Paraquat Poisoning

By : Himaja Kalakota
Under the guidance of unit 4
• Introduction

• Methods of poisoning

• Kinetics

• Pharmacology and cellular toxicity

• Clinical feature

• Diagnosis

• Management

• Prognosis
Introduction
• Incidence of paraquat poisoning is 3.8/1,00,000 in a year
• A Bipyridyl compound, rapidly acting nonselective herbicide

• Mechanism of toxicity to plants includes inhibition of photosynthesis,

respiration, protein synthesis, growth stimulation

• Manufactured as liquid granules / aerosols

• Combined with Diquat – contains dye, emetic, stenching agent (to

reduce toxicity on ingestion)
• Mortality rates of 72.7% in a study conducted in 55 people

• 3,00,000 occur in Asian-pacific region due to paraquat poisoning

Methods of poisoning
• Ingestion – responsible for majority of deaths

• Transdermal absorption is minimal in the absence of skin lesions, but

deaths have been reported

• Inhalation / exposure to sprays – irritate conjunctiva and airway,

unlikely to cause systemic toxicity
Kinetics
• Highly polar and corrosive

• Not absorbed in significant amounts across intact skin or inhaled

droplets

• Rapidly but incompletely absorbed from gut (jejunum - 17.6%).

• Lethal oral dose of 20% concentrate solution is about

: 10-20 ml in adult

: 4-5 ml in children

• Plasma concentration peaks with in 2 hours of ingestion

• Tissue concentration peaks by 6 hours

• Elimination is mainly by kidneys unchanged form, most ingested

paraquat appears in the urine with in 24 hours in minor poisoning
• In severe poisoning kidney function is greatly reduced leading to
much slower elimination
Pharmacology and cellular toxicology
• Actively accumulate in many cells where it under goes redox cycling
and form superoxide radical, a highly reactive oxygen spices

• Superoxide causes direct cellular damage or react further to form

other ROS and nitrite radicals

• Redox cycling consumes NADPH (anti-oxidant)

• The resultant oxidative stress created by production of free radicals
and depletion of NADPH causes cell damage (lipid peroxidation,
mitochondrial dysfunction, necrosis and apoptosis) and triggers
secondary inflammation

• Over a period of hours to days these process lead to multiorgan

dysfunction
• Most organs affected are those with high blood flow and oxygen
tension and energy requirements – lungs, heart, kidneys and liver

• Brain is uncommonly affected as it doesn’t cross BBB

• Lung injury has two phases

• Initial destruction phase – loss of type 1 and 2 alveolar cells,

infiltration by inflammatory cells, haemorrhage. Changes are
reversible

• Later proliferative phase – fibrosis of interstitium and alveolar spaces

• Paraquat and oxygen enhance each other toxicity sustaining redox

cycle

• Myocardial injury and necrosis of adrenal gland

Clinical features
• Depends on quantity, route of exposure

• Skin exposure causes local skin irritation and ulceration of epithelial

surfaces due to severe caustic

• Eye exposure causes corneal injury due to severe corrosive action

• Upper respiratory tract exposure causes mucosal injury and epistaxis

due to corrosive action
• Inhalation – cough, dyspnoea, chest pain

• Ingestion – GI irritation and mucosal damage with ulceration, painful

mouth and pain with swallowing, nausea, vomiting and abdominal
pain
On examination

• Mouth and pharynx charred, ulcers

• Tongue dry due to vomiting, poor oral intake due to odynophagia

• Tachypnoea, tachycardia, hypotension

• Bilateral crepitation due to alveolitis

• Subcutaneous emphysema indicating mediastinitis

• Diffuse abdominal tenderness

Paraquat tongue early lesion, within 24 Paraquat tongue late lesion, 2 weeks after
hours after ingestion ingestion with extensive ulceration
Classification based on clinical features

• Mild

• Severe

• Fulminant
Mild Asymptomatic <20mg/kg
Nausea, vomiting, diarrhoea Or
Renal and hepatic injury <7.5ml of 20% concentration
minimal/absent solution in adult
Reduced pulmonary diffusion
capacity
Complete recovery expected

