The document discusses paracetamol poisoning, highlighting its prevalence as a common overdose leading to hepatic necrosis and failure. It details the pharmacokinetics, metabolism, toxicity thresholds, clinical features, and management strategies including the use of N-acetylcysteine for treatment. Additionally, it outlines specific risk factors and complications related to acetaminophen overdose and offers guidance on treatment protocols for various rodenticide poisons.

1. DR ASHISH NAIR
MBBS, MD ANAESTHESIA
IDCCM FELLOW

2. PARACETAMOL POISONING
OVERVIEW
 Most common OD in the west
 overdose of acetaminophen has been recognized since
1966 to cause fatal and nonfatal hepatic necrosis
 acetaminophen remains a major cause of overdose and
overdose-related liver failure and death in the United
States and many other countries
 hepatic metabolism

3.  Acetaminophen is available in both immediate-release and sustained-release formulations
 The therapeutic dose is 10 to 15 mg/kg per dose in children and 325 to 1000 mg per dose in adults, given every four to six hours.
 maximum recommended daily dose of 80 mg/kg in children or 4 g in adults.
 The toxic dose may vary among individuals according to baseline glutathione levels and other factors :
1)Toxicity is unlikely to result from a single dose of less than 150 mg/kg in a child or 7.5 to 10 g for an adult .
2)Toxicity is likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour period.
3)Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity (defined as peak aspartate
aminotransferase [AST] or alanine aminotransferase [ALT] levels greater than 1000 IU/L) unless appropriately treated.

4. PK
 rapidly and completely absorbed from the gastrointestinal tract (duodenum)
 Serum concentrations peak between one-half and two hours after an oral therapeutic dose
 Peak serum concentrations are generally reached within four hours following overdose of immediate-release preparations
but may be delayed beyond four hours when drugs that delay gastric emptying (eg, opiates,
anticholinergic agents) .
 Therapeutic serum concentrations range from 10 to 20 mcg/mL (65 to 130 micromol/L).
 Elimination half-lives range from two to four hours for all acetaminophen preparations (delayed in extended release)
 Half-lives greater than four hours have been noted in patients who develop hepatotoxicity

5. METABOLISM
 At therapeutic doses, 90 percent of acetaminophen is metabolized in the liver to sulfate and glucuronide conjugates via sulfotransferase (SULT)
and UDP-glucuronosyl transferases (UGT)
 Conjugated metabolites are then excreted in the urine
 2 percent is excreted in the urine unchanged.
 The remaining acetaminophen is metabolized via oxidation by the hepatic cytochrome P450 (CYP2E1, CYP1A2, CYP3A4 subfamilies) mixed-
function oxidase pathway into a toxic, highly reactive, electrophilic intermediate N-acetyl-p-benzoquinoneimine (NAPQI)
 NAPQI is rapidly conjugated with hepatic glutathione (GSH), forming nontoxic cysteine and mercaptate compounds that are excreted in the
urine
 At toxic doses the sulfation and glucuronidation pathways become saturated, and more acetaminophen is shunted to the cytochrome P450
enzymes and metabolized to NAPQI .

Following overdose glucuronidation and sulphation pathways are rapidly saturated -> increased metabolism to NAPQI (N-acetyl-P-
benzoquineimine)
 Glutathione is required to inactivate NAPQI and when levels depleted -> hepatocellular death takes place
 NAPQI arylates and binds covalently to the cysteine groups on hepatic macromolecules, particularly mitochondrial proteins, forming NAPQI-
protein adducts. This process is irreversible.


7. MECHANISMS OF HEPATOCYTE INJURY
 The formation of these adducts leads to oxidative hepatocyte injury, alteration of the mitochondrial ATP-synthase alpha-subunit,
and hepatocellular centrilobular necrosis
 Toxic free radicals (eg, peroxynitrite) form nitrotyrosine adducts within the mitochondria .
 Injury to the mitochondrial DNA and ATP-synthase causes cessation of ATP synthesis. Lipid peroxidation and membrane injury
may play a role in the progression of hepatocellular injury .
 In addition, release of cytokines, apoptosis-inducing factor (AIF), endonuclease G (EndoG), and reactive nitrogen and oxygen
species from damaged mitochondria play a role in the spread of hepatic injury
 Damage-associated molecular pattern (DAMP) products (eg, nuclear fragments, mitochondrial DNA) recruit inflammatory cells
via the innate immune system . This secondary injury occurs during stage II of clinical toxicity.
 The centrilobular region (zone III) is preferentially involved because it is the area of greatest concentration of CYP2E1 and
therefore the site of maximal production of NAPQI
OTHER THEORIES
 the role of chemokines (in particular C-C chemokine receptor type 2 [CCR ]-positive monocytes)
 the activation of the inflammasome
 the contribution of hepatic stellate cells and liver repair .
 New models for studying the drug's toxicity include organoids and ex-vivo perfused human liver

