Paraquate poisoning
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Paraquat Poisoning
Overview
Paraquat (1,1'-dimethyl-4,4'-bipyridinium) is a bipyridylium compound widely used as a non-selective contact herbicide and weed killer. It is sprayed on weeds before planting and becomes inactivated on contact with soil. Commercially available as:
- Gramoxone - brownish concentrated liquid (dichloride salt, 10-30% strength)
- Weedol - brown granules for horticultural use (~5% strength)
- Most products contain a blue dye, a stenchant (foul smell), and an emetic to deter ingestion
Paraquat is responsible for significant morbidity and mortality worldwide, with ingestion being the principal route of fatal poisoning. - The Essentials of Forensic Medicine and Toxicology, 36th edition
Mechanism of Action
Paraquat undergoes NADPH-dependent reduction, forming free radicals that react with molecular oxygen to:
- Reform the paraquat cation (cyclic redox reaction)
- Produce superoxide free radicals (O2•-) and hydroxyl radicals (OH•)
These reactive oxygen species cause:
- Lipid peroxidation and degradation of cell membranes
- Disruption of cellular function and structure
- Cell death (necrosis)
The lungs are particularly vulnerable because paraquat actively accumulates in alveolar cells via a polyamine uptake mechanism. High oxygen concentrations in the lung sustain the redox cycle, making oxygen and paraquat mutually enhance each other's toxicity - this is why supplemental oxygen should be avoided unless absolutely necessary. - Tintinalli's Emergency Medicine
Absorption and Distribution
- Primary route: Gastrointestinal (ingestion)
- Inhalational and transdermal absorption are minimal (unless pre-existing skin lesions)
- Only 5-10% of ingested dose is absorbed; remainder excreted in feces
- Plasma concentration peaks within minutes to 2 hours after ingestion
- Highest concentrations found in kidneys and lungs, followed by muscles
- Muscles can act as a reservoir, redistributing paraquat back into circulation
- More than 90% of absorbed paraquat is excreted unchanged in urine within 24 hours, but can be detected in urine up to 3 weeks after ingestion
Fatal Dose and Period
| Parameter | Value |
|---|---|
| Fatal dose | 5-10 g (or 5 mL of Gramoxone); 1-2 g of Weedol |
| Lethal oral dose (20% concentrate) | ~10-20 mL in adults; 4-5 mL in children |
| Fatal period | 2-5 days (acute hepatorenal failure); up to 2 weeks (pulmonary fibrosis) |
| Fulminant dose | >40-50 mg/kg (death within 1-4 days) |
Clinical Features (Dose-Dependent Toxicity)
Severity Classification
| Category | Amount Ingested | Clinical Features |
|---|---|---|
| Mild | <20 mg/kg (<7.5 mL of 20% solution) | Asymptomatic or nausea, vomiting, diarrhea. Minimal renal/hepatic injury. Complete recovery expected. |
| Severe | 20-40 mg/kg (7.5-15 mL of 20% solution) | GI ulceration; Days 1-4: renal failure, hepatic impairment; 1-2 weeks: pulmonary fibrosis. Majority die within 2-3 weeks. |
| Fulminant | >40-50 mg/kg (>15-20 mL of 20% solution) | Rapid multiorgan failure, pancreatitis, cardiogenic shock, coma, convulsions. Death within 1-4 days. |
System-by-System Effects
Local/GI tract:
- Burning/ulceration of lips, mouth, pharynx, esophagus (within minutes to 1-2 days)
- Nausea, vomiting, hematemesis, diarrhea, dysphagia, aphonia
- Esophageal perforation, mediastinitis, pneumothorax
Lungs (biphasic injury):
- Destructive phase: Loss of type I and II alveolar cells, inflammatory infiltration, hemorrhage, pulmonary edema (may be reversible)
- Proliferative phase: Fibrosing alveolitis (interstitial and alveolar fibrosis) - irreversible; leads to a "rigid, stiff lung" (ARDS)
- Cough, hemoptysis, dyspnea
- Progressive pulmonary fibrosis occurs 5 days to several weeks after exposure
Kidneys:
- Acute tubular necrosis with oliguria/non-oliguric renal failure (within 2-3 days)
- Proximal tubular dysfunction
Liver:
- Centrilobular hepatic necrosis and cholestasis
- Giant mitochondria and crystalline inclusion bodies on electron microscopy
Cardiovascular:
- Hypovolemia (from GI losses), shock, arrhythmias, toxic myocarditis
Pancreas: Pancreatitis
CNS: Late-onset coma, convulsions, cerebral edema
Adrenals: Insufficiency due to necrosis
Bone marrow: Early polymorphonuclear leukocytosis; late anemia
Cause of death: Multi-organ failure or corrosive GI effects; delayed deaths from progressive pulmonary fibrosis - Forensic Medicine and Toxicology, 36th Ed.
