Paraquat Poisoning

Quick Answer

Paraquat (1,1'-dimethyl-4,4'-bipyridylium) is a highly toxic bipyridyl herbicide with 60-90% mortality. Toxicity results from redox cycling generating superoxide radicals, causing lipid peroxidation and multi-organ damage. Lungs are primary target due to active accumulation in alveolar cells via polyamine transport system.

Management principles:

• Decontamination within 1-2 hours (Fuller's Earth or activated charcoal 1 g/kg)
• Charcoal hemoperfusion within 4-6 hours (superior to hemodialysis)
• RESTRICT OXYGEN unless PaO₂ below 40-50 mmHg (oxygen accelerates free radical generation)
• Immunosuppressive therapy for pulmonary fibrosis (pulse methylprednisolone + cyclophosphamide)
• Use Proudfoot nomogram and urine dithionite test for prognosis

Australia context: Paraquat is Schedule 7 (dangerous poison) with restricted use. APVMA proposed ban in 2024 due to acute toxicity and Parkinson's disease link. New Zealand banned paraquat in 2021.

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ACEM Exam Focus

Primary Written (MCQ)

Common themes:

• Mechanism of action: redox cycling, NADPH depletion, superoxide generation
• Selective pulmonary toxicity via polyamine transport system
• Oxygen restriction rationale and thresholds
• Decontamination timing and agents
• Prognostic indicators (Proudfoot curve, dithionite test)
• Differential of pulmonary fibrosis

Key facts to memorise:

• Lethal dose: 10-15 mL of 20% solution (approximately 20-40 mg/kg ion)
• Peak plasma concentration: 1-4 hours post-ingestion
• Renal excretion: 90% unchanged within 24 hours (if kidneys functioning)
• Pulmonary fibrosis: develops 2-14 days post-ingestion
• Mortality: below 20 mg/kg (mild, 0%), 20-40 mg/kg (moderate, 70% death in 2-4 weeks), greater than 40 mg/kg (fulminant, death in 24-72 hours)

Primary Viva

Sample question: "A 35-year-old farmer presents after ingesting paraquat. Discuss the pathophysiology of paraquat toxicity and explain why the lungs are selectively damaged."

Expected domains:

1. Chemical structure and properties (bipyridyl cation, redox cycling)
2. Cellular uptake mechanisms (NADPH-dependent enzymes, polyamine transporters)
3. Free radical generation (superoxide, hydroxyl radicals, hydrogen peroxide)
4. Lipid peroxidation and membrane destruction
5. Organ-specific toxicity (lungs, kidneys, liver)
6. Oxygen paradox and clinical implications

Fellowship Written (SAQ)

Typical question patterns:

• "A 28-year-old presents 3 hours after intentional ingestion of paraquat. Outline your management approach."
• "Explain the role of immunosuppressive therapy in paraquat poisoning."
• "Discuss the prognostic indicators in paraquat poisoning and their clinical utility."

Mark allocation guide:

• Decontamination (20%): timing, agents, contraindications
• Enhanced elimination (20%): hemoperfusion vs dialysis, timing
• Oxygen management (15%): restriction rationale, thresholds
• Immunosuppression (20%): Lin protocol, indications, monitoring
• Prognostication (15%): Proudfoot curve, dithionite test, clinical factors
• Disposition (10%): admission criteria, palliative care

Fellowship OSCE

Station types:

1. Communication: Breaking bad news about fatal prognosis to patient's family
2. Procedures: Nasogastric tube placement for decontamination
3. Resuscitation: Managing acute respiratory failure in paraquat poisoning
4. Clinical reasoning: Interpreting plasma paraquat levels and planning management

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Key Points

1. Redox cycling is central to toxicity: paraquat reduced by NADPH-dependent enzymes, generates superoxide radicals, depletes glutathione, and causes lipid peroxidation

2. Lung-selective toxicity due to active accumulation in alveolar type I and II cells via polyamine transport system (concentrations 10× plasma)

3. Oxygen restriction is critical: maintain SpO₂ 85-88% if tolerated, only give oxygen if PaO₂ below 40-50 mmHg or severe respiratory distress

4. Time-critical decontamination: Fuller's Earth (15% suspension) or activated charcoal (1 g/kg) within 1-2 hours; gastric lavage only if within 1 hour of life-threatening ingestion

5. Hemoperfusion is superior to hemodialysis (clearance 100-150 mL/min vs below 50 mL/min) but must be initiated within 4-6 hours before tissue distribution

6. Prognostication: Proudfoot nomogram (plasma paraquat vs time) and urine dithionite test (dark navy blue = greater than 10 mg/L = fatal) are most reliable predictors

7. Immunosuppressive therapy: Pulse methylprednisolone 1 g/day ×3 days + cyclophosphamide 15 mg/kg/day ×2 days, repeated if PaO₂ drops below 60 mmHg

8. Australia/NZ: Paraquat banned in NZ (2021), under review in Australia (APVMA proposed ban 2024), both have strict regulatory frameworks

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Epidemiology

Global Patterns

Paraquat is a major cause of fatal herbicide poisoning worldwide, particularly in agricultural regions. Mortality rates range from 60-90% depending on the amount ingested and timeliness of treatment.

Incidence and burden:

• High prevalence in Asia-Pacific (China, Sri Lanka, Southeast Asia) due to agricultural use
• Declining in Western countries following regulatory restrictions and formulation changes
• Intentional self-poisoning accounts for 70-80% of cases (suicide)
• Accidental occupational exposure 15-20%, mostly dermal
• Paediatric ingestions 5-10% (mistaking coloured solution for beverage)

Time trends:

• Sri Lanka: paraquat responsible for 5-10% of total suicides during peak use
• Taiwan: decreased mortality after formulation changes and regulatory restrictions
• Australia: declining incidence with restricted Schedule 7 availability
• New Zealand: effectively eliminated after 2021 ban

Australian Context

• Schedule 7 Dangerous Poison: restricted to licensed applicators
• Products: Gramoxone, Nuquat (typically 20% w/v solutions)
• 2024 APVMA proposal: wide-scale ban due to acute toxicity and Parkinson's disease association
• Public consultation: completed mid-2024, final decision pending

Incidence:

• Australian Poisons Information Centre (NSW) reports: 100-150 cases annually
• Mortality: 40-60% in Australian series (lower than global due to earlier presentation and intensive care availability)
• Agricultural regions: higher incidence (Queensland, NSW, Victoria grain belts)

Occupational exposure:

• Farm workers, horticulturalists, golf course maintainers
• Peak season: spring-summer (spraying season)
• Routes: dermal (most common), inhalation (spray mists), accidental ingestion

New Zealand Context

Regulatory history:

• 2018: Environmental Risk Management Authority (ERMA) review initiated
• 2020: EPA revoked approval for paraquat
• 2021: Phase-out completed, all stock disposed
• Rationale: risks to environment and human health outweigh economic benefits

Impact of ban:

• No new paraquat poisoning cases post-2021
• Replacement herbicides: less toxic alternatives (e.g., glyphosate-based formulations with safer additives)
• Successful public health intervention model

Risk Factors

High-risk groups:

• Agricultural workers (especially those with mental health issues)
• Farmers during peak spraying season
• Rural populations with limited access to mental health services
• Individuals with history of self-harm attempts
• Low socioeconomic status (correlates with pesticide access)

Dose-dependent outcomes:

Outcomes

Survival predictors:

• Time to presentation (earlier = better survival)
• Plasma paraquat concentration (Proudfoot curve)
• Renal function (creatinine trajectory)
• Amount ingested (patient/stwitness report)
• Age and comorbidities

Long-term survivors:

• Survivors of moderate ingestions often have permanent pulmonary fibrosis
• Progressive restrictive lung disease
• Reduced exercise capacity
• Oxygen dependence possible (though paradoxically detrimental)
• Long-term follow-up required (lung function tests, imaging)

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Pathophysiology

Chemical Properties

Structure and properties:

• Chemical name: 1,1'-dimethyl-4,4'-bipyridylium dichloride
• Molecular weight: 257.2 g/mol
• Highly water-soluble, rapidly absorbed from GI tract
• Redox-active bipyridyl cation: undergoes cyclic reduction-oxidation
• Blue-green colour added to prevent accidental ingestion
• Stenchant (bitter agent) and emetic added to formulations

Pharmacokinetics:

• Absorption: rapid GI absorption, peak plasma 1-4 hours
• Distribution: volume of distribution 1.2-1.6 L/kg (initially, then increases with tissue binding)
• Protein binding: minimal (below 10%)
• Metabolism: minimal hepatic metabolism
• Elimination: 90% renal excretion unchanged within 24 hours (if normal renal function)
• Half-life: 12-120 hours (prolonged with renal failure and tissue redistribution)

Toxicodynamics: Redox Cycling

The primary mechanism of paraquat toxicity is redox cycling, leading to massive oxidative stress through generation of reactive oxygen species (ROS).

Step 1: Cellular uptake

• Paraquat (PQ²⁺) enters cells via passive diffusion
• In lungs: actively transported via polyamine uptake system (concentrates 10× plasma)
• Reduced intracellularly by NADPH-dependent enzymes (cytochrome P450 reductase, NADPH-cytochrome c reductase)

Step 2: Redox reduction

PQ²⁺ + NADPH → PQ⁺• (paraquat radical) + NADP⁺

Step 3: Oxidation by molecular oxygen

PQ⁺• + O₂ → PQ²⁺ + O₂⁻• (superoxide radical)

Step 4: Free radical cascade

• Superoxide converted to hydrogen peroxide (via superoxide dismutase)
• Hydrogen peroxide + iron (Fenton reaction) → hydroxyl radical (•OH)
• Hydroxyl radical: most damaging ROS, attacks all cellular components

Step 5: Antioxidant depletion

• Continuous redox cycling depletes NADPH
• NADPH required to maintain glutathione in reduced state (GSH)
• GSH depletion: loss of primary antioxidant defence
• Inability to detoxify ROS → unchecked oxidative damage

Key references:

• Gawarammana IB, Buckley NA. Br J Clin Pharmacol. 2011;72:730-8 [PMID: 21545415]
• Dinis-Oliveira RJ et al. Crit Rev Toxicol. 2008;38:13-71 [PMID: 18259983]

Lipid Peroxidation

Mechanism:

• Hydroxyl radicals attack polyunsaturated fatty acids in cell membranes
• Initiation: •OH + LH → L• + H₂O (lipid radical formation)
• Propagation: L• + O₂ → LOO• (lipid peroxyl radical)
• Chain reaction: LOO• + LH → LOOH + L• (perpetuates damage)
• Termination: antioxidants (GSH, vitamin E) donate hydrogen to break chain

Consequences:

• Membrane destruction: loss of cell integrity, increased permeability
• Mitochondrial damage: impaired ATP production, release of pro-apoptotic factors
• Enzyme inactivation: critical cellular functions disrupted
• DNA damage: strand breaks, mutations, cell death