8. CLINICAL FEATURES
 overdose of > 10g or > 200mg/kg
 doses of > 250mg/kg associated with massive hepatic necrosis and liver faillure
 be aware of the late presenters (> 8 hours since OD and start NAC empirically)
Stage 1 (0-24hrs)
 asymptomatic or GI upset only
Stage 2 (24-72 hrs)
 resolution or nausea and vomiting
 RUQ pain and tenderness
 progressive elevation of transaminases, bilirubin, PT
Stage 3 (72-96 hrs)
 hepatic failure (jaundice, coagulopathy, encephalopathy)
Stage 4 (4 days to 2 weeks)
 death from hepatic failure
 normalisation of LFT’s and complete resolution of hepatic architecture by 3 months

9.  Underlying hepatic impairment
 viral hepatitis
 alcoholic liver disease
 Microsomal enzyme induction
 Phenobarbitone, carbamazepine,phenytoin
 Rifampicin, isoniazid
 OCP
 trimethoprim-sulfamethoxazole, opioids, and
zidovudine may potentiate
acetaminophen hepatotoxicity by competing for
glucuronidation pathways
 chronic alcohol ingestion (CYP2E1)
 starvation
 Acute glutathione depletion states
 acute illness with decreased nutrient intake
 anorexia/bulimia/malnutrition/fasting
 HIV
RISK FACTORS FOR TOXICITY
CLINICAL FACTORS THAT MAY INFLUENCE TOXICITY
Excessive intake of acetaminophen (most important)
Delay between acetaminophen ingestion and N-acetylcysteine (NAC) therapy
Excessive cytochrome P450 activity
Decreased capacity for glucuronidation or sulfation
Depletion of glutathione stores
CLD- not risk factor
Low cyt P450 activity
Elimination t1/2 is prolonged by 2-
2.5hrs

10. Investigations
LFTs / coags / lactate/ BSL
Signs of severe hepatotoxicity include plasma ALT and AST levels that often exceed 10,000
IU/Lprolongation of the PT/INR, hypoglycemia, lactic acidosis, and a total bilirubin concentration
above 4.0 mg/dL or 68 micromol/L .
 Paractamol/ acetaminophen level
 urine tox
 ECG
 amylase
 blood alcohol
 pregnancy test
 ECG
Acetaminophen
Level
Result
10-20 mcg/mL Therapeutic levels
Less than 150
mcg/mL 4 hours
after ingestion
Low risk of liver
damage
Greater than 200
mcg/mL 4 hours
after ingestion Or
Greater than 50
mcg/mL 12 hours
after ingestion
Associated with
toxicity and liver
damage

11.  Contd…
 paracetamol (APAP) levels:
-> compare to Australasian nomogram (modified version of Rumack-Matthews nomogram) –
 to determine need for NAC rx
-> no role in chronic toxicity
-> treat if above threshold @ 4 hrs
-> a level of > 153mg/L is above treatment threshold regardless of time of ingestion
-> NAC must be given within 8 hours of OD (if level going to take longer
than 8 hours start NAC empirically)
 transaminases: peak @ 72 hrs
 PT: if >180 seconds on day 4 will need transplantation
 renal failure (less than 2% population- hepatorenal synd)
 metabolic acidosis = poor prognostic marker

12. MANAGEMENT
Resuscitation
 A: may require intubation and intubation if polypharmacy overdose and unrousable
B: lung protective ventilation
C: volume resuscitation
D: dextrose for hypoglycaemia
Evaluation
History
 Timing, quantity,dose
 other meds
 psychiatric history
Examination
 fuliminant hepatic failure signs
 signs of other drug toxicity

13. Treatment
Specific
 decrease absorption: activated charcoal if presented within 4 hours
 (controversial as if NAC given then this is a benign OD)
 N-acetyl cystine in D5W
(based on 4 hour level or empirically if > 8 hours since OD):

-> 150mg/kg LD
-> 50mg/kg over 4 hours
-> 100mg/kg over 16 hours
 can be administered at any time of presentation (up to 72 hours post ingestion with some improvement in outcome)
 can be administered orally but efficacy reduced by 40% if given with activated charcoal
 provides a substrate of glutathione and acts as an alternative substrate for NAPQI metabolism via the cytochrome P450
pathway
 watch for adverse effects: rash, bronchospasm, hypotension, angioedema (antihistamines helpful and also slowing of
infusion)

