QuestionSBA
QuestionChoice
This will be raised in hepatitis but it is not a measure of synthetic liver function or a good prognosticator for fulminant hepatic failure.
52998
b
Alanine transaminase
QuestionChoice
This will be raised in hepatitis but it is not a measure of synthetic liver function or a good prognosticator for fulminant hepatic failure.
52999
c
Aspartate transaminase
QuestionChoice
The international normalised ratio is the best prognostic indicator for patients who have sustained hepatic injury due to paracetamol overdose. This is because it represents the synthetic function of the liver.
52997
a
International normalised ratio
QuestionChoice
The liver produces albumin, the main component of the blood-maintaining oncotic pressure. When albumin levels drop, fluid moves from the intravascular space to the interstitial space, causing peripheral oedema and ascites. The half-life of albumin is 3 weeks; therefore, it is not a good measure of liver function in the acute setting.
53001
e
Albumin
QuestionChoice
Liver injury typically causes prolongation of the prothrombin time and therefore the international normalised ratio. The activated partial thromboplastin time is usually spared.
53000
d
Activated partial thromboplastin time
QuestionComment
why not APTT?

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# Summary
 
Paracetamol overdose accounts for 44% of all adult self-poisoning cases in the UK and results in approximately 150,000 hospital admissions annually. Some patients may be asymptomatic, or present with nausea, vomiting, abdominal pain, jaundice or altered mental state. Investigations should include baseline bloods including a clotting and a blood gas, as well as a paracetamol level. Management depends on the dose taken, timing of ingestion and the patient's clinical condition, with N-acetylcysteine being the mainstay of treatment. The decision to treat is often guided by a nomogram although in certain situations N-acetylcysteine should be started immediately.
 
# Definition 
 
Paracetamol overdose refers to when a potentially toxic dose of paracetamol is taken, either accidentally or in the context of a self-harm or suicide attempt. 
 
# Epidemiology 
 
Paracetamol is the most common agent ingested in the context of intentional self-harm in the UK. Paracetamol overdose accounts for 44% of all adult self-poisoning cases in the UK, with approximately 150,000 people admitted to hospital each year due to poisoning.
 

# Aetiology
 
- The pathophysiology of paracetamol toxicity involves the build-up of its toxic metabolite NAPQI (N-acetyl-p-benzoquinone-imine). 
- Normally, NAPQI is inactivated by glutathione in the blood, but in a paracetamol overdose, glutathione stores are rapidly depleted. 
- NAPQI therefore accumulates, unmetabolised, and binds to cellular proteins, causing cell death.
- This causes both severe hepatotoxicity and nephrotoxicity that can lead to liver and kidney failure. 

# Classification
 
 - **Acute overdose** - excessive paracetamol taken in less than 1 hour, usually in the context of self-harm
 - **Staggered overdose** - excessive paracetamol ingested over longer than 1 hour, usually in the context of self harm
 - **Therapeutic excess** - excessive paracetamol taken with the intent to treat pain or fever and without self-harm intent, ingested at a dose greater than 75mg/kg/24 hours.


# Signs and Symptoms
 
- These depend on how long has passed since the overdose was taken
- In the first 24 hours patients may be asymptomatic or have nausea and vomiting
- After this, up to around 72 hours, right upper quadrant pain and hypotension may develop
- From 72 to 96 hours patients may develop liver and renal failure with resulting metabolic acidosis, encephalopathy and coagulopathy, with symptoms of:
         - Confusion
         - Drowsiness
         - Reduced urine output
         - Loin pain
         - Jaundice
         - Bleeding diathesis

# Differential Diagnosis 

 - **Acute gastroenteritis:** has similar symptoms of nausea, vomiting and abdominal pain; may have diarrhoea and history of unwell contacts
 - **Renal colic:** may also present with haematuria, nausea and vomiting; pain more likely to be "loin to groin" rather than right upper quadrant
 - **Decompensation of chronic liver disease:** can present with jaundice, abdominal pain and encephalopathy
 - **Sepsis:** can lead to a lactic acidosis and acute kidney injury; patients are often febrile and may have localising signs or symptoms of infection
 
# Investigations
 
Blood tests for paracetamol levels should be taken at least 4 hours after ingestion, as this is when plasma paracetamol concentration peaks so an earlier blood test may underestimate levels

Other important blood tests include:
 
 - Full Blood Count (FBC)
 - Urea and Electrolytes
 - Clotting Screen
 - Liver Function Tests
 - Venous Blood Gas (may show metabolic acidosis)
 - Blood glucose (could also do a bedside capillary blood glucose)
 - Salicylate levels (to look for a mixed overdose with aspirin)