Diagnosis
Clinical history: Amount, concentration, timing, and route of exposure are the most critical prognostic factors.
Urine dithiomite (sodium dithionite) test:
- Performed within a few hours of ingestion
- Blue color change = paraquat present; darker blue = worse prognosis
- Clear test between 6-24 hours after exposure favors survival
- Semiquantitative (Paraquat Test Kit by Syngenta CTL also available)
Laboratory investigations:
- Blood and urine paraquat levels (quantitative - for nomogram-based prognosis)
- Serum creatinine: Rise >0.049 mg/dL per hour over 6 hours - associated with death
- Serum lactate: >3.35-4.4 mmol/L - associated with high mortality (74-82% sensitivity)
- Serum cystatin C: Rise >0.009 mg/L over 6 hours - associated with death
- ABG, LFTs, RFTs, CBC
Chest X-ray: Diffuse pulmonary infiltrates, pneumomediastinum, or pneumothorax (all worsen prognosis)
Prognostic nomograms: Based on plasma paraquat concentration vs. time since ingestion - Tintinalli's Emergency Medicine
Treatment
1. Decontamination (immediate)
- Remove all clothing; wash skin thoroughly with soap and water
- Gastric lavage: beneficial if done within 1 hour of exposure
- Emetics are contraindicated
- Eye exposure: copious irrigation
2. Adsorbents (GI tract binding)
- Fuller's earth (15-30% aqueous suspension, 1 L) OR bentonite (7%) - preferred adsorbents
- Follow with 200 mL of 20% mannitol as cathartic
- If adsorbents not available: activated charcoal (1-2 g/kg)
- Repeat cathartic if adsorbent has not appeared in stool within 6 hours
3. Enhanced elimination
- Hemodialysis and hemoperfusion: useful if done within 12 hours of ingestion
4. Critical precaution - Oxygen therapy
- AVOID supplemental oxygen - oxygen enhances paraquat-induced radical toxicity
- Only administer oxygen if SpO2 <70% or PaO2 <40 mmHg (refractory hypoxemia)
5. Supportive care
- Analgesics for pain
- Fluid and electrolyte management
- Renal replacement therapy for acute kidney injury
6. Experimental/investigational treatments
- Antioxidants (N-acetylcysteine, vitamin C, E)
- Immunosuppressive therapy (dexamethasone, cyclophosphamide) - used in some protocols
- Lung transplantation (rarely, as last resort)
Postmortem Appearances
External:
- Ulceration around lips and chin from dribbled paraquat
Internal:
- Mouth/esophagus: Reddened/desquamated mucosa; esophagus may contain casts of shed epithelium
- Stomach: Erosion and patchy hemorrhages
- Liver: Pallor, mottled fatty change, centrilobular necrosis
- Kidneys: Cortical pallor, diffuse tubular damage
- Lungs (in delayed deaths): Large, stiff lungs that hold their shape when removed from chest; alveolar fibrosis (reticulin and collagen deposition); diffuse pulmonary edema/hemorrhage; fibrinous pleurisy; sometimes bloody pleural effusions - can resemble diffuse pneumonia macroscopically
Histology (lungs): Air spaces occluded by mononuclear cells forming rounded-up fibroblasts; progressing to alveolar fibrosis with reticulin and collagen deposition - Parikh's Textbook of Medical Jurisprudence
Key Forensic Points
- Fatalities occur mainly by ingestion; inhalational deaths during spraying are very rare
- Accidental deaths often result from decanting the concentrate from original containers
- A distinctive feature in delayed deaths: lungs maintain their shape when removed from the chest (fibrotic stiff lungs)
- Paraquat can be detected in urine for up to 3 weeks after ingestion
- The dithiomite urine test is a useful bedside screening and prognostic tool
Recent evidence note: A 2025 systematic review in BMC Public Health (PMID 40993561) highlights ongoing controversy over paraquat regulation globally, calling for public-health-first policies given its continued role in pesticide suicides worldwide.