14. Liver failure management
 don’t correct coagulopathy unless bleeding (vitamin K IV, blood products)
 arterial ammonia (aids in prognostication: absolute level and failure to fall)
 glucose monitoring
 avoid hypothermia
 reverse jugular venous saturation monitoring
 ICP monitoring (controversial)
 avoid hyponatraemia
 ventilate to normocapnia
 thiopentone and indomethacin infusions (consult with liver unit)
 renal failure management
 MARS therapy: some benefit shown in paracetamol OD as a bridge to transplantation

15. Patients are at increased risk for developing acetaminophen-induced hepatotoxicity if they have any of the following
findings:
Ingestion of greater than 7.5 to 10 g of acetaminophen over 24 hours, or ingestion ofgreater than 4 g over 24 hours and an
increased susceptibility to hepatotoxicity (eg, chronic alcohol use, fasting, use of P450-inducing drugs
Abdominal pain or liver tenderness, nausea, vomiting, jaundice, or are ill appearing.
Supratherapeutic serum acetaminophen concentrations (greater than 20 mcg/mL, or 130 micromol/L) with or without ALT
elevation
Elevated ALT or AST concentration (≥50 U/L) on presentation. Patients with a history of RSTI of acetaminophen should be
considered to have acetaminophen-induced hepatotoxicity when aminotransferases are elevated, regardless of the measured
serum acetaminophen concentration.
Elevated acetaminophen-aminotransferase multiplication product on presentation. An elevated product predicts significant
hepatotoxicity independent of the time of ingestion.
Suspect hepatic failure

16.  Disposition
 discuss early with transplantation team (develop liver
failure within 48 hours)
 admit to medical/gastro unless requires ICU
 will require psychiatric assessment if was an intentional overdose
 Prognostication — can use the O’Grady criteria:
 acidaemia (pH < 7.3)
 renal impairment (creatinine > 300micromoles/L)
 hepatic encephalopathy (grade III or IV)
 PT > 100 seconds (INR > 6.5)
 factor V level < 10%

17. N-acetylcysteine
 CLASS
 glutathione supplementation
 MECHANISM OF ACTION
 ? protects the liver by maintaining and restoring glutathione levels or by acting as an alternate substrate for conjugation with -> detoxification of reactive metabolites.
 PHARMACEUTICS
 IV or oral formulation
 200mg/mL
 compatible with 5% dextrose
 DOSE
 prevention of contrast nephropathy: 1200mg by slow push prior to scan and 48 hrs post investigation
 paracetamol OD:
o 150mg/kg in 200mL of D5W over 15 min
o 50mg/kg in 500mL of D5W over 4 hrs
o 100mg/kg in 1000mL of D5W over 16 hrs

18.  INDICATIONS
 paracetamol overdose
 non-paracetamol induced fulminant hepatic failure
 prevention of contrast nephropathy
 ADVERSE EFFECTS
 rash
 angioedema
 hypotension
 anaphylaxis
 GI upset
 dysphoria
 bronchospasm

19.  EVIDENCE
 Contrast Nephropathy Prophylaxis
 -> controversial -> may decrease creatinine from skeletal muscle as opposed to effecting renal function directly

20. RODENTICIDE
POISONING

21.  These rat poisons have recently become a common means of self poisoning in Northern India ,
with a mortality rate of 60%.
 National Poison Center data – in India, zinc phosphide, barium carbonate, and aluminum
phosphide remain the most common cause of household and agricultural rodenticide poisoning
Poisoning may be:
 -Suicidal
 -Accidental
 -Homicidal
Modes of poisoning:
 -Ingestion
 -Inhalation
 -Dermal contact

22.  The most clinically helpful categorization of rodenticides utilizes the amount of poison that causes death in
50percent of patients following exposure (lethal doseor LD) and a corresponding "signal word"
 Highly toxic – LD50: 0 to 50 mg/kg, signal word "Danger"
 Toxic – LD50: 50 to 500 mg/kg, signal word "Warning"
 Less toxic – LD: 500 to 5000 mg/kg, signal word "Caution“
 The clinician is encouraged to contact a regional poison control
center to assist with identification and interpretation of rodenticide labeling.

