Paraquat Poisoning

What is Paraquat?

• Gramoxone: brownish concentrated liquid, 10-30% strength
• Weedol: brown granules, ~5% strength (horticultural use)

Mechanism of Action (Pathophysiology)

1. Paraquat is reduced by NADPH to a free radical cation
2. This radical rapidly reacts with molecular oxygen to regenerate the cation and produce superoxide radicals (O2-) and hydroxyl radicals (OH-)
3. These reactive oxygen species (ROS) cause lipid peroxidation, degradation of cell membranes, cell dysfunction, and necrosis
4. The process is self-sustaining because the extensive oxygen and electron supply in the lungs amplifies the redox cycle

Toxicokinetics

Clinical Features by Dose

Mild (<20 mg/kg or <7.5 mL of 20% solution)

• Transient nausea, vomiting, diarrhea - usually resolves within a few days
• Minimal or absent renal/hepatic injury
• Decreased pulmonary diffusion capacity may be present
• Complete recovery expected

Severe (20-40 mg/kg or 7.5-15 mL of 20% solution)

• Days 1-4: Nausea, vomiting, diarrhea, oropharyngeal ulceration, renal failure, hepatic impairment, hypotension
• Days 7-14: Cough, hemoptysis, pleural effusion, progressive pulmonary fibrosis
• Majority die within 2-3 weeks from pulmonary failure; survival possible

Fulminant (>40-50 mg/kg or >15-20 mL of 20% solution)

• Rapid multiorgan failure within 1-4 days: GI ulceration, renal and hepatic failure, pancreatitis, toxic myocarditis, adrenal necrosis, refractory hypotension, coma, convulsions
• Death from cardiogenic shock and multiorgan failure

Organ-by-Organ Effects

Diagnosis

• History of exposure (intentional vs accidental), timing, amount and concentration
• Local corrosive signs: burning in mouth/throat, ulceration within 1-2 days of ingestion

Urine Sodium Dithionite Test (Qualitative)

• Add sodium dithionite to urine: yellow-to-blue color change = positive (confirms paraquat exposure)
• More intense blue = higher exposure
• A clear/negative test at 6-24 hours after exposure favors survival
• Semiquantitative kits are available (Paraquat Test Kit, Syngenta)

Laboratory Testing

• Serum creatinine: rise >0.049 mg/dL per hour over 6 hours is 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 has 74-82% sensitivity for mortality
• Quantitative serum paraquat levels (if available) + nomograms for mortality prediction
• ABG, serial chest X-rays, LFTs, CBC

Prognostic Factors (Worse Outcome)

• Age >50 years
• Pre-existing renal disease
• Sensation of generalized skin burning
• Elevated lactate, rising creatinine
• Pneumomediastinum or pneumothorax on CXR
• Positive dithionite test remains strongly positive at 24 hours

Management

1. Decontamination

• Remove all clothing; wash skin with mild soap and water (avoid abrasions, which increase absorption)
• Eye exposure: copious irrigation with water or saline
• Gastric lavage is contraindicated (corrosive injury risk to esophagus; emetics also contraindicated)
• GI adsorbents (within 2 hours of ingestion, urgent): given orally or via nasogastric tube:
  • Fuller's earth (diatomaceous): 1-2 g/kg in 15% aqueous suspension (preferred adsorbent)
  • Bentonite: 1-2 g/kg in 7% aqueous slurry
  • Activated charcoal: 1-2 g/kg if the above are unavailable
  • Follow with 200 mL of 20% mannitol as cathartic; repeat if adsorbent not seen in stool within 6 hours

2. Supportive Care

• Fluid and electrolyte replacement (significant losses from vomiting/diarrhea)
• Opioid analgesia for pain
• Avoid supplemental oxygen unless patient is severely hypoxic - oxygen enhances paraquat-induced ROS generation. (If hypoxia is severe enough to require oxygen, prognosis is already very poor.)

