Paracetamol Poisoning
Presenter: Dr Choo Hao Jian
Supervisor: Dr Emi
Paracetamol
• Most commonly overdosed drug
(deliberate self-poisoning,
paediatric accidental overdose,
repeated supratherapeutic
exposure)
• Easily available over the counter
• Indication for use: Antipyretic and
analgesic
• Not effective for: Anti-
inflammatory (localised/systemic)
as little to no effect on COX 1 and
COX 2
• Absorption of oral acetaminophen occurs primarily along
the small intestine by passive diffusion. Therefore, the rate-
limiting step is the rate of gastric emptying into the
intestines.
• peak serum concentrations occur within 1– 2 hours for
standard tablet or capsule formulations and within 30
minutes for liquid preparations
• Twenty per cent of the ingested dose undergoes firstpass
metabolism in the gut wall (sulphation)
• Distribution is usually within 4 hours of ingestion for
standard preparations and 2 hours for liquid preparations
• In therapeutic doses, the elimination half-life is 1.5–3
hours.
Bioavailability: Oral: 85-98 %; rapidly absorbed in
GI
Therapeutic range: 10-20 mg/L
Peak concentration: 1-2 hours for tablet, 30 mins for
liquid
Clearance: Paeds 0.12-0.34 L/hour/kg, Adults 0.27
L/hour/kg
Half life: Neonate 4-11 hours, Paeds 1.5-4.2 hours,
Adults 2-3 hours
• About 90% is metabolised to inactive sulphate
and glucuronide conjugates that are excreted in
the urine. Metabolism of the remainder is via
cytochrome P450 enzymes (chiefly CYP2E1 and
CYP3A4) and results in the highly reactive
intermediary compound N-acetyl-p-benzoquinone
imine (NAPQI)
• NAPQI is detoxified by irreversible glutathione-
dependent conjugation reactions to mercapturic
acid and cysteine conjugates.
• In overdose, the increased formation of NAPQI
depletes hepatic glutathione stores (glutathione
depleted to <30 % of normal) and NAPQI
covalently binds to critical cellular proteins, causing
damage to hepatocytes and acute liver injury
Age Group Max Therapeutic Dose
Normal Pediatric (oral) 75 mg/kg/day Or
4g/day
Dose Infant and children (<12 years) (Rectal) 2.6 g per day
Children >=12 years / adolescent 4 g/day
Adult (oral / rectal) 4 g/day
Ingestion Toxic Dose
So, how Single dose ingestion
Paediatric 150 mg/kg, 200
mg/kg in healthy
much is pediatric 1-6 years
Adult 150 mg/kg or 7.5 g
too much? High Risk Group >75mg/kg
High Risk Group:
1. Regular alcohol consumption
2. Chronic Liver Disease
3. Regular use of enzyme inducing drug (carbamazepine, phenytoin,
phenobarbitone, rifampicin)
4. Glutathione depleting condition: malnutrition, HIV, reduced oral intake,
eating disorders, cystic fibrosis
Ingested dose
Time of ingestion
Risk Preparation ingested (e.g. immediate-release or
modified-release)
Assessment Single or staggered ingestion
Most important risk factor: Time before treatment
with acetylcysteine > 8 hours (higher mortality/morbidity)
Signs and Symptoms
Stage 1 2 3 4 A correlation between sign
Timing from First 24 hour Days 2-3 Days 3-4 After day 4, up to 3 weeks and symptoms of paracetamol
ingestion (Hepatic phase)
ingestion with time of
Sign and Loss of Improvement in Recurrent of loss of Clinical improvement and ingestion.
symptoms appetite appetite, less appetite, nausea recovery (7–8 days) or
nausea and and vomiting. Deterioration to multi-
vomiting. organ failure and death
Nausea Abdominal pain Altered mental
(RUQ) status (Hepatic
encephalopathy)
Vomiting Liver tenderness Jaundice
Tachycardia Coagulopathy
Lethargy Hypotension Hypoglycemia
Oliguria Acute Renal Failure
• those with an initial
paracetamol concentration
greater than double the
150mg at 4 h nomogram
line are at higher risk of
acute liver injury and require
higher doses of
acetylcysteine.