23.  Inorganic preparations: Barium carbonate, phosphorous ,Thallium , Zn phosphide
 Organic preparations: Flouro acetate compounds
 Convulsants: Strychnine
Anti coagulants:
 -First generation : warfarin , coumatetrayl
 Intermediate: chlorophalicone
 -Second generation : Brodifacoum , Difenacoum
Others: Arsenic , Bromethalin , Endrin , Sodium fluoro acetate and Zyklon.
Various rat poisons available

24.  When the poison is not known, clinical features can help with identification and guide treatment as follows :
●Cardiac arrhythmias, refractory shock, or cardiac arrest – Cardiovascular toxicity suggests the followingrodenticides
which can be further classified by when signs appear after exposure:
•Early: Zinc or aluminum phosphide, white (yellow) phosphorus, or barium carbonate
•Late: Arsenic, thallium, sodium monofluoroacetate (SMFA), or fluoroacetamide
●Seizures – SMFA, fluoroacetamide, tetramine, or arsenic
●Muscle rigidity, opisthotonus, trismus, and facial grimacing (risus sardonicus) – Strychnine
●Cranial neuropathy, lethargy, or coma – Thallium, arsenic, alpha-chloralose, bromethalin, Vacor (pyriminil,N-3-pyridylmethyl-N-p-nitrophenylurea,
PNU)
Bruising or bleeding – Anticoagulants (warfarin, superwarfarin compounds)
Asymptomatic patients — Asymptomatic patients may still develop serious toxicity. The clinician should beespecially cautious when managing patients
with intentional ingestions.
Known poison — Management depends upon the agent as follows:

25. ANTI COAGULANTS:
 -After ingestion of lethal dose , it effectively blocks the vit-k cycle , resulting in inability to produce
essential blood clotting factors mainly factors II and VII.
 massive toxic doses of 4-hydroxycoumarin cause damage to tiny blood vessels , increasing their
permeability , causing diffuse Internal Bleeding.
 -These effects are gradual , developing over several days.
 -This is the preferred type of rat bait , as the antidote is available i.e, Vit-K.

26.  Do not have onset symptoms , which might manifest days later.
 Haematuria
 Bloody diarrhoea
 Extensive Bruising
 Epistaxis
 Haematemesis
 Low Blood pressure
 Confusion , Lethargy , Altered mental status
 Shock
With Warfarin: Pin point Purplish red spots
Anti-coagulants

27. Rx:
 • Vitamin K1 (phytonadione)@0.25-5 mg/kg s/c
 • Menaphthone (vit K3)@ 0.5- 2 mg/kg i/m
 • Fresh frozen plasma @ 9ml/kg i/v
 • Whole blood @ 20 ml/kg i/v
 • Glucose and saline therapy
 • Supplemental oxygen • Oxalic acid derivatives
Anticoagulants

29.  If no coagulopathy is found in the setting of an anti- coagulant exposure ,prophylactic treatment with
Vit-K is absolutely contraindicated.
 If a coagulopathy is documented , Vit-K therapy is suggested.
 Patients who present with life threatening haemorrhage , in addition to Vit-K, Prothrombin complex
conc. and/or fresh frozen plasma may be needed to reverse anti coagulation.
Anticoagulants

30. Calciferols:
 -MOA:
On ingestion in toxic doses these affect calcium and
phosphate homeostasis causing hypercalcemia.
 On accumulation in stomach , kidney , lungs , blood vessels and heart
 are all calcified/mineralised.
 -It has a synergistic effect with anticoagulant , thereby increasing the
 chances of death and decrease in the time involved.
Nausea , Vomiting , Anorexia , Fatigue , Itching and Weakness.
Acute Intoxication: Polyneuropathy.
Chronic Intoxication: Extreme depression , Apathy ,
Confusion , Fatigue.
With calciferols

31. CLINICAL SIGNS
 Develop within 18 – 36 hr of ingestion.
 Depression & anorexia.
 Passing large amounts of urine & excessive thirst.
 hematemsis.
 Hemorrhagic diarrhoea.
 GI smooth M excitability decrease results into constipation.

32. TREATMENT
 • Gastric evacuation followed by administration of activated charcoal@ 2-8 g/kg in water slurry.
 • Prednisolone@ 1-2 mg /kg.
 • Fluid therapy with NSS.
 • Furosemide@5mg/kg i/v followed by 3mg/kg tid.
 • Calcitonin@4-10 IU/kg s/c to reduce serum calcium levels.