Can u explain mechanism in a bit more simpler way
Paraquat Mechanism - Simplified
Think of it like a "Rust Machine" inside your body
Step-by-Step Breakdown
Step 1 - Paraquat enters the cell
Once swallowed and absorbed, paraquat travels in the blood and gets actively sucked into lung cells (alveolar cells have a special transporter that loves paraquat).
Step 2 - The "Electron Theft" (Redox Cycling)
Your cells use a molecule called NADPH to do normal work. Paraquat hijacks this process:
NADPH → donates an electron to Paraquat
Paraquat becomes Paraquat• (a free radical - unstable, angry molecule)
Step 3 - The "Spark" hits Oxygen
That unstable paraquat radical immediately reacts with oxygen in the lung:
Paraquat• + O₂ → Paraquat (original form) + Superoxide (O₂•⁻)
Two things happen here:
- Paraquat is regenerated (it's not used up - it can repeat this cycle thousands of times)
- A toxic superoxide free radical is produced
Step 4 - Free Radical Chain Reaction
Superoxide converts into even more dangerous species:
Superoxide (O₂•⁻) → Hydrogen Peroxide (H₂O₂) → Hydroxyl Radical (OH•)
↑
Most damaging of all
Step 5 - Cell Membrane Destruction
These hydroxyl radicals attack fat molecules in cell membranes (lipid peroxidation):
OH• + Cell membrane fat → Membrane breaks apart → Cell dies
Why the Lungs are Hit Hardest
| Factor | Explanation |
|---|---|
| Active uptake | Lung cells have a special transporter that concentrates paraquat inside them |
| High oxygen | Lungs have the highest oxygen levels in the body - more O₂ = more free radicals |
| Self-perpetuating | Paraquat is regenerated each cycle, so damage keeps going even from a tiny amount |
This is also why giving extra oxygen makes things WORSE - you're feeding the fire.
Simple Analogy
Imagine paraquat is a spark plug that never burns out. Every time it fires, it creates a tiny explosion (free radical) that damages the cell wall. The more oxygen around, the faster it fires. The lung is essentially a room full of oxygen - so it gets destroyed the fastest.
Summary in One Sentence
Paraquat steals electrons from your cells, uses oxygen to regenerate itself, and produces hydroxyl free radicals in an endless loop that destroys cell membranes - especially in the lungs.