3. Extracorporeal Elimination

• Paraquat is a small molecule, low protein binding, moderate Vd - amenable to extracorporeal removal
• Hemoperfusion (HP) is preferred, started as early as possible; evidence suggests survival benefit if started within 4 hours
• Intermittent hemodialysis (IHD) is an alternative if HP unavailable
• CVVHD removes paraquat but too slowly - use only for managing AKI, not for primary elimination
• Peritoneal dialysis: no benefit
• Extracorporeal therapy after 12 hours is unlikely to be beneficial given rapid tissue distribution

4. Pharmacological Treatments

• Dexamethasone: 8 mg IV every 8 hours for first 72 hours; may be continued for weeks in severe cases (relatively low toxicity, possible benefit in reducing pulmonary injury)
• N-acetylcysteine (acetylcysteine): may provide antioxidant benefit; administer continuously while acute toxicity is present
• Cyclophosphamide + corticosteroids: a large RCT showed no statistically significant benefit (though high-dose steroids alone remain recommended by some)
• Vitamins C and E, superoxide dismutase, deferoxamine, selenium, NAC, thiosulfate, salicylate - none proven to significantly alter outcomes in controlled trials

5. Disposition

• Any paraquat exposure = medical emergency - hospitalize even if asymptomatic
• Observe minimum 12 hours; clinically well patients with negative urine dithionite at 12 hours are unlikely to develop toxicity
• Severe/fatal prognosis cases: provide supportive and palliative care with early palliative team involvement
• Serial pulmonary function tests, CXR, ABG, renal function monitoring

Postmortem Findings

• Ulceration around lips and mouth; reddened oral mucosa
• Esophagus may contain casts of shed epithelium
• Stomach: erosions and patchy hemorrhages
• Kidneys: cortical pallor, diffuse tubular damage
• Lungs: diffuse pulmonary edema and hemorrhage; fibrosis with alveolar occlusion by rounded fibroblasts; rigid "stiff lung" with reticulin and collagen deposition; fibrinous pleurisy; pleural effusion
• Liver: pallor, mottled fatty change, centrilobular necrosis

Key Points Summary

• Paraquat is one of the most toxic ingested substances known; mortality 50-90%
• Mechanism: cyclic ROS generation - especially superoxide radicals - targeting the lungs
• Three dose-dependent clinical syndromes: mild, severe, fulminant
• Two-phase lung injury: initial destructive phase (potentially reversible) followed by proliferative fibrosis (irreversible)
• Avoid oxygen unless mandatory
• GI decontamination with adsorbents (Fuller's earth, charcoal) within 2 hours
• Early hemoperfusion (within 4 hours) offers best chance
• No proven specific antidote
• Palliative care should be planned early in severe cases

Celphos (Aluminium Phosphide) Poisoning

What is Celphos?

Mechanism of Action

AlP + 3H₂O → Al(OH)₃ + PH₃ (Phosphine)

• Inhibits the electron transport chain (preferential inhibition of cytochrome oxidase)
• Disrupts mitochondrial respiration
• Causes widespread cellular hypoxia and cytotoxic damage to all organs

Fatal Dose and Period

Signs and Symptoms

Mild (Inhalation exposure)

• Irritation of mucous membranes
• Acute respiratory distress
• Dizziness, fatigue, tightness in the chest
• Nausea, vomiting, diarrhea, headache

Moderate

• Ataxia, numbness, paresthesia, tremors
• Diplopia
• Jaundice
• Muscular weakness, incoordination, paralysis

Severe / Ingestion (Systemic)

Chemical Tests for Diagnosis

1. Silver Nitrate Breath Test (Clinical)

• A piece of filter paper impregnated with 0.1 N silver nitrate is used as a mask
• Patient breathes through it for 5-10 minutes
• Filter paper turns black = phosphine present (AgNO3 is reduced to metallic silver by PH3)
• Positive only if patient has ingested more than 6 g of ALP

2. Gastric Aspirate Test (Laboratory/Postmortem)

• Mix 5 mL gastric aspirate with 15 mL water in a flask
• Cover the mouth of the flask with silver nitrate-impregnated filter paper
• Heat at 50°C for 15-20 minutes
• Blackening of filter paper = phosphine confirmed

Management

There is NO specific antidote for aluminium phosphide poisoning.

Decontamination

1. Gastric lavage with:
   • 1% copper sulfate, or
   • 1% potassium permanganate (oxidizes phosphine to non-toxic phosphate), or
   • 3-5% sodium bicarbonate, or
   • Mineral oil / liquid paraffin (prevents absorption; excretes ALP from gut)
   • Note: Some recent studies caution against gastric lavage with water because moisture accelerates phosphine liberation from remaining ALP
2. Activated charcoal: 100 g orally, mixed with sorbitol (not water), to adsorb phosphine
3. Antacids: reduce GI symptoms and reduce phosphine absorption

Cardiovascular Support

1. Magnesium sulfate (IV): corrects hypomagnesemia, reduces organ toxicity, and manages arrhythmias
   • 3 g IV bolus, followed by 6 g infusion over 24 hours for 5-7 days; or
   • 1 g repeated for the next 2 hours, then 1-1.5 g every 6 hours for 5-7 days (continuous IV)
2. Calcium salts IV: to correct hypocalcemia and tetany
3. IV fluids: 4-6 liters during the first 3-6 hours (50% normal saline) for shock/hypovolemia
4. Low-dose dopamine infusion: 4-6 mcg/kg/min for cardiogenic/vasodilatory shock

