cause bleeding
• Death

What is the Prognosis of Paraquat Toxicity?

• Patients who survive more than 3 months after paraquat ingestion with stable vital signs and stable lung function rarely die of secondary paraquat-related issues ⁴
• Overall mortality is approximately 50% to 100% ²¹
  • In cases of intentional ingestion, mortality approaches 100% ¹⁸
  • Mortality is greater than 50% in patients with moderate to severe toxicity ²
  • Mortality is significantly higher in patients with renal failure ⁴
  • Patients with plasma paraquat levels less than 2, 0.6, 0.3, 0.16, and 0.1 mg/L at 4, 6, 10, 16, and 24 hours after paraquat ingestion, respectively, have the lowest mortality ⁴
• In patients with severe paraquat toxicity, death occurs within hours to days (24-48 hours) ¹
• Time until negative result on urine dithionite test predicts prognosis; the longer it takes to reach a negative result, the poorer the prognosis, with higher risk of essential organ failure and death ⁴
  • Longer than 34.5 hours is associated with a 100% incidence of acute kidney injury and an 85% incidence of respiratory failure ⁴

Screening and Prevention

Prevention

• Many paraquat formulations contain an emetic to stimulate autodecontamination and prevent absorption of potentially toxic dosages

References

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