Plasma paraquate conc
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paraquat plasma concentration nomogram survival prediction values mg/L hours
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Plasma Paraquat Concentration
Why It Matters
Plasma paraquat concentration is the single most important prognostic marker in paraquat poisoning. The higher the level at any given time after ingestion, the worse the outcome. It is used alongside time since ingestion to predict survival using nomograms. - Brenner and Rector's The Kidney
Key Pharmacokinetics
| Parameter | Value |
|---|---|
| Molecular weight | 186 Da |
| Protein binding | ~5% (essentially free in plasma) |
| Oral bioavailability | <30% |
| Peak plasma concentration | ~2 hours after ingestion |
| Peak tissue distribution | 2-8 hours post-ingestion |
| Volume of distribution | ~1.0 L/kg |
| Elimination half-life (normal renal function) | 12 hours |
| Elimination half-life (impaired renal function) | >48 hours |
| Route of excretion | Predominantly renal (unchanged) |
Nomogram - Survival Prediction
Nomograms plot plasma paraquat concentration (mg/L or µg/mL) vs. time since ingestion (hours) to predict survival. Patients falling above the predictive line are expected to die; those below are expected to survive.
Hart et al. Survival Curve (Classic Nomogram)
This is the most cited nomogram - it shows the boundary between predicted survival and predicted death based on 375 patients:
| Time after ingestion | Plasma level below which survival likely |
|---|---|
| 4 hours | ~2.0 mg/L |
| 6 hours | ~0.9 mg/L |
| 10 hours | ~0.3 mg/L |
| 16 hours | ~0.1 mg/L |
| 24 hours | ~0.05 mg/L |
The principle: the same concentration is more dangerous if measured later (because tissue distribution is complete and damage is already underway).
Korean Nomogram Formula (PLOS ONE, 2136 patients)
A more modern validated formula:
Probability of survival = exp(logit) / (1 + exp(logit))
logit = 1.3544 + [−3.4688 × log₁₀(plasma PQ µg/mL)]
+ [−2.3169 × log₁₀(hours since ingestion)]
This model had a C-statistic of 0.964 - extremely accurate. Overall survival in this cohort was 44%.
Severity Index of Paraquat Poisoning (SIPP)
SIPP = Plasma paraquat concentration (µg/mL) × hours since ingestion
| SIPP Score | Predicted Outcome |
|---|---|
| <10 | Survival likely |
| 10-50 | Uncertain / severe |
| >50 | Death very likely |
This is a quick bedside calculation that doesn't need a nomogram graph.
Practical Prognostic Cutoffs
From clinical studies:
| Marker | Value | Significance |
|---|---|---|
| Plasma paraquat | >0.2 mg/L at any time | Poor prognosis; hemoperfusion target to reduce below this |
| Serum creatinine rise | >0.049 mg/dL/hour over 6 hours | Associated with death |
| Serum cystatin C rise | >0.009 mg/L over 6 hours | Associated with death |
| Serum lactate | >3.35-4.4 mmol/L | 74-82% sensitivity for mortality |
Urine Dithionite (Dithiomite) Test - Qualitative Bedside Proxy
When quantitative plasma levels are not available (common in resource-limited settings):
Method: Add sodium dithionite to urine sample
| Result | Interpretation |
|---|---|
| No color change | Paraquat absent or very low |
| Light blue | Low exposure, better prognosis |
| Intense blue | High exposure, worse prognosis |
| Clear test at 6-24 hours post-exposure | Favors survival |
This test is semiquantitative - color intensity correlates roughly with plasma level.
Role in Treatment Decisions
- Hemoperfusion should be started as soon as possible (ideally within 4 hours); target is to reduce plasma paraquat to <0.2 mg/L
- Up to 7 hemoperfusion sessions of 6-8 hours each have been proposed, maintained until levels drop below 0.2 mg/L - Syngenta Clinical Guidelines
- Patients with very high concentrations (many times the lethal dose) do not benefit from hemoperfusion - prognosis is already fatal and treatment shifts to palliative/supportive care - Tintinalli's Emergency Medicine
- Rebound in plasma levels is commonly observed after each ECTR session due to redistribution from tissues back into plasma - Brenner and Rector's The Kidney
Key Caveat
Quantitative plasma paraquat assays are not available in most hospitals (require HPLC or specialized immunoassay). The urine dithionite test and clinical/biochemical markers (creatinine, lactate) are the practical tools in most settings. - Tintinalli's Emergency Medicine
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