Pulmonary and Metabolic Support

1. IV Hydrocortisone: 400 mg every 4-6 hours - highly effective; reduces pulmonary edema and reduces dopamine requirement
2. Oxygen therapy: for hypoxia and respiratory distress
3. Sodium bicarbonate: 50 mEq every 15 minutes (IV) until arterial bicarbonate >15 mmol/L - corrects metabolic acidosis
4. Antibiotics: for secondary infection
5. Peritoneal dialysis or hemodialysis: useful for renal failure management

Postmortem Appearances

External

• Cyanosis
• Froth over mouth and nostrils (blood-stained froth)
• Characteristic garlic-like/fishy odor from mouth, nostrils, and gastric contents

Internal

• All internal organs: congested with petechial hemorrhages
• GI mucosa: congestion of esophagus (lower part), stomach, and duodenum; decreasing congestion in small intestine
• Lungs: congested and edematous (pulmonary edema well established; phosphine gas causes direct irritation)
• Liver: pallor; centrilobular/centrizonal hemorrhagic necrosis
• Spleen, kidneys, brain: congested

Histopathology

Medicolegal Aspects

• Manner: Poisoning is usually suicidal (very commonly in India), occasionally accidental, and rarely homicidal
• Misused with homicidal intent particularly in dowry deaths in rural India; only a part of a tablet is sufficient for homicidal purpose
• High incidence in Haryana, Punjab, Uttar Pradesh, and Rajasthan (states of North India)
• The tablet closely resembles a medicinal preparation (easy to administer covertly), is easily available, cheap, and requires only a small amount for a lethal dose - making it a highly dangerous agent

Key Points

• Celphos = Aluminium Phosphide; each 3 g tablet liberates 1 g phosphine gas
• Mechanism: phosphine inhibits cytochrome oxidase → disrupts electron transport → cellular hypoxia
• Reaction is accelerated by gastric HCl and moisture
• No specific antidote
• Cardiogenic shock is the leading cause of death
• Garlic/fishy odor is the hallmark clinical and postmortem sign
• Silver nitrate filter paper test: blackening confirms phosphine in breath/gastric aspirate
• Magnesium sulfate + hydrocortisone + dopamine + aggressive fluid resuscitation are the mainstays of treatment
• Mortality: 35-100%; fatal in as little as 6-12 hours

Celphos (Aluminium Phosphide) Poisoning - Harrison's Framework

Important Note on Coverage

"Poisonings not covered in this chapter are discussed in specialized texts."

Harrison's General Approach to Poisoning (Chapter 470)

1. Support of vital signs
2. Prevention of further poison absorption (decontamination)
3. Enhancement of poison elimination
4. Administration of specific antidotes
5. Prevention of re-exposure

Phases of Poisoning (Harrison's)

ALP Poisoning Through Harrison's Lens

Toxidrome Classification

• Phosphine inhibits cytochrome oxidase (Complex IV of the mitochondrial electron transport chain)
• This is a cellular/histotoxic asphyxiant mechanism - identical in principle to cyanide and hydrogen sulfide poisoning
• Cells cannot utilize oxygen despite adequate delivery → tissue hypoxia, lactic acidosis, multiorgan failure

Mechanism of Toxicity

• Reaction is accelerated by gastric HCl
• Phosphine undergoes NADPH-dependent redox cycling, generating reactive oxygen species (superoxide, hydroxyl radicals)
• Inhibits cytochrome c oxidase → blocks mitochondrial electron transport
• Causes lipid peroxidation, membrane damage, and cell death in all organs
• Heart and lungs are the primary targets due to high metabolic activity

Fatal Dose and Period

• Fatal dose: 1-3 tablets (1-3 g ALP; each 3 g tablet releases ~1 g phosphine)
• Fatal period: 6-12 hours; most deaths within 24 hours
• Inhaled PH3: 400-600 ppm fatal within 1 hour
• Mortality: 35-100% - among the highest of any acute poisoning

Clinical Features (Organ-Based)

Cardiovascular (leading cause of death)

• Refractory hypotension and cardiogenic shock
• ECG: sinus tachycardia, bradycardia, ST-T changes, heart block, ventricular arrhythmias
• Acute myocarditis, pericarditis, congestive cardiac failure
• Right ventricular failure (from pulmonary hypertension)