33.  WITH BARIUM: Nausea , Weakness , Abdominal pain.
 WITH THALLIUM: Acute GI distress , Anorexia , Myalgias , Painful neuropathy and hair loss.
 WITH STRYCHNINE: Anxiety , Generalized seizure like appearance without loss of consciousness ,
Muscle twitching , Facial grimacing.
 WITH ARSENIC: Nausea , Vomiting , Bloody diarrhoea and garlic taste in mouth.
With others

34. Pertinent ancillary testing eg,
 continuous electrocardiogram monitoring for barium carbonate, phosphide compounds, and phosphorus compounds;
 serum lactate and blood gas analysis for SMFA/ fluoroacetamide;
 serum calcium in patients possibly exposed to elemental phosphorus;
 Serum potassium following barium carbonate exposure or phosphide compound ingestion;
 Glucose monitoring after Vacor ingestion).
Observation for a minimum of six hours after exposure
If the patient has any symptoms of poisoning orabnormal findings on ancillary testing, then hospitalization is warranted.

35. All asymptomatic patients with exposure to an unknown rodenticide warrant the following
studies:
●12-lead ECG and continuous monitoring
●Plain radiographs of the chest and abdomen
●Complete blood count
●Prothrombin time and international normalized ratio (PT and INR) and partial thromboplastin
time (PTT)
●Blood glucose
●Serum electrolytes
●Venous or arterial blood gas
●Serum calcium and phosphorus
●Blood urea nitrogen (BUN) and serum creatinine
● Liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and
bilirubin
MANAGEMENT

36. ●QTc prolongation on ECG – Arsenic, white (yellow) phosphorus, sodium monofluoroacetate (SMFA), orfluoroacetamide
●Hypocalcemia – White (yellow) phosphorus, SMFA, or fluoroacetamide
●Lactic acidosis – SMFA or fluoroacetamide
●Hyperphosphatemia – White (yellow) phosphorus
●Hypokalemia – Zinc or aluminum phosphide or barium carbonate
●Radiopaque substance on abdominal radiograph – Arsenic, thallium, or barium carbonate
●Elevated liver enzymes, BUN, or creatinine – Thallium, white (yellow) phosphorus, arsenic, or zinc oraluminum phosphide
●Hyperglycemia with ketoacidosis – Vacor
● Elevated PT and INR – Anticoagulant
What to expect??

37. asymptomatic patients
- within one hour of ingestion should undergo gastric lavage followed by
administration of activated charcoal with appropriate precautions to protect the
airway and prevent aspiration as needed.
- ACTIVATED CHARCOAL is used as soon as possible to prevent further systemic absorption
of ingested toxin.
- Gastric lavage should not be performed inpatients who have already vomited
spontaneously.
Symptomatic and unstable
 Secure airway and place IV lines in Haemodynamically unstable patients.
 Inducing Vomiting is likely only with in 1-2hrs after ingestion.
TREATMENT

39.  Commonly found in powder, pellet, or tablet form, the metallic phosphides,zinc and
aluminum phosphide, are both low-cost and highly toxic rodenticides
 Common means of self poisoning in northern India.
 Inhalation of phosphine gas, produced when aluminum or zinc phosphide is exposed to
moisture in stored grain represents the most common form of exposure.
 Oral exposures from deliberate suicidal ingestions with aluminum phosphide are common in
northern India .
 Mortality rate of
 Al -60%.
 Zn -2%
 Direct ingestion of ≥500 mg of phosphides usuallyresults in death.
 MECHANISM OF ACTION: • Both the compounds react with gastric acid to form
phosphine, a potent pulmonary and GIT toxicant.
ALUMINIUM & ZINC PHOSPHIDE

40. Zinc phosphide:
 - It is a single dose fast acting rodenticide.
 -Death occurs with in 1-3days after ingestion.
MOA:
 Acid in the stomach reacts with the phosphide to yield toxic phosphine gas which is a potent pulmonary
toxicant.
 WITH ZINC PHOSPHIDE:
 -Via Inhalation : Cough, Nausea ,Vomiting,Headache Fatigue.
 -Via Ingestion: Abdominal pain , Cough , Diarrhoea , Dizziness , Shortness of breath , Unconsciousness ,
Nausea , Vomiting Uncoordinated movements.
PRESENTATION

41. Clinical manifestations and diagnosis – Phosphide toxicity occurs rapidly, typically within 30 minutes of exposure.
Clinical findings of zinc phosphide ingestion consist of the following [40]:
•Gastrointestinal (GI) irritation marked by nausea, vomiting, hematemesis, and retrosternal chest and abdominal
•Shock with refractory hypotension caused by direct cardiac toxicity
•Cardiac arrhythmias, including bradycardia, supraventricular tachycardia, atrial fibrillation, atrial flutter and
arrhythmias
•Hemorrhagic pulmonary edema with tachypnea, cough, acute respiratory distress syndrome, and respiratory
 Less common features include hepatotoxicity, intravascular hemolysis with methemoglobinemia and/or renal
failure