• The nomogram cannot be
applied in those presenting
more than 24 hours post
ingestion or if the time of
ingestion cannot be
determined with confidence
by the treating clinician, or in
modified-release
• TDM Sampling time:
at 4 hours after ingestion or on
admission if already past 4
hours post ingestion. Sample
immediately also for repeated
supra-therapeutic ingestion.
• Other bloods:
LFT (focus on ALT > AST), RP,
Coag, RBS, Lipase, Amylase, ABG
and ammonia (clinically
compromised)
Toxicity may be defined also as
AST/ALT greater than 1000 IU/L,
rapid progression to 3000 IU/L or
higher reflect worsening
hepatotoxicity
General Management: Red Flags!
• Repeated supra therapeutic ingestion
• Multiple/staggered ingestion of sustained release paracetamol
• Co-ingestion with other preparations
• Level plotted in normogram double treatment line
• INFORM EP / TOXICOLOGIST STAT
General Management: Resuscitation
• Airway, Breathing, Circulation (ABC) first!
• Altered mental state? DEFG (Don’t ever forget Glucose!) Hypoglycaemia
• In exceptional cases, massive ingestion causing extremely high serum paracetamol
concentrations (usually above 800 mg/L or > 5000 μmol/L) may be associated with an
early decrease in level of consciousness and lactic acidosis – Haemodialysis may have a
role in this case.
• Acetylcysteine is the mainstay of treatment
• Patient not suitable for Acetylcysteine? Methionine aka Acimethin (New drug oral
preparation available in HTJ only, require import permit, not in drug formulary)
NAC
General Management: NAC initiation
• < 4 hours post ingestion
– 50 g activated charcoal orally (1g/kg in children) if within 1-2 hours
- if ingested > 30 g, give up to 4 hours post ingestion. TDM PCM at 4 hours and plot nomogram, commence NAC
if indicated.
• 4-8 hours post ingestion
- TDM PCM stat, commence NAC if indicated
• 8-24 hours post ingestion
- Empirical NAC if reported dose toxic. Continue if above or on treatment line or abnormal ix (ALT), stop if
below line and normal ix.
• > 24 hours or unknown time of ingestion
- Empirical NAC if dose toxic or not confident of history. Continue if detectable PCM (10 mcg/ml), pt
symptomatic or abnormal ix.
NAC (N-Acetylcysteine)
• Treatment with acetylcysteine ensures survival if administered within 8 hours of
paracetamol ingestion. Beyond 8–10 hours after ingestion, efficacy decreases with
increasing delay to treatment
• Those with an initial paracetamol concentration greater than double the
nomogram line have been shown to benefit from an increased dose of
acetylcysteine. The second bag in the two-bag acetylcysteine regimen should be
doubled to 200 mg/kg IV acetylcysteine over 16 hours (instead of 100 mg/kg over
16 hours)
3 bag NAC
protocol
(Old)
• 1st Bag: 200 mg/kg in 500 ml of Dextrose 5 % over
Latest 4h
• 2nd Bag: 100 mg/kg in 1 l of Dextrose 5 % over 16
Protocol: h)
• For paeds:
2 bag NAC Children (<=20 kg): 200 mg/kg in 7 ml/kg NS over
4 hours, then 100 mg/kg in 14 ml/kg NS over 16
hours
Children (20-40 kg): 200 mg/kg in 250 ml NS over
4 hours, then 100 mg/kg in 500 ml NS over 16
hours
• Dose calculated based on actual body weight
• Can be discontinued when resolution or absence
Latest of liver injury (asymptomatic, ALT/AST stable or
declining)
Protocol: • Blood ix repeated 3 hours before completion of
NAC
2 bag NAC • Continue at 150 mg/kg in 3 pint D5% over 24
hours if pt symptomatic, abnormal lab test, PCM
still detectable in blood
NAC Adverse Reactions
• Look out for: Rash, wheeze (bronchospasm) and hypotension
• More likely in predisposed individuals (Asthmatics)
• Severe life threatening reactions to be treated with adrenaline as
required
• If occurs, to halt infusion and give antihistamine,
corticosteroid, bronchodilator as required.
• To continue once adverse reaction settled down at slower rate. To
complete dose.
Methionine
• Adult and children > 6 years old
2.5 g QID 4 doses
• Under 6 years old
1 g QID 4 doses
• However only licensed for use in
over 12 years old
Gastric Decontamination: Activated
charcoal (50 g in an adult)
• recommended in awake and cooperative patients
• Within 2 hours of ingesting a toxic dose of paracetamol [≥ 10 g or ≥ 200 mg/kg (whichever is less)].