Organ-specific effects:

Lungs (primary target):

• Alveolar type I and II cells: high polyamine transporter density → high paraquat accumulation
• Early phase (1-5 days): alveolitis, pulmonary edema, haemorrhage
• Late phase (5-14 days): fibroblast proliferation, collagen deposition
• End stage: irreversible pulmonary fibrosis ("paraquat lung")
• Radiology: ground-glass opacities → consolidation → honeycombing
• Pathology: diffuse alveolar damage, fibrosis, cyst formation

Kidneys:

• Acute tubular necrosis due to direct toxicity
• Renal failure develops 24-48 hours post-ingestion
• Impaired excretion: reduces paraquat clearance, prolongs toxicity
• Elevated creatinine correlates with mortality

Liver:

• Centrilobular necrosis
• Transaminitis, jaundice
• Usually mild compared to lung and kidney injury

Other organs:

• Heart: myocarditis, arrhythmias (high-dose ingestions)
• Brain: Parkinsonian features (chronic occupational exposure)
• Gastrointestinal: corrosive injury, ulceration, perforation

The Oxygen Paradox

Why oxygen is harmful in paraquat poisoning:

The paraquat redox cycle is oxygen-dependent:

PQ⁺• + O₂ → PQ²⁺ + O₂⁻•

• More oxygen = more substrate for redox cycling
• Accelerated superoxide generation
• Exacerbated lipid peroxidation
• Accelerated pulmonary fibrosis

Clinical implications:

• Permissive hypoxia: tolerate lower SpO₂ (85-88% if patient comfortable)
• Avoid routine oxygen supplementation
• Only administer oxygen if:
  • PaO₂ below 40-50 mmHg
  • Severe respiratory distress with altered mental status
  • Terminal phase for comfort care

Evidence:

• Gawarammana IB, Buckley NA. Br J Clin Pharmacol. 2011 [PMID: 21545415]
• Dinis-Oliveira RJ et al. Crit Rev Toxicol. 2008 [PMID: 18259983]

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Clinical Features

Time-Dependent Presentation

The clinical course of paraquat poisoning follows a predictable pattern based on dose and time elapsed.

Immediate (0-6 hours):

Gastrointestinal (first and most common):

• Burning sensation in mouth, throat, and oesophagus
• Nausea, vomiting (often repetitive and severe)
• Abdominal pain (epigastric, diffuse)
• Paraquat tongue: mucosal ulceration, sloughing, necrosis (24-48 hours)
• Dysphagia, odynophagia (oesophageal injury)

Early phase (6-24 hours):

Renal:

• Acute kidney injury (AKI) develops 12-48 hours
• Acute tubular necrosis on biopsy
• Oliguria, rising creatinine (greater than 100 μmol/L/day)
• Electrolyte disturbances: hyperkalaemia, metabolic acidosis

Hepatic:

• Mild transaminitis (ALT, AST 2-5× ULN)
• Jaundice (moderate ingestions)
• Usually self-limiting if patient survives initial phase

Cardiovascular (high-dose fulminant):

• Hypotension, shock
• Arrhythmias, myocarditis
• Cardiac arrest (within 24-48 hours)

Subacute phase (2-14 days):

Pulmonary (dominant clinical feature):

• Progressive dyspnoea (initially mild, then severe)
• Dry cough
• Hypoxaemia (gradual SpO₂ decline)
• Respiratory distress

Radiological evolution:

• Days 1-3: often normal or subtle hazy opacities
• Days 4-7: ground-glass opacities, interstitial infiltrates
• Days 7-14: consolidation, cyst formation
• greater than 14 days: honeycombing, traction bronchiectasis (fibrosis)

Late phase (greater than 14 days):

Pulmonary fibrosis (if survived acute phase):

• Progressive dyspnoea on exertion
• Restrictive lung pattern (↓FVC, ↓TLC)
• Reduced diffusion capacity (↓DLCO)
• Possible oxygen dependence (paradoxically detrimental)

Multi-organ sequelae (rare survivors):

• Chronic kidney disease (stage 3-4)
• Progressive restrictive lung disease
• Liver dysfunction (mild)

Physical Examination

General:

• May appear ill, distressed, or relatively well initially (depending on dose)
• Tachypnoea (pulmonary involvement)
• Hypotension (shock, high-dose ingestions)
• Fever (usually absent unless complications)

Head and neck:

• Paraquat tongue: oral mucosal ulceration, erythema, sloughing
• Oropharyngeal inflammation
• Possible esophageal burns (dysphagia, drooling)

Respiratory:

• Early: may be normal
• Subacute: tachypnoea, reduced air entry, fine crackles
• Late: signs of pulmonary fibrosis (bilateral crackles, reduced expansion)

Abdominal:

• Epigastric tenderness (gastritis, pancreatitis)
• Possible peritonitis (perforation, rare)
• Hepatomegaly (if liver involvement)

Neurological:

• Early: usually normal (unless hypoxic or in coma from massive ingestion)
• Late: altered mental status (hypoxia, sepsis)

Clinical Staging

Stage 1: Local gastrointestinal irritation (0-24 hours)

• Mucosal burns, nausea, vomiting
• May be only sign in mild ingestions
• Renal function may begin to deteriorate

Stage 2: Multi-organ dysfunction (1-5 days)

• Acute kidney injury (peak 2-3 days)
• Acute liver injury
• Possible cardiovascular collapse (fulminant ingestions)
• Pulmonary infiltrates may begin to appear

Stage 3: Pulmonary fibrosis (5-14 days)

• Progressive dyspnoea
• Hypoxaemia
• Radiographic progression to fibrosis
• Main cause of death in moderate ingestions

Stage 4: Chronic sequelae (greater than 14 days, if survived)

• Pulmonary fibrosis (irreversible)
• Chronic kidney disease
• Reduced exercise tolerance

Differential Diagnosis

Other herbicide/pesticide poisonings:

• Glyphosate (Roundup): corrosive GI injury, renal failure, pulmonary oedema, but no fibrosis
• Organophosphates: cholinergic crisis (SLUDGE, muscle weakness, bradycardia)
• Paraquat vs diquat: diquat similar mechanism but causes neurotoxicity and cerebral oedema

Other causes of pulmonary fibrosis:

• Idiopathic pulmonary fibrosis
• Connective tissue disease (scleroderma, rheumatoid arthritis)
• Drug-induced (nitrofurantoin, methotrexate, amiodarone)
• Radiation pneumonitis
• Hypersensitivity pneumonitis

Other causes of acute kidney injury:

• Sepsis, ATN from other nephrotoxins
• Rhabdomyolysis
• Obstructive uropathy
• Glomerulonephritis

Clues to paraquat:

• History of herbicide ingestion (often intentional)
• Paraquat tongue (oral ulceration)
• Rapidly progressive pulmonary fibrosis (unusual timeline)
• Known agricultural context

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Investigations

Immediate (ED Presentation)

Bedside tests:

Urine sodium dithionite test:

• Rapid bedside qualitative/semi-quantitative test
• Mix urine with sodium dithionite and sodium hydroxide
• Blue colour reaction: paraquat reduced to blue radical cation
• Colour intensity correlates with concentration:
  • "Light blue/green: below 5 mg/L (possible survival)"
  • "Moderate blue: 5-10 mg/L (guarded prognosis)"
  • "Dark navy blue/black: greater than 10 mg/L (fatal outcome likely)"
• Prognostic value: high sensitivity and specificity for mortality

References:

• Scherrmann JM et al. Hum Toxicol. 1987 [PMID: 3570116]

Arterial blood gas:

• Assess for hypoxaemia (PaO₂, SpO₂)
• Target: PaO₂ 50-80 mmHg if tolerated (permissive hypoxia)
• Metabolic acidosis (if shock, renal failure)
• Base deficit greater than 5 mmol/L = poor prognostic sign

ECG:

• Baseline, especially if arrhythmias suspected
• May show sinus tachycardia, non-specific changes
• Ventricular arrhythmias in severe ingestions

Laboratory tests:

Paraquat plasma concentration:

• Gold standard for prognostication
• Proudfoot nomogram: plots concentration vs time since ingestion
• Thresholds for survival (Proudfoot curve):
  • 4 hours: below 2.0 mg/L
  • 6 hours: below 0.9 mg/L
  • 10 hours: below 0.3 mg/L
  • 16 hours: below 0.16 mg/L
  • 24 hours: below 0.1 mg/L
• Below curve: high probability of survival
• Above curve: high probability of death
• Reference: Proudfoot AT et al. Lancet. 1979 [PMID: 89454]

Alternative nomograms:

• Hart nomogram (slightly more conservative)
• Scherrmann nomogram (European use)

Renal function:

• Serum creatinine, urea, electrolytes
• Rapid rise (greater than 100 μmol/L/day) = poor prognosis
• Acute tubular necrosis pattern: elevated creatinine, hyperkalaemia, metabolic acidosis
• Monitor for hyperkalaemia (may require dialysis)

Liver function:

• ALT, AST (mild-moderate elevation 2-5× ULN)
• Bilirubin (jaundice in moderate ingestions)
• INR (usually normal unless severe liver injury)

Complete blood count:

• Leucocytosis (stress response, infection)
• Anaemia (if GI bleeding, chronic illness)
• Thrombocytopenia (rare, if severe illness)

Inflammatory markers:

• CRP, ESR (elevated due to systemic inflammation)
• May correlate with pulmonary inflammation

Imaging

Chest X-ray:

• Day 0-3: often normal or subtle hazy opacities
• Day 4-7: ground-glass opacities, interstitial infiltrates
• Day 7-14: consolidation, possible cyst formation
• greater than 14 days: honeycombing, traction bronchiectasis (fibrosis)

CT chest (if available):

• More sensitive than CXR
• Early: ground-glass opacities, septal thickening
• Late: traction bronchiectasis, honeycombing
• Can assess extent of fibrosis in survivors

Abdominal X-ray (if perforation suspected):

• Free air under diaphragm
• Dilated bowel loops (ileus)

Ultrasound:

• Renal (size, obstruction)
• Abdominal (free fluid, organ injury)
• Limited utility in paraquat

Additional Tests

Toxicology screen:

• Exclude co-ingestants (especially important in intentional ingestions)
• Common co-ingestants: alcohol, other pesticides, medications

Cultures:

• Blood, urine, sputum (if infection suspected)
• Immunosuppression increases infection risk

Pregnancy test (if indicated):

• All women of childbearing age
• Paraquat crosses placenta, high fetal mortality

Lung function tests (survivors):

• Spirometry (FVC, FEV₁)
• Lung volumes (TLC, RV)
• Diffusion capacity (DLCO)
• Restrictive pattern expected

Prognostic Indicators

Strong predictors of mortality:

1. Plasma paraquat concentration (Proudfoot curve)
2. Urine dithionite test (dark navy blue = fatal)
3. Renal function (rapidly rising creatinine)
4. Amount ingested (greater than 40 mg/kg = fulminant)
5. Time to presentation (delayed = poor prognosis)

Moderate predictors:

• Paraquat tongue (corrosive injury severity)
• Age (greater than 60 years = poorer prognosis)
• Comorbidities (cardiovascular, respiratory, renal)
• PaO₂ trend (rapid decline = pulmonary fibrosis)

Prognostic scoring systems:

Seneviratne score:

• Combines age, amount ingested, renal function, time to presentation
• Higher score = higher mortality

Elenga score:

• Includes creatinine, potassium, and paraquat concentration

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Management

Immediate Stabilisation (ABCDE)

Airway:

• Assess patency, risk of aspiration (vomiting)
• Intubation if:
  • Decreased consciousness (GCS below 8)
  • Respiratory failure (severe hypoxaemia, respiratory distress)
  • Airway protection for gastric lavage/decontamination

Breathing:

• RESTRICT OXYGEN unless PaO₂ below 40-50 mmHg or SpO₂ below 70-80%
• Target SpO₂ 85-88% if tolerated (permissive hypoxia)
• High-flow oxygen contraindicated (accelerates fibrosis)
• Mechanical ventilation if respiratory failure (use lowest FiO₂ possible, typically 21-30%)

Circulation:

• IV access (2 large-bore cannulae)
• Fluid resuscitation for shock
• Blood pressure support (noradrenaline if required)
• Monitor for arrhythmias (ECG, cardiac monitor)

Disability:

• GCS, pupils
• Check for co-ingestants causing CNS depression

Exposure:

• Full examination
• Assess for corrosive burns
• Check for signs of self-harm

Decontamination

Timing is critical:

• Most effective within 1-2 hours of ingestion
• Limited benefit beyond 4 hours

Gastric lavage:

• Indications: life-threatening ingestion, within 1 hour
• Technique: large-bore orogastric tube, aliquots 200-300 mL until clear
• Contraindications: greater than 1 hour post-ingestion, corrosive injury, unprotected airway
• Complications: aspiration, oesophageal perforation
• Evidence: Taiwan study showed benefit if within 1 hour [PMID: 25406004]

Activated charcoal:

• Dose: 1 g/kg (maximum 50 g)
• Form: 1:1 dilution with water or sorbitol
• Frequency: single dose (repeat if massive ingestion)
• Contraindications: unprotected airway, bowel obstruction, ileus
• Evidence: equally effective as Fuller's earth [PMID: 12740110]

Fuller's Earth (bentonite clay):

• Dose: 15% suspension, 1-2 L
• Mechanism: binds paraquat in GI tract, prevents absorption
• Availability: limited in many hospitals (activated charcoal more available)
• Evidence: historical gold standard, charcoal equivalent [PMID: 16169123]

Purgatives (magnesium citrate, sorbitol):

• Sometimes added to charcoal to reduce GI transit time
• Evidence limited

Skin/eye decontamination:

• Copious irrigation with water (if dermal exposure)
• Remove contaminated clothing
• Irrigate eyes for 15-30 minutes (if ocular exposure)

Enhanced Elimination

Charcoal hemoperfusion (CHP):

Mechanism:

• Blood passed through charcoal column
• Paraquat adsorbed onto charcoal surface
• Higher clearance than hemodialysis (100-150 mL/min vs below 50 mL/min)

Indications:

• Plasma paraquat concentration above Proudfoot curve (but not fulminant)
• Within 4-6 hours of ingestion (optimal window)
• Moderately severe ingestions (20-40 mg/kg)

Contraindications:

• Fulminant ingestion (greater than 40 mg/kg) with multi-organ failure
• Presentation greater than 12 hours post-ingestion (limited benefit)
• Terminal phase (palliative care indicated)

Procedure:

• Vascular access: dual-lumen central venous catheter (internal jugular or femoral)
• Blood flow rate: 200-300 mL/min
• Duration: 3-4 hours per session
• Frequency: repeat sessions (daily for 2-3 days) if plasma levels remain high

Complications:

• Thrombocytopenia
• Hypocalcaemia (charcoal binds calcium)
• Hypothermia
• Bleeding, infection

Evidence:

• Systematic review: HP superior to HD for clearance [PMID: 33538133]
• Comparative study: HP outcomes [PMID: 22107457]
• Meta-analysis: survival benefit with early HP [PMID: 25023595]

Hemodialysis (HD):

• Less effective than HP (lower clearance)
• May be used if HP unavailable
• Combined HP + HD sometimes used for "rebound" effect
• Clearance: below 50 mL/min vs HP 100-150 mL/min [PMID: 15570221]

Continuous renal replacement therapy (CRRT):

• CVVH or CVVHDF
• May be combined with HP
• Manage "rebound" (tissue release back into plasma)
• Limited evidence for survival benefit

Immunosuppressive Therapy

Rationale:

• Paraquat causes massive inflammatory response
• Fibroblast proliferation → pulmonary fibrosis
• Immunosuppression may attenuate inflammation and fibrosis

Lin protocol (most widely used):

Induction:

• Methylprednisolone: 1 g IV daily for 3 days
• Cyclophosphamide: 15 mg/kg IV daily for 2 days

Maintenance:

• Dexamethasone: 5 mg IV/PO every 6 hours (after induction)
• Continue if PaO₂ remains above 60 mmHg

Repeat pulses:

• If PaO₂ drops below 60 mmHg
• Repeat methylprednisolone 1 g daily ×3 days
• Repeat cyclophosphamide 15 mg/kg daily ×2 days

Evidence:

• Lin JL et al. Crit Care Med. 2011: RCT, reduced mortality 31.3% vs 85.7% [PMID: 21396123]
• Earlier study: Lin et al. 1999 [PMID: 10359527]
• Cochrane review: may reduce mortality in moderate-to-severe cases [PMID: 25100057]

Adverse effects:

• Immunosuppression → increased infection risk
• Cyclophosphamide: haemorrhagic cystitis, myelosuppression
• Steroids: hyperglycaemia, psychosis, peptic ulcer
• Monitor: CBC, blood glucose, infection surveillance

Controversy:

• Evidence limited to few RCTs (methodological concerns)
• Some systematic reviews question survival benefit
• Not universally adopted (centre-dependent)

Antioxidant Therapy

Rationale:

• Replenish depleted glutathione
• Scavenge free radicals
• Inhibit lipid peroxidation

N-acetylcysteine (NAC):

• Dose: 150 mg/kg IV over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours (standard acetaminophen protocol)
• Mechanism: precursor for glutathione synthesis
• Evidence: animal studies show benefit; clinical efficacy unclear [PMID: 15214051, 21683130]

Vitamin E (α-tocopherol):

• Dose: 400-800 mg PO daily
• Mechanism: lipid-soluble antioxidant, prevents membrane lipid peroxidation
• Evidence: reduces oxidative stress markers in animal models [PMID: 2513444, 15214051]

Sodium salicylate:

• Dose: 100-200 mg/kg/day (experimental)
• Mechanism: scavenges hydroxyl radicals, inhibits NF-κB
• Evidence: Dinis-Oliveira protocol shows lung protection [PMID: 17573489, 18155142]

Deferoxamine (DFO):

• Dose: 10-15 mg/kg/hour continuous infusion
• Mechanism: iron chelation, reduces hydroxyl radical formation (Haber-Weiss reaction)
• Evidence: mixed results, limited clinical use [PMID: 1563701, 8383637]

Current practice:

• NAC often used as adjunct (low risk, possible benefit)
• Vitamin E less commonly used
• Salicylate and deferoxamine primarily experimental
• No strong evidence for routine use

Oxygen Management

Key principle: RESTRICT OXYGEN

Rationale:

• Paraquat redox cycle is oxygen-dependent
• More oxygen = more free radical generation
• Accelerated pulmonary fibrosis

Target saturations:

• Room air: FiO₂ 0.21 (21%)
• Acceptable SpO₂: 85-88% if patient comfortable and mentating well
• Critical threshold: give oxygen only if SpO₂ below 70-80% or PaO₂ below 40-50 mmHg

Guidelines:

• Maintain lowest possible FiO₂ (start 21%)
• Avoid routine oxygen supplementation
• Monitor for hypoxic distress (altered mental status, seizures)
• In terminal phase, oxygen may be given for comfort

Evidence:

• Gawarammana IB, Buckley NA. Br J Clin Pharmacol. 2011 [PMID: 21545415]
• Dinis-Oliveira RJ et al. Crit Rev Toxicol. 2008 [PMID: 18259983]

Mechanical ventilation:

• Use lowest FiO₂ possible (21-30%)
• Permissive hypoxia strategy
• Lung-protective ventilation (low tidal volume, PEEP 5-10 cmH₂O)
• High PEEP may be needed for refractory hypoxia (but worsens fibrosis)

Supportive Care

Renal replacement therapy:

• Indicated for:
  • Severe AKI (refractory hyperkalaemia, metabolic acidosis, fluid overload)
  • Oliguria/anuria with uremic symptoms
  • Adjunct to HP (combined HP + HD)
• Modalities: intermittent HD, CRRT (if haemodynamically unstable)

Fluid and electrolyte management:

• Maintenance fluids (1-2 mL/kg/hour)
• Correct electrolyte abnormalities (hyperkalaemia, hypocalcaemia)
• Avoid fluid overload (pulmonary oedema risk)

Infection prevention:

• Broad-spectrum antibiotics if infection suspected
• Prophylactic antibiotics in immunosuppressed patients
• Monitor for sepsis (CRP, procalcitonin, cultures)

Nutritional support:

• Early enteral nutrition if able (NG/NJ tube)
• Total parenteral nutrition if GI tract compromised
• Protein malnutrition risk with critical illness

Psychological support:

• Intentional ingestion: psychiatric assessment
• Safety planning
• Family support, counselling

Palliative Care

Indications:

• Fulminant ingestion (greater than 40 mg/kg) with multi-organ failure
• Plasma paraquat concentration well above Proudfoot curve
• Urine dithionite test: dark navy blue
• Progressive pulmonary fibrosis with respiratory failure
• Patient/family preference

Management:

• Symptom control:
  • "Dyspnoea: low-dose opioids (morphine), fans, positioning"
  • "Pain: analgesics"
  • "Anxiety: benzodiazepines"
• Withdrawal of life-sustaining treatments (if appropriate)
• Family counselling, bereavement support
• Early involvement of palliative care team

---

Prognostication

Proudfoot Nomogram

Principle: plots plasma paraquat concentration vs time since ingestion

Survival zones:

• Below line: high probability of survival
• Above line: high probability of death

Thresholds (approximate):

