paracetamol poisoning

Question 1

how does paracetamol induce toxicity?

Answer 1

15% of paracetamol is metabolised to NAPQI which is toxic. This NAPQI is detoxified by glutathione which we obtain from our diet. In an overdose, more NAPQI is produced and the glutathione stores are used up so it cannot be detoxified. NAPQI has direct oxidising and arylating effects causing hepatic injury and renal damage.

Question 2

what factors influence paracetamol hepatotoxicity?

Answer 2

• the dose of paracetamol that is absorbed
• the plasma paracetamol concentration
• the time to antidote administration
• whether tablets were taken as a single acute event or in a staggered fashion

Question 3

How does the ingested dose of paracetamol effect heapatotoxicity?

Answer 3

• less than 75mg/kg is unlikely to cause any severe liver damage
• 75-150 mg/kg is rare to cause any severe liver damage
• more than 150mg/kg is more possible to cause severe liver damage

Question 4

how does plasma paracetamol concentration effect hepatotoxicity?

Answer 4

There is a graph that shows plasma paracetamol concentration vs hours after ingestion (see in notes). you should take the patients blood and plot this on the graph and if it lies under the line then severe liver damage is unlikely and if it lies over the line then severe liver damage is likely.
NOTE - you have to wait 4 hours since last paracetamol ingestion to give an accurate measure as otherwise all the paracetamol may not have been absorbed. There is also no evidence base after 16 hours so this is based only on extrapolation.

Question 5

how does time to antidote administration affect hepatotoxicity?

Answer 5

The 8 hour rule - provided a patient is treated within 8 hours of overdose they are not at risk of significant liver damage. If you can get the plasma paracetamol concentration result will be back before this 8 hour window is up then you should wait for the results but if there is a risk of missing the 8 hour window then you should start straight away because it can always be stopped if results come back that it is not needed. For late presenters, antidotal treatment does not guarantee protection from liver damage and the later the antidote is given the less likely it is to work.

Question 6

what antidotal treatment is given for paracetamol overdose and how?

Answer 6

glutathione precursors are given as this supplements dietary glutathione to detoxify NAPQI. Acetylcysteine is the most commonly used.
IV acetylcysteine is currently given in a 3 bag 21 hour course (this is in the process of changing to a 12 hour course)
- bag 1 = 150mg/kg in 200ml 5% glucose over 1 hour
- bag 2 = 50mg/kg in 500ml 5% glucose over 4 hours
- bag 3 = 100mg/kg in 100ml 5% glucose over 16 hours

Question 7

what are the common side effects of paracetamol antidotes?

Answer 7

anaphylactoid features in 10-15% of individuals - this is more likely if the plasma concentration is low (flushing, urticaria, pruritis, bronchospasm, rarely angioedema, wheezing, respiratory distress and hypertension)

this is a histamine mediated reaction and is treated with antihistamines

Question 8

how does whether the tablets were taken as an acute event or in a staggered fashion affect hepatotoxicity?

How is this managed?

Answer 8

a staggered OD is defined as a patient taking a paracetamol overdose over more than 60 minutes
This makes it harder to determine plasma concentration and estimate toxicity and therefore all patients with a staggered overdose should be treated with acetylcysteine.
this acetylcysteine therapy can be stopped in patients who are not considered to be at risk of clinically significant hepatotoxicity which is unlikely if the following are present after 4 hours of most recent ingestion
- concentration is less than 10mg/l
- AND the ALT is within the normal range
- AND the INR is 1.3 or less
- AND the patient has no symptoms suggestive of liver damage

Question 9

outline the clinical presentation of a patient with an untreated paracetamol overdose

Answer 9

day 1

• asymptomatic
• may have GI symptoms - nausea, vomiting, pallor, abdominal pain, anorexia

day 2

• in patients who had GI upset on day 1 they may become asymptomatic
• nausea and vomiting
• hepatic tenderness and generalised abdominal pain
• occasionally mild jaundice

day 3

• jaundice
• back pain and renal angle tenderness
• cardiac arrhythmias

Question 10

what biochemical and haematological abnormalities will be found in a patient who has had an untreated paracetamol OD?

Answer 10

increased AST and ALT 
increased bilirubin 
decreased blood sugar 
decreased phosphate 
metabolic acidosis 
increased prothrombin time (INR)
decreased clotting factors II, V, VII 
decreased platelets

Question 11

How do you treat someone who has presented late with a paracetamol overdose?

Answer 11

Late presenters will still benefit from acetylcysteine therapy even if they are already in fulminant hepatic failure. Administer bag 1 and 2 and normal and then keep repeating bag 3 until there are one of three outcomes: complete recovery, liver transplant or death.

you can use the following biomarkers to assess prognosis

• PT/INR
• creatinine
• pH
• presence of encephalopathy
• age