Respiratory

• Cough, dyspnea, cyanosis
• Pulmonary edema, ARDS
• Respiratory failure

Gastrointestinal

• Nausea, vomiting (often projectile)
• Burning pain in epigastrium, retrosternal pain
• Diarrhea, massive GI bleeding
• Characteristic garlicky/fishy odor from breath (exhaled phosphine)

CNS

• Headache, dizziness, anxiety, restlessness
• Altered mental status, acute hypoxic encephalopathy
• Convulsions, coma

Metabolic

• Metabolic (lactic) acidosis - hallmark of cellular asphyxiant poisoning (Harrison's principle)
• Hypomagnesemia, hypocalcemia
• Hypoglycemia or hyperglycemia

Renal

• Oliguria, acute tubular necrosis, renal failure

Hepatic

• Jaundice, hepatitis, centrilobular necrosis

Diagnosis

Clinical

• History of ALP/Celphos ingestion (suicidal, accidental, or homicidal)
• Garlicky/fishy odor on breath and from gastric contents
• Rapidly progressive multiorgan failure in a young patient from South Asia - strongly suspect ALP

Silver Nitrate Breath Test

• Filter paper impregnated with 0.1 N silver nitrate held over the patient's mouth for 5-10 min
• Blackening = positive (phosphine reduces AgNO₃ to metallic silver)
• Positive in patients who ingested >6 g ALP

Gastric Aspirate Test

• Mix gastric aspirate with water in a flask, heat at 50°C; silver nitrate filter paper over mouth of flask
• Blackening = phosphine confirmed

Laboratory (Harrison's approach - reflect multiorgan failure)

• ABG: metabolic acidosis, hypoxemia
• ECG: monitor continuously for arrhythmias
• Serum electrolytes: hypomagnesemia, hypocalcemia, hypokalemia
• Troponin, CK-MB: myocardial damage
• LFTs, creatinine, CBC
• Serum lactate: elevated (cellular asphyxia)
• Chest X-ray: pulmonary edema, ARDS pattern

Management (Harrison's Principles Applied)

1. Supportive Care (Harrison's Priority #1)

• ICU admission - indicated (coma, hypotension, arrhythmias, respiratory depression, progressive deterioration)
• Airway: early endotracheal intubation if CNS depression or respiratory failure
• Oxygen therapy - for hypoxia (unlike paraquat, oxygen is NOT contraindicated)
• Continuous cardiac monitoring, pulse oximetry, arterial line
• IV access; fluid resuscitation (4-6 L in first 3-6 hours; 50% normal saline)
• Mechanical ventilation if needed

2. Decontamination (Harrison's Priority #2)

• Gastric lavage: with 1% KMnO₄ (oxidizes phosphine to non-toxic phosphate), 1% copper sulfate, or 3-5% sodium bicarbonate - repeat 2-3 times
  • Note: Controversial - some experts advise against because added moisture increases PH₃ liberation from unabsorbed ALP; if done, only after endotracheal intubation
• Activated charcoal: 1-2 g/kg mixed with sorbitol (not water) - adsorbs phosphine
• Antacids: reduce gastric acidity and phosphine absorption
• Liquid paraffin: aids excretion of ALP from gut; reduces absorption

3. Enhancement of Elimination (Harrison's Priority #3)

• Hemodialysis / peritoneal dialysis: useful for managing AKI and correcting metabolic derangements; limited role in primary elimination (phosphine distributes rapidly to tissues)
• No proven effective extracorporeal elimination technique for phosphine itself

4. Specific Treatments (Harrison's Priority #4)

No specific antidote exists.

5. Prevention of Re-exposure (Harrison's Priority #5)

• Psychiatric evaluation (majority of cases are suicidal)
• Regulatory and social interventions
• Restricted access to ALP tablets in high-risk populations

Harrison's ICU Admission Criteria (Applied to ALP)

• Coma or altered mental status
• Respiratory depression / hypoxia
• Hypotension / cardiogenic shock
• Cardiac arrhythmias and conduction abnormalities
• Seizures
• Progressive multiorgan failure

Postmortem Findings

• Garlic/fishy odor from body cavities and gastric contents
• Blood-stained froth at mouth and nostrils
• All organs: congested with petechial hemorrhages
• Lungs: pulmonary edema, alveolar desquamation, lymphocytic infiltration
• Liver: centrilobular hemorrhagic necrosis
• Heart: focal myocardial necrosis, fiber fragmentation
• Kidneys: tubular degeneration and necrosis
• Adrenals: cortical necrosis and lipid depletion

Summary Table

Paraquat Poisoning - Harrison's Based (22nd Edition, 2025)

Harrison's Direct Mentions of Paraquat

"Pulmonary edema (adult respiratory distress syndrome [ARDS]) can be caused by poisoning with carbon monoxide, cyanide, an opioid, paraquat, phencyclidine, a sedative-hypnotic, or salicylate..."