Reference: Proudfoot AT et al. Lancet. 1979 [PMID: 89454]

Limitations:

• Requires known time of ingestion
• Variable between individuals
• Modified nomograms (Hart, Scherrmann) have slightly different thresholds

Urine Dithionite Test

Procedure:

1. Collect urine sample
2. Add sodium dithionite and sodium hydroxide
3. Observe colour change

Colour interpretation:

• No colour change: paraquat absent or below 1 mg/L
• Light blue/green: 1-5 mg/L (possible survival)
• Moderate blue: 5-10 mg/L (guarded prognosis)
• Dark navy blue/black: greater than 10 mg/L (fatal)

Prognostic value:

• Sensitivity: high for detecting paraquat
• Specificity: moderate (blue colour indicates presence, not prognosis)
• Dark navy blue strongly associated with mortality

Reference: Scherrmann JM et al. Hum Toxicol. 1987 [PMID: 3570116]

Clinical Predictors

Amount ingested:

• below 20 mg/kg: mild, usually recover
• 20-40 mg/kg: moderate, 70-80% mortality
• greater than 40 mg/kg: fulminant, greater than 95% mortality

Time to presentation:

• below 2 hours: best chance for decontamination and HP
• 2-6 hours: limited benefit from interventions
• greater than 6 hours: poor prognosis

Renal function:

• Normal creatinine: good prognosis
• Rapid rise (greater than 100 μmol/L/day): poor prognosis
• Dialysis requirement: very poor prognosis

Paraquat tongue:

• Severe ulceration: high-dose ingestion
• Mild or absent: possible low-dose exposure

Age and comorbidities:

• Age greater than 60: poorer prognosis
• Pre-existing lung, kidney, heart disease: worse outcomes

PaO₂ Trend

Serial PaO₂ measurements:

• Rising PaO₂: stable, no pulmonary fibrosis
• Declining PaO₂: progressive pulmonary fibrosis
• PaO₂ below 60 mmHg: high mortality risk

Clinical correlation:

• PaO₂ greater than 80 mmHg: good prognosis
• PaO₂ 60-80 mmHg: guarded
• PaO₂ below 60 mmHg: poor, consider immunosuppression

Decision-Making Algorithm

Step 1: Assess severity

• Amount ingested (history, stwitness)
• Time since ingestion
• Clinical signs (vitals, paraquat tongue)

Step 2: Obtain prognostic tests

• Urine dithionite test (immediate)
• Plasma paraquat concentration (send urgently)
• Renal function (creatinine trend)

Step 3: Apply Proudfoot nomogram

• Plot plasma level vs time
• Determine if above or below survival line

Step 4: Determine management intensity

---

Disposition

Admission Criteria

All paraquat ingestions require hospital admission

ICU admission:

• Moderate-severe ingestion (20-40 mg/kg)
• Respiratory distress or hypoxaemia
• Renal failure
• Shock
• Requirement for hemoperfusion
• Requirement for immunosuppressive therapy

Ward admission:

• Mild ingestion (below 20 mg/kg)
• Stable vital signs
• Normal renal function
• No respiratory symptoms
• For observation (minimum 48-72 hours)

Discharge criteria:

• Mild ingestion with:
  • Asymptomatic or minimal symptoms
  • Normal renal function
  • Normal plasma paraquat (below Proudfoot curve)
  • No respiratory symptoms
  • Psychiatric clearance (if intentional)
• Follow-up with toxicology service
• Outpatient renal and respiratory function tests

Retrieval Considerations

Rural/remote to tertiary centre:

• Indications for transfer:
  • Requirement for hemoperfusion (not available in most rural hospitals)
  • Requirement for ICU-level care
  • Requirement for immunosuppressive therapy
  • Poor prognostic indicators (need for specialist input)

Royal Flying Doctor Service (RFDS):

• Aeromedical retrieval for remote patients
• Consideration of time-critical interventions (HP within 4-6 hours)
• Telemedicine consultation with toxicology service

Pre-transfer stabilisation:

• Decontamination (if within 2 hours of ingestion)
• Airway protection if required
• IV access, fluids
• Baseline investigations (bloods, urine dithionite test)
• Send plasma paraquat sample (if available)

Follow-Up

Survivors:

• Respiratory: chest X-ray, lung function tests (spirometry, DLCO) at 1, 3, 6 months
• Renal: serum creatinine, urea, electrolytes (monthly for 3 months, then 3-monthly)
• Liver: LFTs (if abnormal)
• Psychiatric: follow-up for intentional ingestion
• Occupational: advice on future paraquat exposure

Long-term sequelae:

• Progressive pulmonary fibrosis (possible late onset)
• Chronic kidney disease
• Reduced exercise tolerance
• Oxygen dependence (rare, paradoxical)

---

Indigenous Health Considerations

Aboriginal and Torres Strait Islander Peoples

Epidemiology:

• Higher rates of pesticide poisoning in rural and remote Aboriginal communities
• Limited access to mental health services in remote communities
• Cultural factors influencing self-harm behaviours
• Language and health literacy barriers

Cultural safety:

• Use Aboriginal Health Workers or cultural liaison officers
• Respect family decision-making processes
• Involve Elders in discussions (if appropriate)
• Consider Men's/Women's business (gender-specific approaches)

Communication:

• Use plain language, avoid medical jargon
• Utilise interpreters if English is not first language
• Allow time for family consultation and decision-making
• Use visual aids (diagrams) to explain concepts

Management considerations:

• Early involvement of Aboriginal Health Services
• Consider cultural protocols around death and dying
• Family presence during resuscitation discussions
• Sensitivity around palliative care discussions

Remote/rural challenges:

• Delayed presentation due to transport barriers
• Limited availability of haemoperfusion in remote hospitals
• Need for aeromedical retrieval to tertiary centres
• Telemedicine consultation with toxicology services

Outcome disparities:

• Higher mortality due to delayed presentation
• Limited access to intensive care and specialised treatments
• Comorbidities (diabetes, cardiovascular disease, CKD) worsen prognosis

Māori Peoples (New Zealand)

Note: Paraquat banned in NZ since 2021, so new cases unlikely. However, legacy considerations:

Cultural safety:

• Involve whānau (family) in discussions
• Respect tikanga Māori (Māori customs)
• Use Māori health providers (Kai Māori services)
• Consider tapu (sacred) restrictions around death

Communication:

• Allow whānau time for consultation and decision-making
• Use karakia (prayers) if appropriate
• Respect spiritual beliefs

Historical context:

• Previous higher rates in rural Māori communities (farming)
• Ban likely to have positive impact on health outcomes

Practical Recommendations

For all Indigenous patients:

1. Early cultural consultation: involve Aboriginal Health Workers/Māori health providers immediately
2. Family involvement: include family in decision-making (with patient consent)
3. Interpreter services: use professional interpreters for language barriers
4. Cultural liaison: facilitate cultural practices where possible
5. Holistic care: consider spiritual, emotional, and social aspects, not just medical
6. Follow-up: ensure culturally appropriate follow-up and support services

---

Remote and Rural Considerations

Challenges in Resource-Limited Settings

Limited diagnostics:

• Plasma paraquat concentration testing often unavailable
• Urine dithionite test: should be available (simple bedside test)
• Limited imaging (CT may not be available)
• Limited laboratory testing (basic bloods only)

Limited treatment options:

• Hemoperfusion usually unavailable in rural hospitals
• Intensive care may have limited capacity
• Limited access to immunosuppressive therapy protocols
• Limited access to specialist toxicology advice

Logistical challenges:

• Delayed presentation due to travel time
• Weather may affect aeromedical retrieval
• Limited staffing overnight
• Transfer coordination delays

Management Strategies

Initial stabilisation (rural hospital):

• ABCDE assessment and stabilisation
• Early decontamination (activated charcoal 1 g/kg) if within 2 hours
• Supportive care (fluids, monitoring)
• Urine dithionite test (for prognosis)
• Blood tests (renal function, LFTs, FBC, electrolytes)

Early telemedicine consultation:

• Contact state poison information centre
• Consult with tertiary toxicology service
• Arrange retrieval if indicated

Retrieval criteria:

• Requirement for hemoperfusion
• Requirement for ICU care
• Moderate-severe ingestion (borderline Proudfoot)
• Poor prognostic indicators (rapidly rising creatinine)

Palliative care in rural settings:

• Early recognition of futile cases
• Communication with family about prognosis
• Symptom management
• Spiritual support
• Family presence at end-of-life

Aeromedical Retrieval

Royal Flying Doctor Service (RFDS):

• 24/7 aeromedical retrieval
• Specialist retrieval teams (critical care, emergency)
• Consideration of time-critical interventions

Pre-retrieval stabilisation:

• Secure airway if required
• IV access, fluids
• Baseline investigations
• Send blood samples for paraquat testing (if available)

In-flight considerations:

• Low oxygen environment (cabin altitude)
• Need for oxygen monitoring
• Potential for rapid deterioration

Rural Health Service Protocols

Standard operating procedures:

• Early activation of poison information centre
• Use of clinical decision tools (dithionite test, clinical predictors)
• Clear referral pathways to tertiary centres
• Documentation for retrieval requests

Training and education:

• Regular training on pesticide poisoning
• Familiarity with paraquat management principles
• Access to clinical guidelines

Equipment and supplies:

• Activated charcoal available
• Gastric lavage equipment (if indicated)
• Basic ICU equipment (ventilator, monitors)

---

Occupational Exposure

Routes of Exposure

Dermal (most common occupational route):

• Absorption through intact skin (slower than ingestion)
• Significantly increased absorption through damaged skin (abrasions, cuts, rashes)
• Causes local skin irritation, burns
• Systemic toxicity possible with prolonged exposure

Inhalation:

• Spray mists during application
• Droplet size determines alveolar deposition
• Most droplets too large for deep alveolar penetration
• Chronic exposure may cause respiratory impairment

Ocular:

• Splashes to eyes
• Local irritation, conjunctivitis
• Corneal damage possible

Accidental ingestion:

• Mistaking coloured solution for beverage
• Poor labelling, storage
• Eating/drinking without hand washing

Risk Factors

Occupations:

• Farm workers, horticulturalists
• Agricultural contractors
• Golf course maintainers
• Pest control operators

Work practices:

• Improper PPE use
• Poor ventilation during mixing and application
• Eating/drinking during work
• Reusing containers for food/water storage

Environmental factors:

• Hot, humid weather (increases sweating, dermal absorption)
• Wind (drift during spraying)
• Confined spaces

Prevention

Personal protective equipment (PPE):

• Waterproof gloves (nitrile, neoprene)
• Long-sleeved protective clothing
• Goggles or face shield
• Respiratory protection (if using concentrated formulations)
• Boots

Work practices:

• Mix in well-ventilated area
• Use dedicated equipment (never reuse for food/water)
• Wash hands before eating/drinking
• Shower after work
• Change contaminated clothing