• Within 4 hours of ingesting ≥ 30 g of immediate-release paracetamol
• Within 4 hours of ingesting a toxic dose
• Activated charcoal administered within 2 hours of an immediate release paracetamol ingestion
reduces the absorbed paracetamol dose and the likelihood that acetylcysteine will subsequently be
required, reduced risk of acute liver injury
• Significant hepatic injury is extremely rare after acute single accidental paracetamol ingestion in
children under 6 years of age, and it is very uncommon for them to have concentrations that require
acetylcysteine treatment – hence charcoal usually not indicated in children even if consumed toxic dose
Liver Transplant (Liver Failure)
Criteria
• INR > 3.0 at 48 hours or > 4.5 at any time,
• oliguria or creatinine > 200 µmol/L,
• persistent acidosis (pH < 7.3) or arterial lactate > 3 mmol/L,
• systolic hypotension with BP < 80mmHg, despite resuscitation,
• hypoglycaemia, severe thrombocytopenia or encephalopathy of any
degree,
• any alteration of consciousness (GCS < 15) not associated with
sedative co-ingestions
Case Study
18 year old girl,
ADL independent
completed COVID-19 vaccination
studying in college- KKTM Rembau
LMP: 16/7/2022
Underlying:
1/ ?Anxiety/MDD- previously under IIUMMC, Kuantan follow up
- defaulted medication since January 2022 as pt migrate to Negeri Sembilan
- previously on Clonazepam and escitalopram ?anxiety
Brought by lecturer, alleged PCM ingestion at college around 10am today
- took 12 tab pcm 500mg at same time, found by lecturer pt unconscious at bathroom
- suicidal attempt and intention
- pt stress as patient will having assembly tonight with senior student in college regarding social interaction
between male and female student and worried will be scolded by one of her senior as had been seen
together at 'Dewan Makan'
-claimed had multiples suicidal ideation before since early this year
- precipitator: stress study, family issue - auditory hallucination past 2years
- flash memories of scolding voices causing anxiety attack
Post ingestion:
+ vomitting x1 + bloatedness, belching, No sob
Upon arrival in ED,
O/E:
Alert, GCS full, warm peripheries, crt < 2 sec, good pulse volume
BP 123/77 PR 73 SPO2 100% under RA TEMP 36.4 REFLO 5.7
Lungs clear
cvs drnm
abd soft, non tender
no pedal edema
Noted total pcm 6g/day (103mg/kg)
Blood ix:
FBC: TWC 5.3/ Hb 13.1/ Plt 291
Urea 1.53/ creat 46/ Na 138/ K 3.4
TP 71.6/ Alb 42.5/ ALP 55.5/ ALT 6.9/ AST 16.5/ T bili 13.4
Calcium 2.29/ Mg 0.81/ Po4 0.89
VBG: pH 7.448/ PCO2 32.6/ PO2 35.2/ HCO3 22/ Lactate 1.64
INR 1.1/ PT 13.6/ APTT 36.4
UFEME negative, UPT negative
case referred to Dr Gangga, Psy SP oncall HTJS
- case noted, suicidal precaution
- treat current cause
- to get medical hx from previous hospital
- to get family member to stay together while pt being admitted as pt 18 yo
- if aggressive, for 2 point strained
Case referred to Dr Manesha, Physcian medical HTJS oncall
- to start NAC regime weight 58kg) IV NAC 150mg/kg/H (8700mg or 43.5ml) in 200cc D5% over 1H (run
200cc/h) IV NAC 12.5mg/kg/H (725mg or 3.7ml) in 1 pint D5% over 1H4 H (run 125ml/h) IV NAC
6.25mg/kg/H (363mg or 1.8 ml) in 1 pint D5% over 16H (run 62ml/h)
- suicidal precaution
- admit ward hospital rembau
- trace serum acetaminophen, salicylate acid
Imp:
Alleged PCM ingestion with deliberate self-harm with U/L anxiety/MDD
References
Chiew Al, Reith D, Pomerleau
A, et al. Updated guidelines
Management Guideline of for the management of
Paracetamol Poisoning ETD paracetamol poisoning in
HTJS Updated June 2022 Australia and New Zealand.
Med J Aust 2019; doi:
10.5694/mja2.50428.