• Oxidative phosphorylation inhibitors
• AGMA (Anion Gap Metabolic Acidosis) inducers
• Cytochrome oxidase inhibitors
• Membrane-active agents

Harrison's Toxidrome Classification of Paraquat

Discordant Physiologic State

• It causes oxidative phosphorylation disruption - cells cannot produce ATP despite normal oxygen delivery
• It causes AGMA (anion gap metabolic acidosis) from lactic acidosis
• It produces pulmonary toxicity out of proportion to other features
• It causes multiorgan failure through ROS-mediated injury

Mechanism of Toxicity (Harrison's Pathophysiology Framework)

1. Paraquat undergoes NADPH-dependent reduction → forms a free radical cation
2. This radical reacts with O₂ → regenerates paraquat cation + superoxide (O₂⁻) and hydroxyl radicals (OH•)
3. These ROS cause lipid peroxidation, membrane degradation, and cell death
4. The process is self-sustaining - the redox cycle repeats continuously

Toxicokinetics

Clinical Features

Dose-Dependent Syndromes

Harrison's ARDS Framework Applied to Paraquat

• Destructive phase: Loss of type I and II alveolar cells, hemorrhage, inflammatory infiltration (potentially reversible)
• Proliferative phase: Interstitial and alveolar fibrosis → irreversible "stiff lung" → refractory hypoxemia

Organ-by-Organ Effects

Diagnosis - Harrison's Approach

Step 1: History + Physiologic State Assessment

Step 2: Laboratory Assessment (Harrison's Chapter 470)

Step 3: Toxicologic Testing

• Urine sodium dithionite test: Yellow → blue color change = paraquat present; clear at 6-24 h favors survival; darker blue = worse prognosis
• Serum paraquat concentration + time-of-ingestion nomogram: predicts mortality
• Serum cystatin C rise >0.009 mg/L over 6 h: associated with death

Prognostic Markers (Worse Outcome)

• Age >50 years
• Pre-existing renal disease
• Generalized skin burning sensation
• Persistent dark blue dithionite test at 24 hours
• Rising lactate, creatinine, cystatin C
• Pneumomediastinum or pneumothorax on CXR

Management - Harrison's Five Treatment Goals

Goal 1: Supportive Care

• Respiratory depression → pulmonary edema, ARDS
• Hypotension → hypovolemic + distributive shock
• Progressive clinical deterioration (multiorgan failure)

• Endotracheal intubation for airway protection if CNS depression
• Mechanical ventilation for ARDS
• Critical Harrison's principle: Do NOT give supplemental O₂ unless the patient is severely hypoxic - added oxygen sustains the superoxide radical redox cycle and worsens paraquat toxicity
• If O₂ is required (severe hypoxia), prognosis is already very poor
• Harrison's mentions ECMO as an emerging tool for severe but reversible respiratory failure

• Volume resuscitation for hypovolemia (GI fluid losses)
• If hypotension unresponsive to fluids: norepinephrine or high-dose dopamine (Harrison's recommendation)
• Intraaortic balloon pump / venoarterial perfusion for severe but reversible cardiac failure
• Pain management: opioid analgesics

Goal 2: Decontamination

Goal 3: Enhancement of Elimination

Goal 4: Antidotes

Harrison's principle: No specific antidote exists for paraquat.

• IV sodium bicarbonate for AGMA correction (Harrison's standard for AGMA poisonings)
• Benzodiazepines for seizures (Harrison's first-line for toxin-induced seizures)

Goal 5: Prevention of Re-exposure

• Psychiatric evaluation for all intentional ingestions
• Continuous observation and self-harm precautions until no longer suicidal
• Linkage to harm reduction services
• Notification of regulatory agencies (paraquat is a restricted substance in many countries)
• Early integration of palliative care team - given disastrous outcomes, Harrison's principles support this as appropriate and humane

Harrison's Global Considerations (Chapter 470)

"Patterns of travel, immigration, and internet consumerism should always be considered in patients suspected of poisoning without clear etiology. Immigrants may have underlying poisoning from work or environment where they previously lived..."

• South and Southeast Asia (Sri Lanka, India)
• Sub-Saharan Africa
• Latin America

Summary: Harrison's Framework for Paraquat