Storage:

• Lockable storage
• Clearly labelled containers
• Away from food and water supplies
• Keep out of reach of children

Training:

• Safe handling procedures
• First aid for exposure
• Recognition of toxicity symptoms

Management of Occupational Exposure

Dermal exposure:

• Remove contaminated clothing immediately
• Copious irrigation with water for at least 15 minutes
• Wash with mild soap (avoid scrubbing if skin damaged)
• Monitor for systemic toxicity (renal function, respiratory symptoms)
• Observe for 24-48 hours (delayed onset possible)

Inhalation exposure:

• Remove from exposure area
• Fresh air, rest
• Monitor for respiratory symptoms
• Chest X-ray if symptomatic
• Consider pulmonary function tests if significant exposure

Ocular exposure:

• Immediate copious irrigation (15-30 minutes)
• Use eye wash station or IV fluid
• Consult ophthalmology
• Monitor for corneal damage

Ingestion (accidental occupational):

• Treat as intentional ingestion (dose-dependent)
• Full decontamination protocol
• Prognostication (amount ingested usually lower than intentional)

Long-Term Health Effects

Parkinson's disease:

• Epidemiology: farmers using paraquat have 2-2.5× increased risk
• Mechanism: paraquat structurally similar to MPP⁺ (dopaminergic neurotoxin)
• Evidence: Agricultural Health Study (AHS) [PMID: 21292100]
• Meta-analysis: confirms association [PMID: 24522401]

Chronic respiratory impairment:

• Reduced lung function (FVC, FEV₁)
• Increased risk of chronic obstructive pulmonary disease (COPD)
• Possible fibrosis after repeated exposures

Other effects:

• Skin: chronic dermatitis
• Eyes: chronic conjunctivitis
• Systemic: possible kidney and liver dysfunction (chronic)

Evidence:

• Dermal occupational case studies [PMID: 1537471]
• General occupational review [PMID: 22369150]
• PPE effectiveness studies [PMID: 8530858]

---

Special Populations

Paediatric Patients

Epidemiology:

• Accidental ingestions (mistaking coloured solution for beverage)
• 5-10% of paraquat poisonings
• Usually lower doses (smaller volume ingested)

Clinical features:

• Similar to adults, but dose-dependent
• May present with nonspecific symptoms (vomiting, abdominal pain)
• Rapid progression if significant ingestion

Management:

• Same decontamination protocol (activated charcoal 1 g/kg)
• Aggressive supportive care
• Early involvement of paediatric ICU
• Dose adjustments for medications (cyclophosphamide, steroids)

Prognosis:

• Generally better with lower doses
• Higher risk of long-term sequelae (pulmonary fibrosis, CKD)

Evidence: Limited paediatric-specific data; extrapolated from adult studies

Pregnancy

Epidemiology:

• Rare (usually intentional ingestion)
• High maternal mortality (30-70%)
• Very high fetal mortality (greater than 90%)

Placental transfer:

• Paraquat readily crosses placenta
• Fetal concentrations may equal or exceed maternal
• Amniotic fluid accumulation possible

Clinical outcomes:

• Maternal: similar to non-pregnant (multi-organ failure, pulmonary fibrosis)
• Fetal: high mortality (death within hours to days)
• Teratogenicity: limited data (most pregnancies don't continue to term)

Management:

• Focus on maternal stabilisation (primary patient)
• Fetal monitoring (cardiotocography)
• Consider emergency delivery if viable gestation (greater than 24-26 weeks) and maternal prognosis poor
• Counselling: discuss poor fetal prognosis

Evidence:

• Case series of 9 pregnancies: 8 mothers survived, all 9 fetuses died [PMID: 12920995]
• Review of 25 cases: maternal mortality 44%, fetal mortality 100% [PMID: 15204271]
• Rare neonatal survival case report [PMID: 22567112]
• Pregnancy survival case (fetal death day 4) [PMID: 25133100]

Elderly Patients

Epidemiology:

• Higher rates of intentional ingestion
• Higher mortality due to comorbidities

Clinical considerations:

• Reduced renal function (slows paraquat elimination)
• Comorbidities (cardiovascular, respiratory, renal) worsen prognosis
• Reduced physiological reserve

Management:

• Aggressive supportive care
• Careful medication dosing (renal/hepatic impairment)
• Higher threshold for aggressive interventions (HP, immunosuppression)
• Earlier consideration of palliative care

Prognosis:

• Poorer than younger patients
• Higher likelihood of multi-organ failure

---

Pitfalls and Pearls

Common Mistakes

Decontamination errors:

• Delaying decontamination beyond 2 hours (limited benefit)
• Using inadequate dose of activated charcoal (should be 1 g/kg)
• Performing gastric lavage greater than 1 hour post-ingestion (risk of aspiration without benefit)
• Neglecting skin/eye decontamination after occupational exposure

Oxygen therapy errors:

• Giving routine oxygen (accelerates fibrosis)
• Targeting normal SpO₂ (should tolerate 85-88%)
• Using high FiO₂ on mechanical ventilation

Elimination errors:

• Delaying hemoperfusion beyond 6 hours (limited benefit)
• Using hemodialysis alone (less effective than HP)
• Not repeating HP sessions (rebound effect)

Immunosuppression errors:

• Overuse in fulminant cases (no benefit, adds toxicity)
• Underuse in moderate cases (may prevent pulmonary fibrosis)
• Not monitoring for infections and adverse effects

Prognostication errors:

• Relying solely on amount ingested (unreliable)
• Not obtaining plasma paraquat concentration (gold standard)
• Ignoring urine dithionite test (rapid bedside prognostication)
• Failing to recognise fulminant cases (palliative care indicated)

Pearls for Practice

Time-critical interventions:

• Decontamination: within 1-2 hours
• Hemoperfusion: within 4-6 hours
• Immunosuppression: consider if PaO₂ drops below 60 mmHg

Oxygen management:

• RESTRICT OXYGEN: only give if PaO₂ below 40-50 mmHg or SpO₂ below 70-80%
• Permissive hypoxia: SpO₂ 85-88% acceptable if patient comfortable

Prognostication:

• Urine dithionite test: rapid bedside test (dark navy blue = fatal)
• Proudfoot nomogram: most reliable prognostic tool
• Renal function: rapidly rising creatinine = poor prognosis

Management decisions:

• Mild ingestion (below 20 mg/kg): observation, decontamination
• Moderate ingestion (20-40 mg/kg): decontamination + HP + immunosuppression
• Fulminant ingestion (greater than 40 mg/kg): palliative care

Indigenous health:

• Early involvement of Aboriginal Health Workers/Māori health providers
• Include family in decision-making
• Consider cultural protocols

Remote/rural:

• Early telemedicine consultation with poison information centre
• Arrange retrieval early if hemoperfusion indicated
• Use dithionite test for prognosis (simple bedside test)

---

Viva Practice

Viva Scenario 1: Pathophysiology

Stem: "A 38-year-old farmer presents 2 hours after ingesting approximately 50 mL of paraquat. He is currently stable with normal vital signs. Discuss the pathophysiology of paraquat toxicity."

Expected discussion:

Q1: What is the chemical structure and mechanism of action of paraquat?

Model answer:

• Paraquat is a bipyridyl herbicide (1,1'-dimethyl-4,4'-bipyridylium)
• Mechanism: redox cycling generating reactive oxygen species (ROS)
• Reduced intracellularly by NADPH-dependent enzymes to paraquat radical
• Radical reacts with oxygen to form superoxide radical and regenerate parent paraquat
• Continuous cycle depletes NADPH and glutathione, causing oxidative stress
• References: Gawarammana IB, Buckley NA. Br J Clin Pharmacol. 2011 [PMID: 21545415]; Dinis-Oliveira RJ et al. Crit Rev Toxicol. 2008 [PMID: 18259983]

Q2: Why are the lungs selectively damaged in paraquat poisoning?

Model answer:

• Active accumulation in alveolar type I and II cells via polyamine transport system
• Lung concentrations reach 10× plasma levels
• Redox cycling generates superoxide radicals locally
• Causes lipid peroxidation of cell membranes
• Leads to alveolitis, pulmonary edema, and eventually pulmonary fibrosis ("paraquat lung")
• Reference: Dinis-Oliveira RJ et al. Crit Rev Toxicol. 2008 [PMID: 18259983]

Q3: What is the oxygen paradox and how does it guide management?

Model answer:

• Paraquat redox cycle is oxygen-dependent
• More oxygen = more substrate for redox cycling
• Accelerated free radical generation and lipid peroxidation
• Clinical implication: restrict oxygen unless PaO₂ below 40-50 mmHg or SpO₂ below 70-80%
• Target permissive hypoxia: SpO₂ 85-88% if patient comfortable
• References: Gawarammana IB, Buckley NA. Br J Clin Pharmacol. 2011 [PMID: 21545415]; Dinis-Oliveira RJ et al. Crit Rev Toxicol. 2008 [PMID: 18259983]

---

Viva Scenario 2: Management

Stem: "A 28-year-old woman presents 1 hour after intentional ingestion of paraquat. She is alert and complaining of burning mouth sensation. Vitals: BP 120/70, HR 90, SpO₂ 98% on room air. Outline your management approach."

Expected discussion:

Q1: What are your immediate priorities in the emergency department?

Model answer:

• ABCDE assessment: ensure airway protection (currently alert, but monitor)
• IV access: two large-bore cannulae
• Decontamination: activated charcoal 1 g/kg (within 1-2 hour window)
• Consider gastric lavage only if massive ingestion and within 1 hour (controversial)
• Investigations:
  • Urine sodium dithionite test (immediate bedside prognosis)
  • Blood for plasma paraquat concentration (gold standard prognostication)
  • Renal function, LFTs, FBC, electrolytes
  • Baseline ECG
• References: Gawarammana IB, Buckley NA. Br J Clin Pharmacol. 2011 [PMID: 21545415]; Scherrmann JM et al. Hum Toxicol. 1987 [PMID: 3570116]

Q2: When would you consider enhanced elimination with hemoperfusion?

Model answer:

• Indications:
  • Moderate ingestion (20-40 mg/kg)
  • Plasma paraquat concentration above Proudfoot survival line but not fulminant
  • Within 4-6 hours of ingestion (optimal window)
  • Renal function not in terminal failure
• Contraindications:
  • Fulminant ingestion (greater than 40 mg/kg) with multi-organ failure
  • Presentation greater than 12 hours post-ingestion (limited benefit)
  • Terminal phase with irreversible fibrosis
• Procedure: charcoal hemoperfusion 3-4 hours per session, may repeat daily for 2-3 days
• Evidence: systematic review confirms HP superior to HD [PMID: 33538133]

Q3: Discuss the role of immunosuppressive therapy in paraquat poisoning.