# Management
 
**Conservative:**

- Weigh patient (important for determining dose of paracetamol taken per kg and to calculate N-acetylcysteine dosing)
- Consider if any other substances may have been taken with paracetamol
- If overdose was intentional, refer to liaison psychiatry for a mental health assessment
        - Consider if 1:1 observations are required for high-risk patients
        - Assess risk to self and ongoing suicidal ideation
        - Discharge planning and assess need for ongoing psychiatric input
- Treat any other self-harm

**Medical:**

Decisions on medical treatment are guided by a nomogram which plots paracetamol levels against time from ingestion. 

The management of paracetamol overdose is dependent on the timing of ingestion, the dose taken, and the patient's clinical condition:
 
 - **Ingestion less than 1 hour ago + dose >150mg/kg**: Administer activated charcoal
 - **Ingestion 1-4 hours ago**: Wait until 4 hours to take a level and treat with N-acetylcysteine (NAC) based on level
 - **Ingestion within 4-8 hours + dose >150mg/kg**: Start NAC immediately if there is going to be a delay of ≥8 hours in obtaining the paracetamol level, otherwise wait for level and treat if level high (above the treatment line on the nomogram)
 - **Ingestion within 8-24 hours + dose >150mg/kg**: Start NAC immediately
 - **Ingestion >24 hours ago**: Start NAC immediately if the patient has jaundice, right upper quadrant tenderness, elevated ALT, INR >1.3 or if the paracetamol concentration is detectable
 - **Staggered overdose**: Start NAC immediately
 
NAC is given as an IV medication - it acts by increasing glutathione levels thereby preventing toxicity. 

There are two ways to give NAC:

- Standard regimen of 3 consecutive infusions totalling 21 hours in duration 
- The newer SNAP protocol (now recommended by Royal College of Emergency Medicine as standard) where the same dose of NAC is given over 12 hours in two infusions
- If after either of these are completed, bloods show deranged LFTs, clotting or renal function NAC infusions should be continued and the patient discussed with local liver transplant services
- Anaphylactoid reactions are a common side effect of NAC, characterised by urticaria, angioedema, nausea and vomiting, tachycardia and bronchospasm but rarely shock
- These are managed by suspending treatment and giving chlorphenamine and salbutamol nebulisers before restarting (possibly at a slower rate)
 
**Surgical:**

Patients who develop acute liver failure may require an urgent liver transplant as a life-saving measure - the following groups of patients should be transferred to a liver transplant centre:

- INR > 3 at 48 hours or > 4.5 at any time
- Oliguric or creatinine > 200
- pH < 7.3 despite fluid resuscitation
- Hypotension (systolic blood pressure < 80mmHg)
- Severe thrombocytopenia
- Encephalopathy
  
The King's College Criteria is used to predict mortality from paracetamol overdose and to identify those patients who would potentially benefit from liver transplantation. It advises consideration of liver transplantation if:
 
- Blood pH < 7.3
 

Or **all** of:
 
- Serum creatinine > 300 µmol/L
- INR > 6.5 (Prothrombin time > 100s)
- Grade III or IV hepatic encephalopathy

# NICE Guidelines

[NICE CKS - Poisoning or overdose](https://cks.nice.org.uk/topics/poisoning-or-overdose/)

# References

[BNF - Poisoning](https://bnf.nice.org.uk/treatment-summary/poisoning-emergency-treatment.html)

[MHRA - Treating paracetamol overdose with intravenous acetylcysteine](https://www.gov.uk/drug-safety-update/treating-paracetamol-overdose-with-intravenous-acetylcysteine-new-guidance)

[RCEM - SNAP Protocol Position Statement](https://rcem.ac.uk/wp-content/uploads/2021/11/Use_of_SNAP_for_Treatment_of_Paracetamol_Toxicity_Nov_2021.pdf)

[Life in the Fast Lane - liver transplanation for paracetamol toxicity](https://litfl.com/liver-transplantation-for-paracetamol-toxicity/)
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Paracetamol Overdose
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Gastroenterology
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In paracetamol overdose, an elevated International Normalised Ratio (INR) is an important prognostic indicator, as it signifies liver dysfunction and a higher risk of severe complications, including bleeding and potential liver failure
A 28-year-old man presents to A&E after an overdose of paracetamol. He said he took 40 tablets over a 6-h period yesterday evening. It is now 11 a.m.

Which of the following tests provides the best prognostic indicator?
a