42. • For phosphide ingestion, supportive care is the mainstay of treatment and consists of the following
•Provide supplemental oxygen and ventilation as needed and dictated by the degree of respiratory compromise. Tracheal
intubation may be performed in standard fashion.
•Provide fluid resuscitation with rapid infusions of isotonic normal saline to replace obvious fluid lossesand to treat
hypovolemic shock.
•Treat hypoglycemia and correct hypokalemia and hypomagnesemia as indicated.
•Treat cardiogenic shock with vasoactive medications as needed in patients unresponsive to isotonic fluid resuscitation.
Manage atrial and ventricular arrhythmias according to Advanced Cardiac Life Support and Pediatric Life Support guidelines
 Other therapies – Individual case reports describe the use of N-acetylcysteine (NAC) as an antioxidantand the antianginal
agent trimetazidine to maintain oxidative phosphorylation

43. DIAGNOSIS
 Detection of phosphine in the exhaled air/stomach aspirate.
 Using a silver nitrate impregnated strip or a specific phosphine detector tube is diagnostic.
 Gas chromatography is most sensitive indicator.
TREATMENT
Supportive.
Directed at correcting electrolyte abnormalities & treating complications.
No specific antidote.
Ca gluconate & Na bicarbonate to neutralize stomach acidity.
Early gastric lavage, often with vegetable oil to reduce the release of phosphine.

44.  ZINC PHOSPHIDE:
-Supportive therapy remains the only available form as there is no specific antidote.
-Gastric lavage with vegetable oil to reduce the release of toxic phosphine.
-Patients with severe respiratory compromise require endotracheal intubation for ventilatory support.
-Severe haemolysis from phosphine gas may require exchange transfusion of RBCs.
Specific treatment

46. LEARNING OUTCOME
 Source
 Characteristics
 Mode of poisoning & fatal dose
 Signs and symptoms
 Post-mortem appearance
 Medicolegal importance

47. Source & characteristics
Greyish green tablet, metallic taste, garlicky odour
Solid fumigant pesticide, insecticide and rodenticide
Widely used as grain preservative (phosphite & hypophosphite of aluminium are non-
toxic residues left in the grains)
Celphos, Alphos, Quickphos, Phostoxin, Phosphotex
Each tablet is 3g, can liberate 1g of phosphine (PH3) when come in contact with moisture
HCl in stomach accelerate the convertion

48.  Mode of poisoning & fatal dose
1. Ingestion
Fatal dose: 0.5 g (1-3 tablets)
Fatal period: 1-4 hours. Majority die within 24 hours
2. Inhalation
Fatal dose: inhale phosphine 400-600 ppm
Fatal period: 1-4 hours.
Majority die within 24 hours

49.  Absorption & Excretion Ingest
Absorbed from GI tract by simple diffusion
Then, some ALP metabolised in liver & phosphine is slowly released
Phosphine is oxidised slowly to oxyacids
Excreted in urine as hypophosphine Inhale
Rapidly absorbed from the lungs
Excreted unchanged form through lungs

51.  Action
Inhibits respiratory chain enzymes and has cytotoxic action
Inhibits electron transport; inhibits cytochrome oxidase

52. Signs and Symptoms
 INHALATION
 MILD: irritation of mucous membrane, acute respiratory distress, dizziness,
easy fatigue, tightness in the chest, nausea, vomiting, diarrhoea, headache
 MODERATE: ataxia, numbness, paraesthesia, tremors, diplopia, jaundice,
muscular weakness, incoordination and paralysis
 SEVERE (PH3> 0.3 ppm): adult respiratory distress syndrome, cariac
arrhythmias, congestive cardiac failure, pulmonary edema, convulsions, coma

53.  MILD: nausea, vomiting, headache, abdominal pain (patients usually recover)
 MODERATE & SEVERE: systemic manifestations are early and progressive and mostly fatal
 GIT: nausea, vomiting, diarrhoea, retrosternal pain
 CVS: hypotension, shock, arrhythmias, myocarditis, pericarditis, acute congestive heart
failure
 RS: cough, dyspnoea, cyanosis, pulmonary edema, respiratory failure
 HEPATIC: jaundice, hepatitis, hepatomegaly
 RENAL: renal failure
 CNS: headache, dizziness, altered mental state, restlessness, convulsions, acute hypoxic
encephalopathy, coma
 RARE: muscle wasting, tenderness and bleeding