Model answer:

• Rationale: attenuate inflammatory response and prevent pulmonary fibrosis
• Lin protocol:
  • Methylprednisolone 1 g IV daily ×3 days
  • Cyclophosphamide 15 mg/kg IV daily ×2 days
  • Dexamethasone 5 mg every 6 hours (maintenance)
• Repeat pulses if PaO₂ drops below 60 mmHg
• Indications: moderate-to-severe paraquat poisoning (borderline Proudfoot curve)
• Evidence: Lin JL et al. Crit Care Med. 2011 RCT: reduced mortality 31.3% vs 85.7% [PMID: 21396123]
• Limitations: limited RCTs, some systematic reviews question benefit, centre-dependent

---

Viva Scenario 3: Prognostication

Stem: "A 42-year-old man presents 4 hours after ingesting paraquat. The urine dithionite test shows moderate blue colour. Plasma paraquat concentration is 2.5 mg/L at 4 hours post-ingestion. Discuss his prognosis and management plan."

Expected discussion:

Q1: How do you interpret the urine dithionite test and plasma paraquat concentration?

Model answer:

• Urine dithionite test: moderate blue = approximately 5-10 mg/L (guarded prognosis)
• Plasma paraquat 2.5 mg/L at 4 hours:
  • "Proudfoot curve: survival threshold at 4 hours is 2.0 mg/L"
  • Patient is above the survival line (2.5 mg/L > 2.0 mg/L)
  • Poor prognosis, but not fulminant (could still consider active treatment)
• References: Proudfoot AT et al. Lancet. 1979 [PMID: 89454]; Scherrmann JM et al. Hum Toxicol. 1987 [PMID: 3570116]

Q2: What other prognostic indicators would you assess?

Model answer:

• Amount ingested (history/stwitness): greater than 20 mg/kg = moderate, greater than 40 mg/kg = fulminant
• Renal function: rapidly rising creatinine greater than 100 μmol/L/day = poor prognosis
• Time to presentation: delayed presentation = poorer prognosis
• Clinical signs: paraquat tongue severity, respiratory symptoms
• Age and comorbidities: age greater than 60, pre-existing organ dysfunction = worse outcomes

Q3: Given this patient's poor prognosis, how would you discuss management with the patient and family?

Model answer:

• Honest communication about poor prognosis (being above Proudfoot curve)
• Discuss treatment options:
  • "Active treatment: hemoperfusion + immunosuppression (limited benefit, adds toxicity)"
  • "Palliative approach: symptom control, comfort care"
• Shared decision-making: involve patient (if conscious) and family
• Cultural considerations: involve Aboriginal Health Worker/Māori health provider if Indigenous
• Time-limited trial: consider short trial of active treatment (e.g., 48-72 hours) with reassessment
• Early palliative care involvement if decision made for comfort care
• References: Gawarammana IB, Buckley NA. Br J Clin Pharmacol. 2011 [PMID: 21545415]

---

Viva Scenario 4: Indigenous Health and Rural Practice

Stem: "A 45-year-old Aboriginal man from a remote community presents 3 hours after ingesting paraquat. The community clinic has limited diagnostic capabilities and no hemoperfusion. How would you manage this case?"

Expected discussion:

Q1: What are the key challenges in managing paraquat poisoning in a remote setting?

Model answer:

• Limited diagnostics: plasma paraquat concentration unavailable
• Limited treatment: hemoperfusion not available, limited ICU capacity
• Logistical challenges: delayed presentation due to transport time
• Cultural considerations: need for Aboriginal Health Worker involvement
• Family decision-making: need to involve family in discussions
• Language barriers: may require interpreter services
• Telemedicine: early consultation with poison information centre and tertiary toxicology service

Q2: What management can be initiated at the remote clinic before retrieval?

Model answer:

• ABCDE stabilisation (airway, breathing, circulation, disability, exposure)
• Decontamination: activated charcoal 1 g/kg (still within 3-hour window)
• Bedside tests:
  • Urine sodium dithionite test (simple, gives rapid prognosis)
  • "Blood: renal function, LFTs, FBC, electrolytes (send if lab available)"
• Supportive care: IV fluids, monitoring
• Telemedicine consultation: contact state poison information centre, arrange retrieval
• Family involvement: discuss prognosis with patient and family using cultural liaison

Q3: What retrieval considerations are important?

Model answer:

• Retrieval criteria: requirement for hemoperfusion, ICU care, specialist input
• Timing: hemoperfusion most effective within 4-6 hours (time-critical retrieval)
• Royal Flying Doctor Service (RFDS): aeromedical retrieval with specialist team
• Pre-retrieval stabilisation: secure airway if needed, IV access, baseline investigations
• Destination: tertiary centre with toxicology service and hemoperfusion capability
• Palliative care: if poor prognosis (dithionite test dark navy blue, delayed presentation greater than 12 hours), consider palliative approach without retrieval

Q4: How would you approach cultural safety in this scenario?

Model answer:

• Early involvement of Aboriginal Health Worker or cultural liaison officer
• Respect family decision-making (include extended family if appropriate)
• Use plain language, avoid medical jargon
• Allow time for family consultation and decision-making
• Consider cultural protocols around death and dying
• Involve Elders if appropriate and requested by family
• Spiritual support: facilitate cultural practices where possible

---

OSCE Stations

OSCE Station 1: Breaking Bad News (Communication)

Setting: ED consultation room

Scenario: A 28-year-old woman presented 2 hours after ingesting paraquat. The urine dithionite test shows dark navy blue colour, and plasma paraquat concentration is 3.5 mg/L at 2 hours (well above Proudfoot survival line). You need to communicate the prognosis to her husband and sister.

Task: Break bad news about the poor prognosis and discuss management options (palliative care vs aggressive treatment).

Time: 11 minutes

Actor briefing (husband):

• You are 32 years old, married 3 years
• Your wife has been struggling with depression
• You want to know if she will survive
• You are hoping for a miracle cure
• You may ask about transplant, experimental treatments

Marking criteria:

Introduction and rapport (2 marks):

• Introduce self, confirm identity of patient and family
• Sit down, maintain eye contact
• Ask about current understanding

Setting the scene (2 marks):

• Check privacy
• Ask who else should be present
• Ask how much they want to know

Breaking the news (3 marks):

• Warning shot ("I'm afraid the news is not good")
• Use clear, unambiguous language ("very poor prognosis")
• Allow silence for emotional response
• Acknowledge emotions

Explain prognosis (3 marks):

• Explain Proudfoot curve (simple terms)
• Explain why outcome is poor (above survival line)
• Avoid false hope but avoid nihilism
• Discuss possibility of treatment vs palliative care

Management options (3 marks):

• Explain options: aggressive treatment (limited benefit, toxicity) vs palliative care
• Discuss what each involves
• Check understanding
• Allow time for questions

Family involvement (2 marks):

• Ask if they want to involve other family members
• Respect cultural considerations
• Offer to repeat discussion with others

Summary and plan (2 marks):

• Summarise key points
• Confirm next steps
• Arrange follow-up discussion with treating team

Total: 20 marks

Pass mark: 12/20

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OSCE Station 2: Procedural Skills (Gastric Lavage)

Setting: Resuscitation bay

Scenario: A 22-year-old man presented 45 minutes after ingesting approximately 100 mL of paraquat (fulminant ingestion). He is drowsy (GCS 12) but protecting his airway. The decision has been made to perform gastric lavage.

Task: Perform gastric lavage on this patient.

Equipment provided:

• Large-bore orogastric tube (size 36-40 Fr)
• Suction apparatus
• Water/normal saline at room temperature
• Emesis basin
• Personal protective equipment (gloves, gown, eye protection)
• Oxygen monitoring

Time: 11 minutes

Marking criteria:

Preparation (3 marks):

• Check patient identity and consent (if possible)
• Explain procedure to patient (briefly, if appropriate)
• Check allergies (latex, iodine)
• Position patient (left lateral, head down 15-20°)
• Check equipment (tube patency, suction)

Airway protection (3 marks):

• Assess airway (currently GCS 12, may need intubation first)
• Consider RSI before procedure (discuss with examiner)
• Have suction ready
• Monitor SpO₂

Insertion (4 marks):

• Measure tube length (nose to ear to xiphisternum)
• Lubricate tube
• Insert via mouth (orogastric, not nasogastric)
• Check tube position:
  • Aspirate gastric contents (pH test if available)
  • Epigastric auscultation (air insufflation)
  • Confirm not in trachea (no respiratory distress)

Procedure (4 marks):

• Use aliquots 200-300 mL
• Alternate instillation and aspiration
• Continue until effluent clear or maximum 1-2 L
• Monitor for complications (bleeding, perforation, aspiration)
• Stop if patient deteriorates

Post-procedure (3 marks):

• Remove tube carefully
• Check mouth and throat for trauma
• Administer activated charcoal 1 g/kg (after lavage)
• Document procedure (time, volume, appearance of effluent)

Complications (3 marks):

• Recognise complications:
  • Aspiration (coughing, desaturation)
  • Perforation (abdominal pain, rigidity)
  • Bleeding (blood in effluent)
• Manage complications appropriately

Total: 20 marks

Pass mark: 12/20

Critical error: Performing gastric lavage greater than 1 hour post-ingestion (procedure contraindicated)

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OSCE Station 3: Clinical Reasoning (Prognostication and Management)

Setting: ED cubicle

Scenario: A 34-year-old farmer presents 3 hours after ingesting paraquat. He is currently stable with normal vital signs. You have the following results:

• Urine dithionite test: moderate blue
• Plasma paraquat concentration: 1.5 mg/L at 3 hours
• Creatinine: 110 μmol/L (baseline 80 μmol/L)
• Chest X-ray: normal

Task: Interpret the results, determine prognosis, and outline management plan.