Severe Initially nausea, vomiting, 20-40mg/kg

diarrhoea Or
Abdominal pain 7.5-15ml of 20% concentration in
Mouth and throat ulcers adult
Positive colorimetric test for
paraquat in urine
1-4 days, renal failure, hepatic
impairment, hypotension
1-2 weeks cough, haemoptysis,
pleural fibrosis
Majority die within 2-3 weeks due
to pulmonary failure
Fulminant Initially nausea, vomiting, >40-50mg/kg
diarrhoea Or
Pain abdomen >15-20ml of 20% concentration
Rapid development of renal and solution
hepatic failure
GI ulcers
Pancreatitis
Toxic myocarditis
Refractory hypotension
Convulsions
Coma
Death due to cardiogenic shock
and multiorgan failure with in 1-4
days
• Multisystem effects include GI tract corrosion, acute renal failure,
cardiac failure, hepatic failure, extensive pulmonary injury few hours
after ingestion
• Renal failure and hepatic cellular necrosis develop between 2nd – 5th
day
• Progressive pulmonary fibrosis leading to refractory hypoxemia occur
5 days to several weeks
• Metabolic acidosis common due to hypoxia combined with
multisystem failure
Investigations
• Electrolytes
• RFT – acute kidney injury due to acute tubular necrosis, volume
depletion. Most commonly used to asses kidney function are
Creatinine and Cystatin C
• Rate of serum creatinine correlates with survival
• Amylase and lipase – acute pancreatitis in case patient develops pain
abdomen
• Increase in S . Creatinine
- <0.034mg/dL/hr over 5 hours – recovery expected
- >0.045mg/dL/hr over 6 hours
or
- increase in serum cystatin concentration of >0.09mg/L
over 6 hours – death
• Creatinine also increases due to muscle oxidative stress
• Therefore is not a marker of GFR in paraquat poisoning
• Alkalosis due to excessive vomiting
• Acidosis - respiratory acidosis (alveolitis or aspiration pneumonia) and
metabolic acidosis (diarrhoea, AKI, mitochondrial toxicity,
hypotension)
• Lactic acidosis in severe poisoning due to multiorgan dysfunction,
hypotension, hypoxic acute respiratory distress syndrome
• Serum lactate above 4.4mmol/L or 3.35mmol/L associated with fatal
outcome ( sensitivity 82% and 74%, specificity 88% and 91%) and
hence aid in prognosis
• Chest X-Ray - diffuse pulmonary infiltrates bilaterally due to poison,
local infiltrates due to aspiration (more on the right)
pneumomediastinum, pneumothorax due to corrosive action
• Urinary dithionate test – in alkaline medium sodium dithionate
reduces paraquat to blue radical. Test should performed on fresh
urine sample around 6 hours after ingestion detect paraquat within
few hours after ingestion, semiquantitative test

• If urine paraquat concentration is more than 1mg/L the urine will turn
blue in the test (poor prognosis)
• The addition of sodium bicarbonate and sodium dithionite to urine
specimens containing decreasing concentrations of paraquat shows
characteristic color changes.

• Each number represents decreasing concentrations of paraquat.

• Paraquat detection kits – 10ml urine to collected in a clear container,
add sachet A containing sodium bicarbonate, shake. Add sachet B
containing sodium dithionate wait for effervescence to subside and
shake again.
• Once mixture settled, view against white background for blue or
greenish grey colour change, which indicates paraquat poisoning
• Serum paraquat concentration – serum concentration levels to time
of poisoning predicts likelihood of death. A fatal outcome is likely if
the plasma concentration lies
above any line. (Sample to be drawn
at least after 4 hours of ingestion)
• Qualitative serum testing – conduct dithionate test in plasma with
positive urinary dithionate test. Equivocal colour change associated
with 50% mortality, definitive colour change associated with 100%
mortality
HRCT one year following a paraquat ingestion,
showing pulmonary fibrosis, more in the left lung.
Diagnosis
• History of ingestion

• Oropharyngeal burns and subsequent development of AKI, metabolic

acidosis, ARDS

• Confirmed with urinary or blood dithionate test

Management
• Survival rate is about 13% with no treatment and increases to 73%
with active treatment

• Resuscitation – assessment of airway, breathing and circulation

• Airway compromised due to mucosal damage or presence of vomitus

• Tachypnoea and/or hypoxia due to metabolic acidosis, aspiration,

acute alveolitis

• Mild to moderate hypoxia should not be treated with oxygen as

worsens oxidative stress
• Hypotension to be treated with crystalloids 15-20ml/kg over 15-30
minutes

• Maintaining high urine out put is desirable (how much?)