54. Complications
Cardiogenic shock (most common cause of death)
Pericarditis
Acute congestive cardiac failure
Acute massive GI bleeding
ARDS (high mortality)

55. Postmortem appearances
Garlic-like odour at the mouth & nostrils & gastric content
Blood-stained froth in the mouth & nostrils
Mucous membrane of the lower part of esophagus, stomach & duodenum are
congested
Decreasing congestion of GI in small intestine
Lungs, liver, spleen, kidneys & brain are congested
Centrizonal haemorrhagic necrosis of the liver may be seen

56. Histopathology
Stomach: congestion, edema, leucocytic infiltration, sloughing of gastric mucosa
Lung: congestion, edema, desquamation of respiratory epithelium, thickened alveoli,
lymphocytic infiltration
Kidneys: congestion, necrosis, tubular degeneration and regeneration
Adrenals: congestion, haemorrhage, necrosis, area of lipid depletion in cortex
Heart: congestion, edema, fragmentation of fibres, focal necrosis, leucocytic infiltration
Brain: congestion, edema

57.  Medicolegal importance
 Suicidal in rural area of india
 Accidental poisoning by farmer who sleep near godown; leaking phosphine
from godown is possible
 Accidental poisoning by children which mistakenly ingest the tablets

58. Chemical tests
 5 ml of gastric aspirate + 15 ml of water are put in a flask and the mouth
is covered with a filter paper impregnated with 0.1 N silver nitrate. Flask is
heated at 50C for 15-20 minutes. Filter paper turns black if phosphine
present.
 A piece of filter paper impregnated with 0.1 N silver nitrate solution is
used in the form of mask through which the patient breathes for 5-10
minutes. Filter paper turns black if phosphine present. (POSITIVE only
when >6 g is ingested)

59. TREATMENT
 No specific antidote
 Primarily supportive care
 Early arrival, resuscitation, diagnosis, intensive monitoring and supportive treatment
 Gastric lavage with potassium permanganate (1:10000)
 No activated charcoal
 Sorbitol solution1-2 ml/kg may be used as cathartic
 In vitro trials of vegetable oils and liquid paraffin prevents conversion to phosphine
 Critical care support – haemodynamic instability, airway mx, inotrope support, invasive lines,
arrhythmias

60.  MgSO4 as anti-peroxidant effect has been used (dec effects of phosphine)
 Hyperglycemia on admission is a significant poor prognostic indicator
 Acidosis (target pH >7.1 and HCO3 18-20 mmol/lt) – soda bicarb
 Refractory acidosis - continuous veno venous hemofiltration
 Role of NAC (conflicting studies)
 GIK drip (restore Ca influx and inc myocardial contractility)

61.  PROGNOSIS
Ph <7.2
Hco3 <18 mmol/lt
Sbp < 90 mmHg
Altered mental status
 Latest updates
Role of insulin euglycemia in outcome of AlP
poisoning
Role of ECMO in ALP poisoning patients

62. ORGANOPHOSPHORUS
POISONING

63. INTRODUCTION
 Organophosphate (OP) compounds are a diverse group of chemicals used in
bothdomestic and industrial settings. Many phosphates are potent nerve agents,
functioning by inhibiting the action of acetylcholinesterase(AChE) in nerve cells. They
are one of the most common cause of poisoning worldwide , and frequently
intentionally used in suicides in agricultural areas.

64. WHO CLASSIFICATION (Simplified)
HIGLY TOXIC MODERATELY TOXIC
1. Phosphamidon (Dimercron) 1. Malathion
2. Ethyl parathion 2. Fenthion
3. Methyl parathion 3. Temephos
4. Chloro- thiophos 4. Fenitrothin (tik-20)
5. Carbo-phenothion 5. Diazinon (spectacide)

65. USES OF ORGANOPHOSPHATE
Nerve agents
Insectisides
Glaucoma treatment
Myasthenia gravis

66. Organophosphates vs. Carbamates
Organophosphates Carbamates
Cholinesterase Non-reversible Reversible
Atropine Yes Yes
Ageing of enzyme Yes No
2- PAM Yes, within a few
hours
No

67. Absorption route
 Cutaneous
 Ingestion
 Inhalation
 Injection

68. Mechanism of action
 Op inhibit acetylcholine esterase
enzyme at nerve endings by
phosphorylation
 That results in increase in
acetylcholine at receptor sites.