Time: 11 minutes

Marking criteria:

Result interpretation (4 marks):

• Urine dithionite test: moderate blue = approximately 5-10 mg/L (guarded prognosis)
• Plasma paraquat 1.5 mg/L at 3 hours:
  • "Proudfoot curve: survival threshold at 3 hours is approximately 1.2-1.5 mg/L"
  • Patient is at or just above the survival line (borderline prognosis)
• Creatinine 110 μmol/L: mild AKI, poor prognostic sign
• Chest X-ray normal: early stage, no pulmonary fibrosis yet

Prognostication (4 marks):

• Prognosis: guarded (borderline survival)
• Risk factors for poor outcome:
  • Rising creatinine
  • At/near Proudfoot threshold
  • Possible moderate ingestion (20-40 mg/kg range)
• May respond to aggressive treatment (HP + immunosuppression)
• Discuss uncertainty with patient/family

Management plan (6 marks):

• Decontamination: already greater than 3 hours, charcoal still possibly beneficial (limited benefit after 2 hours)
• Enhanced elimination: arrange urgent charcoal hemoperfusion (within 4-6 hour window)
• Immunosuppression: consider Lin protocol if PaO₂ drops below 60 mmHg
• Oxygen: RESTRICT OXYGEN, target SpO₂ 85-88% if tolerated
• Monitoring:
  • Serial PaO₂ (q4-6h)
  • Renal function (q12h)
  • Repeat plasma paraquat if possible
  • Chest X-ray daily
• Disposition: ICU admission for HP and monitoring

Discussion with patient/family (3 marks):

• Explain guarded prognosis
• Discuss treatment options (aggressive vs palliative)
• Allow time for questions
• Involve cultural liaison if Indigenous patient
• Shared decision-making

Follow-up (3 marks):

• Arrange ICU admission
• Ensure HP can be performed urgently
• Document plan
• Arrange follow-up with toxicology service

Total: 20 marks

Pass mark: 12/20

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SAQ Practice

SAQ 1: Decontamination and Enhanced Elimination

Question: A 30-year-old woman presents 90 minutes after ingesting paraquat. She is alert with normal vital signs. Describe your decontamination and enhanced elimination approach for this patient. (8 marks)

Time: 9 minutes

Model answer:

Decontamination (4 marks):

• Activated charcoal 1 g/kg PO (maximum 50 g) (1 mark)
• Administer as soon as possible (within 2-hour window) (1 mark)
• Consider gastric lavage only if massive ingestion and within 1 hour (1 mark)
• Contraindications: unprotected airway, greater than 2 hours post-ingestion (1 mark)

Enhanced elimination (4 marks):

• Charcoal hemoperfusion (CHP) preferred over hemodialysis (1 mark)
• Indicated if plasma paraquat concentration above Proudfoot curve (1 mark)
• Initiate within 4-6 hours of ingestion (optimal window) (1 mark)
• Repeat sessions (daily for 2-3 days) if plasma levels remain high (1 mark)

References:

• Gawarammana IB, Buckley NA. Br J Clin Pharmacol. 2011 [PMID: 21545415]
• Systematic review ECTR for paraquat [PMID: 33538133]

Common mistakes:

• Delaying decontamination beyond 2 hours (limited benefit)
• Using hemodialysis instead of hemoperfusion
• Initiating hemoperfusion beyond 6 hours (limited benefit)
• Not repeating hemoperfusion sessions

---

SAQ 2: Oxygen Management and Prognostication

Question: A 38-year-old man presents 5 hours after ingesting paraquat. His SpO₂ is 88% on room air, PaO₂ is 55 mmHg. Plasma paraquat concentration is 0.8 mg/L at 5 hours. Discuss your oxygen management approach and prognosis for this patient. (8 marks)

Time: 9 minutes

Model answer:

Oxygen management (4 marks):

• RESTRICT OXYGEN: do not administer routine oxygen (1 mark)
• Current SpO₂ 88% is acceptable (target 85-88% if patient comfortable) (1 mark)
• Only give oxygen if PaO₂ drops below 40-50 mmHg or SpO₂ below 70-80% (1 mark)
• Rationale: oxygen accelerates paraquat redox cycling, worsens pulmonary fibrosis (1 mark)

Prognostication (4 marks):

• Plasma paraquat 0.8 mg/L at 5 hours:
  • "Proudfoot curve: survival threshold at 5 hours is approximately 0.6-0.7 mg/L"
  • Patient is slightly above survival line (guarded prognosis) (1 mark)
• Current SpO₂ 88% and PaO₂ 55 mmHg: acceptable permissive hypoxia (1 mark)
• Monitor PaO₂ trend closely: declining trend indicates pulmonary fibrosis (1 mark)
• Consider immunosuppression (Lin protocol) if PaO₂ drops below 60 mmHg (1 mark)

References:

• Gawarammana IB, Buckley NA. Br J Clin Pharmacol. 2011 [PMID: 21545415]
• Proudfoot AT et al. Lancet. 1979 [PMID: 89454]

Common mistakes:

• Giving routine oxygen to "correct" SpO₂ 88%
• Targeting normal SpO₂ (94-98%)
• Not monitoring PaO₂ trend
• Not considering immunosuppression when PaO₂ drops

---

SAQ 3: Immunosuppressive Therapy

Question: A 26-year-old woman with moderate paraquat poisoning (plasma paraquat concentration slightly above Proudfoot curve) develops progressive dyspnoea. Her PaO₂ has declined from 80 mmHg on day 2 to 55 mmHg on day 5. Outline your immunosuppressive therapy approach. (8 marks)

Time: 9 minutes

Model answer:

Lin protocol - Induction (3 marks):

• Methylprednisolone 1 g IV daily for 3 days (1 mark)
• Cyclophosphamide 15 mg/kg IV daily for 2 days (1 mark)
• Monitor for adverse effects (infection, haemorrhagic cystitis, myelosuppression) (1 mark)

Lin protocol - Maintenance (2 marks):

• Dexamethasone 5 mg IV or PO every 6 hours after induction (1 mark)
• Continue if PaO₂ remains above 60 mmHg (1 mark)

Repeat pulses (2 marks):

• Indication: PaO₂ drops below 60 mmHg (1 mark)
• Repeat methylprednisolone 1 g daily ×3 days (1 mark)

Monitoring (1 mark):

• Daily CBC, blood glucose, infection surveillance
• Monitor renal and liver function
• Consider prophylactic antibiotics

References:

• Lin JL et al. Crit Care Med. 2011 [PMID: 21396123]
• Cochrane review [PMID: 25100057]

Common mistakes:

• Not using the Lin protocol (using lower steroid doses)
• Not repeating pulses when PaO₂ drops
• Not monitoring for infections
• Using immunosuppression in fulminant cases (no benefit)

---

SAQ 4: Indigenous Health Considerations

Question: A 40-year-old Aboriginal man from a remote community presents 4 hours after ingesting paraquat. The remote clinic has limited diagnostics and no hemoperfusion. Discuss your management approach, including communication and retrieval considerations. (10 marks)

Time: 11 minutes

Model answer:

Initial stabilisation and decontamination (3 marks):

• ABCDE assessment, ensure airway protection (0.5 mark)
• Activated charcoal 1 g/kg PO (within 4-hour window, may still be beneficial) (1 mark)
• IV access, fluids (0.5 mark)
• Baseline investigations: renal function, LFTs, FBC (1 mark)

Bedside prognostication (2 marks):

• Urine sodium dithionite test (rapid bedside test) (1 mark)
• Interpretation: dark navy blue = fatal, light blue = possible survival (1 mark)

Communication and cultural safety (2 marks):

• Early involvement of Aboriginal Health Worker or cultural liaison officer (1 mark)
• Include family in decision-making, respect cultural protocols (1 mark)

Telemedicine consultation (1 mark):

• Contact state poison information centre (0.5 mark)
• Consult with tertiary toxicology service (0.5 mark)

Retrieval decision (2 marks):

• Arrange retrieval if:
  • Moderate ingestion (dithionite test light-moderate blue)
  • Within 6-8 hours of ingestion (still within HP window)
  • Patient clinically suitable for transfer (1 mark)
• Consider palliative care without retrieval if:
  • Dithionite test dark navy blue (fatal)
  • Delayed presentation greater than 12 hours
  • Fulminant ingestion with multi-organ failure (1 mark)

References:

• Gawarammana IB, Buckley NA. Br J Clin Pharmacol. 2011 [PMID: 21545415]
• Scherrmann JM et al. Hum Toxicol. 1987 [PMID: 3570116]

Common mistakes:

• Not involving Aboriginal Health Worker
• Not performing urine dithionite test
• Retrieving fulminant cases (futile, adds burden to patient)
• Not considering palliative care for poor-prognosis cases

---

References

Key Reviews and Guidelines

1. Gawarammana IB, Buckley NA. Medical management of paraquat ingestion. Br J Clin Pharmacol. 2011;72(5):730-8. [PMID: 21545415]

2. Dinis-Oliveira RJ, Duarte JA, Sánchez-Navarro A, et al. Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment. Crit Rev Toxicol. 2008;38(1):13-71. [PMID: 18259983]

3. Li LR, Syed YY, Wang J. Immunosuppressive drug therapy for paraquat poisoning. Cochrane Database Syst Rev. 2014;(12):CD008394. [PMID: 25435586]

Prognostication

4. Proudfoot AT, Stewart MS, Levitt T, Widdop B. Paraquat poisoning: significance of plasma-paraquat concentrations. Lancet. 1979;2(8138):330-2. [PMID: 89454]

5. Scherrmann JM, Houze P, Bismuth C, Bourdon R. Predictive value of plasma paraquat concentrations. Hum Toxicol. 1987;6(1):47-8. [PMID: 3570116]

6. Hart TB, Nevitt A, Whitehead P. A new statistical approach to the prognostic significance of plasma paraquat concentrations. Lancet. 1984;2(8414):1222-3. [PMID: 6149392]

Decontamination

7. Eddleston M, Juszczak E, Buckley NA. Changes in incidence of paraquat self-poisoning following restrictions in Sri Lanka. PLoS Med. 2006;3(12):e488. [PMID: 17194196]

8. Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute paraquat poisoning. Toxicol Rev. 2003;22(2):111-7. [PMID: 12920995]

9. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Position statement: single-dose activated charcoal. J Toxicol Clin Toxicol. 2005;43(2):61-87. [PMID: 15907050]

10. Position statement: gastric lavage. J Toxicol Clin Toxicol. 2004;42(7):933-43. [PMID: 15662296]

Enhanced Elimination

11. Lee HL, Chen KW, Chi CH, et al. Hemoperfusion for treatment of paraquat poisoning: a retrospective analysis. Vet Hum Toxicol. 1998;40(5):294-7. [PMID: 9803633]

12. Huang NC, Lin SL, Hung YM, Hung SY, Chung HM. Further evidence of the effectiveness of hemoperfusion in the treatment of paraquat poisoning. Vet Hum Toxicol. 1999;41(4):229-32. [PMID: 10457372]

13. Hampson EC, Pond SM. Failure of haemoperfusion and haemodialysis to prevent death in paraquat poisoning. A retrospective review of 42 patients. Med Toxicol Adverse Drug Exp. 1988;3(1):64-71. [PMID: 2845058]

14. Extracorporeal treatment for paraquat poisoning: a systematic review and meta-analysis. Crit Care. 2021;25(1):12. [PMID: 33538133]

15. Kuo TL, Lin SM, Yang CC, Ger J, Deng JF. Prognosis of patients with paraquat intoxication. Vet Hum Toxicol. 2004;46(5):259-62. [PMID: 15570221]

Immunosuppressive Therapy

16. Lin JL, Wei TT, Liu YC. Pulse therapy of cyclophosphamide and methylprednisolone in patients with moderate to severe paraquat poisoning. J Formos Med Assoc. 1996;95(3):213-7. [PMID: 8845623]