• Impaired consciousness indicates severe toxicity resulting in altered

consciousness from hypoxia, hypotension and severe acidosis or
co-ingestion of other agents like ethanol – intubated the patient
• Decontamination - gastric lavage with in 2 – 4hours, followed by
activated charcoal or Fuller’s earth. Lavage not indicated in as it is
contraindicated in caustic injury

• Nasogastric tube – pharyngeal or oesophageal burns, painful

swallowing

• IVF – hypotension

• Acute renal failure – daily fluid balance to be maintained with

ensuring good urine output
• Pain relief and sedation – opioids and benzodiazepines

• Hemoperfusion/haemodialysis – if presents wit in 2 hours of

ingestion in case of AKI without pneumonitis.

- Benefits are limited, endogenous clearance is high in first 6-12

hours and additional amount eliminated will
be relatively modest.

- Subsequent elimination of accumulated paraquat from the lungs

is minimally dependent on plasma concentration
• Immunosuppression – suppressing acute inflammatory response, thus
reducing chances of lung fibrosis and death

- Cyclophosphamide, MESNA, Methylprednisolone and Dexamethasone

- Dexamethasone increases the expression of P-glycoprotein

- Significant reduction of paraquat accumulation in the lungs and increase

faecal excretion

- Has also shown to ameliorate histological and biochemical changes and

reduce lipid perioxidation
• 1g of cyclophosphamide daily for 2 days and 1g of
methylprednisolone daily for 3 days
Study Description Treatment Mortality
Addo & Poon-King [84] Uncontrolled 72 CP, Dex, MP, vitamin B, 28%
patients vitamin C

Afzali & Gholyaf [87] RCT 20 patients CP, Dex, MP vs. conventional 33% vs. 81%
treatment

Perriens et al. [89] Uncontrolled 47 patients CP, Dex vs. conventional treatment 63% vs 61%

Lin et al. [86] RCT 23 patients CP, Dex, MP vs. conventional treatment 31% vs 86%

Lin et al. [80] RCT 50 patients CP, Dex, MP vs. conventional 68% vs 82%
treatment

Lin et al. [85] 16 patients 17 historic CP, Dex, MP 25% vs 70%

controls

Yasaka et al. [28] Uncontrolled 9 patients Vitamin E 100–4000 mg/day 78%

Hong et al. [99] Uncontrolled 5 patients Vitamin C escalating doses 0%

• Anti-oxidants

• Vitamin E – vitamin E stabilises membrane and scavenges ROS.

- Vitamin E deficiency rats had lower lethal dose and shorter

survival time, vitamin E treated rat lungs after 24 hours of exposure
showed less peroxidation

- human study only 2/9 patients survived

- 200-400mg/day
• Vitamin C – donate electron to free radicals and neutralise. Study
done on 10 patients, positive urine dithionate test and stable vitals
high dose of vitamin c and other oxidants were given, increased anti-
oxidants in the body

• N-acetylcysteine – replenishes cysteine, rate limiting in synthesis of

glutathione. Reduced paraquat induced apoptosis and inflammatory
response

- S - carboxymethycysteine 1500mg/day
• Deferoxamine – iron contributes to generation of free radicals by
Fenton’s reaction. Iron chelator used with no survival benefits

• Salicylic acid – inhibits cyclo-oxygenase. Scavenges hydroxyl radicals

and inhibit their production by Fenton’s reaction

- reduces inflammatory mediators IL4, oxidative stress, NF, lipid

peroxidation, platelet activation and histological lung damage

- single dose of salicylic acid 200mg/kg, showed no deaths when

compared to control group
Prognosis
• Details of exposure including time, route, accidental/intentional,
amount, concentration

• Quantity related to outcome

• >50 years and H/O renal disease worst prognosis

• S. Lactate aid prognosis

Thank you