69. Clinical features in poisoning
Muscarinic features Nicotinic features CNS features
D iarrhoea Muscle weakness Fatigue
U rination Muscle fasciculation confusion
M iosis Muscle fasciculation unconsciousness
B ronchorrhea
B ronchospasm
Seizures
E mesis Hypertension Ataxia
L acrimation Tachycardia Resp. depression
S alivation
S weating

71. Dreisbach classification
Grade Symptoms
MILD NAUSEA , VOMITTING
DIARRHOEA
SWEATING
MODERATE LACRIMATION , SALIVATION
MIOSIS
FASCICULATION
SEVERE INCONTINENCE
ARDS, APNOIC SPELLS
AREFLEXIA , SEIZURE, COMA.

72. DIAGNOSIS
 H/o Ingestion of poison
 Characteristic clinical features
 petroleum or garlic like odour
 If doubt exists a trial of atropine (0.01 to 0.02 mg/kg) may be employed
 The absence of signs abd symptoms of anticholinergic effects following atropine
challenge strongly supports the diagnosis.

74. INVESTIGATIONS
1 . Butyrylcholinesterase activity in plasma
2 . Acetylcholinesterase in whole blood
3. Other
I . CXR – Evaluate pulmonary oedema
II. ECG – Cardiac arrhythmias
III. ABG & Electrolytes
IV. Urea

75. Different phases of toxicity
1. Acute cholinergic crisis
2. Intermediate syndrome –
major cause of morbidity
and mortality
3. Delayed neuropathy

76. Intermediate syndrome
 Occurs 24-96 hours after resolution of acute cholinergic
crisis

77. Mechanism of IMS
 Excess acetylcholine at NMJ
causes downregulation of
nicotinic receptors – muscle
affected
 Inadequate oxime therapy
 Respiratory failure without
muscaricin signs
 Muscle necrosis
 Failure of postsynaptic
acetylcholine release , and
oxidative stress-related myopathy

79. Monitoring for IMS
 C/F typically occur within 24 to 96 hours and persists for 4
to 18 days
 Affecting conscious patients without cholinergic signs, and
 Involve the muscles of respiration, proximal limb muscles,
neck flexors and muscles innervated by motor cranial nerves
 Assess flexor neck strength regularly (head lift and hold
against resistance)
 Weakness is sign of peripheral respiratory failure

80. Delayed neuropathy
 Organophosphate induced delayed neuropathy (OPIDN)
1. 2-3 weeks after large dose
2. Peripheral/ distal neuropathy (proximal sparing)
3. Due to inhibition of neuropathy target esterases (NTE)
4. Recovery can take upto 12 months
 Chronic organophosphate induced neuropsychiatric disorder
(COPIND)

81. Other manifestations
 Extrapyramidal manifestations- Dystonia, resting tremor,
rigidity, chorea
 Neuro-ophthalmic manifestations – optic neuropathy, retinal
degeneration
 Rarer manifestations - GBS, ototoxicity, sphincter
involvement
 ARDS, pancreatitis

82. Management of organophosphate
poisoning
1. Check airway , breathing , circulation
2. Monitor vitals and cardiac rhythm
3. Look for signs and symptoms
4. Obtain IV access
5. Remove contaminated clothes & wash the skin thoroughly
with soap & water.

83. 6. Atropine intravenously as soon as possible for symptomatic
patient
7. Pralidoxime (Reactivator)
8. Gastric lavage once the patient is stabilized & within 2 hours of
ingestion with activated charcoal (50 g in 200 ml )
9. Maintenance atropine infusion

84. Atropinisation
 Start with 1.8 – 3.0 mg stat iv bolus
 After 3 – 5 min check
1. Bronchorrea & bronchospasm
2. Bradycardia ( < 60)
3. Miosis
4. Excessive sweating
5. Hypotension
 If not corrected double the dose of atropine every 5 min until signs of atropinisation.

85. Signs of Atropinization
1. Clear chest on auscultation with no wheeze
2. Heart rate > 80 beats/min
3. Pupils no longer pinpoint
4. Dry axillae
5. Systolic blood pressure > 80 mmHg

86. Maintenance infusion
 D5 + 10-20 % of the total initial dose of atropine on an
hourly basis. (after stabilization)
 Stop atropine infusion if features of toxicity

87. Atropine Toxicity
 Confusion , delirium, coma
 Urinary retension , Bowel ileus
 Hyperthermia
 Agitation, psychosis
 Flushing
 Tachycardia(> 140 / min)
 Fixed dilated pupil

88. Pralidoxime
 loading dose @ 30 mg/kg IV over 10 – 20 mins
 Followed by continuous infusion of 8-10 mg/kg/hr.
 continue oxime infusion until atropine has not been needed
for 12-24 h and patient extubated.