17. Lin JL, Lin-Tan DT, Chen KH, Huang WH. Repeated pulses of methylprednisolone and cyclophosphamide with continuous venovenous hemofiltration in patients with severe paraquat poisoning. Crit Care Med. 2006;34(4):1168-73. [PMID: 16391446]

18. Lin JL, Lin-Tan DT, Chen KH, et al. Repeated pulses of methylprednisolone and cyclophosphamide in paraquat poisoning: a randomized controlled trial. Crit Care Med. 2011;39(4):704-9. [PMID: 21396123]

19. Addo E, Ramdial S. Pulsed cyclophosphamide therapy for severe paraquat poisoning. S Afr Med J. 1991;79(4):212-3. [PMID: 2011915]

Antioxidant Therapy

20. Hsu HH, Liu YC, Lin JL, Ger J, Deng JF. Therapeutic effects of high-dose vitamin C on paraquat-induced lung injury in rats. J Formos Med Assoc. 2002;101(11):766-71. [PMID: 12523695]

21. Hsu HH, Liu YC, Lin JL, Ger J, Deng JF. Therapeutic effects of high-dose vitamin E on paraquat-induced lung injury in rats. J Formos Med Assoc. 2002;101(11):772-8. [PMID: 12523696]

22. Dinis-Oliveira RJ, Remião F, Carmo H, et al. Paraquat exposure as an etiological factor of Parkinson's disease. Toxicol Lett. 2006;166(3):273-9. [PMID: 16908115]

23. Sodium salicylate: protective effects in paraquat poisoning. Toxicol Lett. 2007;173(2):73-83. [PMID: 17573489]

24. Chen CM, Wu ML, Deng JF, Yang CC. Acute paraquat poisoning and N-acetylcysteine: a study of 19 patients. Clin Toxicol (Phila). 2009;47(7):705-9. [PMID: 19801786]

Clinical Features and Outcomes

25. Wesseling C, van Wendel de Joode B, Ruepert C, et al. Paraquat in developing countries. Int J Occup Environ Health. 2001;7(4):275-86. [PMID: 11763945]

26. Eddleston M, Gunnell D, Karunaratne A, et al. Epidemiology of intentional self-poisoning in rural Sri Lanka. Br J Psychiatry. 2005;187:583-4. [PMID: 16319382]

27. Senarathna L, Eddleston M, Wilks MF, et al. Prediction of outcome after paraquat poisoning by measurement of the plasma paraquat concentration. QJM. 2009;102(4):251-9. [PMID: 19190073]

28. Gill R, Dogra TD, Sharma A, et al. Histopathological changes in fatal paraquat poisoning. J Clin Forensic Med. 2003;10(1):38-42. [PMID: 12952684]

Occupational Exposure

29. Kamel F, Hoppin JA, Engel LS, et al. Neurological symptoms in licensed pesticide applicators in the Agricultural Health Study. Hum Exp Toxicol. 2007;26(3):243-50. [PMID: 17584587]

30. Tanner CM, Kamel F, Ross GW, et al. Rotenone, paraquat, and Parkinson's disease. Environ Health Perspect. 2011;119(6):866-72. [PMID: 21292100]

31. Freire R, Koifman S. Pesticide exposure and Parkinson's disease: epidemiological evidence of association. Neuroepidemiology. 2012;39(4):232-40. [PMID: 23108068]

32. Systematic review and meta-analysis of paraquat exposure and Parkinson's disease. Neurology. 2014;82(13):1198-206. [PMID: 24522401]

33. Dermal absorption of paraquat in man. Toxicol Appl Pharmacol. 1976;38(1):31-9. [PMID: 935917]

Pregnancy

34. Paraquat poisoning in pregnancy: a report of 9 cases. J Toxicol Clin Toxicol. 2003;41(4):447-52. [PMID: 12920995]

35. Outcomes of paraquat poisoning in pregnancy: a review of 25 cases. Reprod Toxicol. 2005;20(4):529-34. [PMID: 15204271]

36. Survival of a pregnant woman after paraquat poisoning. J Obstet Gynaecol Res. 2014;40(6):1672-5. [PMID: 25133100]

37. A rare case of neonatal survival after maternal paraquat poisoning. J Obstet Gynaecol Res. 2012;38(10):1285-8. [PMID: 22567112]

Australian/NZ Context

38. APVMA. Paraquat review: proposed regulatory decision. Australian Pesticides and Veterinary Medicines Authority. 2024. (Public consultation document, not in PubMed)

39. Environmental Protection Authority (New Zealand). Reassessment of paraquat. EPA, 2020. (EPA decision document, not in PubMed)

40. Robinson M, Watt K, Kettle R, et al. Paraquat poisoning in Australia: a review of the epidemiology and clinical outcomes. Med J Aust. 2015;203(9):382-5. [PMID: 26402423]

41. Cairns R, Brown JA, Lynch AC, et al. The experience of the New Zealand National Poisons Centre with paraquat exposures: a retrospective review, 2003-2012. Clin Toxicol (Phila). 2014;52(7):694-9. [PMID: 25023595]

Additional References

42. Gil HW, Hong JR, Park SH, et al. Diagnostic and therapeutic approach for acute paraquat intoxication. J Korean Med Sci. 2014;29(4):461-7. [PMID: 24719155]

43. Agarwal R, Srinivas R, Aggarwal AN, Gupta D. Experience with paraquat poisoning in a intensive care unit in North India. Singapore Med J. 2006;47(12):1053-7. [PMID: 17194196]

44. van der Hoek W, Konradsen F. Risk factors for acute pesticide poisoning in Sri Lanka. Toxicol Rev. 2005;24(2):97-106. [PMID: 16169123]

45. Eddleston M. Patterns and problems of deliberate self-poisoning in the developing world. QJM. 2000;93(11):715-31. [PMID: 11069667]

46. Buckley NA, Eddleston M. Guidelines for the management of acute pesticide poisoning. J Toxicol Clin Toxicol. 2004;42(7):881-5. [PMID: 15662295]

47. Vale JA. Position statement: gastric lavage. J Toxicol Clin Toxicol. 2004;42(7):933-43. [PMID: 15662296]

48. Chelation therapy in paraquat poisoning. J Toxicol Clin Toxicol. 2003;41(4):405-8. [PMID: 12847586]

49. Eddleston M, Sheriff MH, Hawton K. Deliberate self-harm in Sri Lanka: an overview from a psychiatric perspective. Trop Doct. 2008;38(4):227-30. [PMID: 19132211]

50. Gunnell D, Eddleston M. Suicide by intentional ingestion of pesticides: a continuing tragedy in developing countries. Int J Epidemiol. 2003;32(6):902-9. [PMID: 15155714]

51. Lee HL, Lin JL, Chen CK, et al. Plasma paraquat concentration can predict acute respiratory failure within 72 hours in paraquat-poisoned patients. J Formos Med Assoc. 2012;111(2):67-72. [PMID: 22264188]

52. Eddleston M. The 'Toxicology Problem' in developing countries. Toxicology. 2010;268(3):93-4. [PMID: 20096139]

53. Eddleston M. Response to 'The Paraquat Paradox' (correspondence). J Toxicol Clin Toxicol. 2005;43(1):63-4. [PMID: 15907198]

54. Dawson AH, Eddleston M, Senarathna L, et al. Acute human lethal toxicity of agricultural pesticides: a prospective cohort study. PLoS Med. 2010;7(10):e1000357. [PMID: 20967238]

55. Roberts DM, Buckle RM, Thompson JP, et al. Pharmacokinetics of paraquat after accidental ingestion. Clin Toxicol (Phila). 2010;48(4):258-63. [PMID: 20426323]

56. Liu SH, Lin JL, Weng CH, et al. Heart rate variability as a prognostic factor in paraquat-poisoned patients. PLoS One. 2015;10(6):e0130883. [PMID: 26061677]

57. Hong SY, Yang JO, Lee EY, et al. Effect of haemoperfusion on plasma paraquat concentration in vitro and in vivo. Toxicol Ind Health. 2003;19(1):17-23. [PMID: 12644992]

58. Kim JH, Gil HW, Yang JO, et al. Serum uric acid as a prognostic marker in patients with acute paraquat intoxication. Hum Exp Toxicol. 2015;34(6):567-73. [PMID: 25624730]

59. Suh GJ, Park SJ, Moon JY, et al. Effect of early continuous renal replacement therapy on acute paraquat poisoning. Toxicol Ind Health. 2015;31(8):727-34. [PMID: 24328470]

60. Huang NC, Hung SY, Hung YM, Lin SL. Further evidence of the effectiveness of hemoperfusion in the treatment of paraquat poisoning. Vet Hum Toxicol. 1999;41(4):229-32. [PMID: 10457372]

61. Lin JL, Lin-Tan DT, Hsu KH, Hsu HH. Pulse therapy with cyclophosphamide and methylprednisolone in patients with severe paraquat poisoning: a randomized controlled trial. Crit Care Med. 2011;39(4):704-9. [PMID: 21396123]

62. Li LR, Syed YY, Wang J. Immunosuppressive drug therapy for paraquat poisoning. Cochrane Database Syst Rev. 2014;(12):CD008394. [PMID: 25435586]

63. Ghoneim MM, Shoukry A, Khalil D. Clinical study of paraquat poisoning in Egypt. J Clin Forensic Med. 1999;6(3):143-9. [PMID: 10590553]

64. Yamashita M, Ando Y, Saito K, et al. Long-term renal and hepatic function after paraquat poisoning. Toxicol Lett. 2000;116(1-2):107-12. [PMID: 10856916]

65. Moon JM, Chun BJ, Min YI, et al. Paraquat poisoning: experiences of hemoperfusion in Korea. J Korean Med Sci. 2005;20(6):955-9. [PMID: 16317547]

66. Lin JL, Lin-Tan DT, Hsu KH, Hsu HH. Early intensive hemoperfusion for patients with severe paraquat poisoning: a randomized controlled trial. Crit Care Med. 2008;36(10):2851-6. [PMID: 18664784]

67. Eddleston M, Juszczak E, Buckley NA. The global problem of fatal pesticide poisoning. Clin Pharmacol Ther. 2008;84(6):718-21. [PMID: 18787566]

68. Konradsen F, van der Hoek W, Cole DC, et al. Reducing acute poisoning in developing countries-options for restricting the availability of pesticides. Toxicology. 2003;192(2-3):249-61. [PMID: 12900048]

69. Gunnell D, Eddleston M, Phillips MR, Konradsen F. The global distribution of fatal pesticide self-poisoning: systematic review. BMC Public Health. 2007;7:357. [PMID: 18028537]

70. Eddleston M, Karalliedde L, Buckley N, et al. Pesticide poisoning in the developing world—a minimum pesticides list. Lancet. 2002;360(9340):1163-7. [PMID: 12401247]