Paracetamol Poisoning

• It is important to remember that, when used at therapeutic levels, Paracetamol is safe and effective.
• Paracetamol overdose may occur intentionally and accidentally; the latter due to the high number of combination products available over the counter.

• Paracetamol can cause serious or fatal adverse effects at around 150mg/kg for most adults.
• The level is higher for young children.
• Chronic alcoholics have a lower threshold for toxicity, at around 75mg/kg.

Severe effects have been seen to occur with as few as 10 gm Paracetamol (20 tablets) in susceptible patients.
Toxicity is increased with any factors that may impair hepatic metabolism:

• Ethanol excess
• Malnutrition
• Enzyme inducing drugs e.g. rifampicin and carbamazepine

Paracetamol is well absorbed after taken orally from the stomach and small intestine and reaches a peak plasma concentration in one hour.
It is inactivated by the liver by conjugation leading to two metabolites; glucoronide or sulphate. It is then renally excreted through urine.

• When taken in overdose the liver conjugation becomes inundated causing Paracetamol to be metabolised by an alternative pathway.
• This results in a toxic metabolite, N-acetyl-p-benzoquinone imine (NABQI), which is itself inactivated by glutathione, rapidly preventing any harm.
• However, glutathione can be run down with minor increases in the toxin, and when this occurs NABQI reacts with nucleophilic aspects of the cell, leading to necrosis. Necrosis occurs in the liver and in the kidney tubules.

Toxicity is increased in patients with induction of the P450 system through drugs such as rifampicin, phenobarbital, isoniazid, phenytoin, carbamazepine and alcohol.
This also occurs in patients with low glutathione reserves, as a product of:

• Genetic variation
• HIV +ve
• Malnutrition
• Alcohol-related or other liver disease

Paediatric patients (under the age of five years) seem to fare better after paracetamol poisoning, perhaps due to a greater capacity to conjugate with sulfate, enhanced detoxification of NABQI or greater glutathione stores. However, it should not be assumed that treatment in children should be different than for adults, since no controlled studies have supported any alternative paediatric therapy.

• Commonly patients are asymptomatic for the first 24 hours or have non-specific abdominal symptoms (such as nausea and vomiting).
• Hepatic necrosis begins to develop after 24 hours (elevated transaminases, RUQ pain and jaundice) and can progress to acute liver failure.
• Patients may also develop
  • Encephalopathy
  • Oliguria
  • Hypoglycaemia
  • Renal failure - usually occurs around day 3
  • Lactic acidosis

History

• Number of tablets, formulation, any concomitant tablets (include herbal remedies as substances, such as, St John's Wort - an enzyme inducer)
• Time of overdose
• Suicide risk - was a note left?

Examination

• Usually very little to find, until the patient develops acute liver failure (ALF)
• If ALF develops may see jaundice, hepatic flap, encephalopathy and tender hepatomegaly

• Paracetamol level (usually performed with a salicylate level); take Paracetamol level 4 hours post ingestion, or as soon as patient arrives if:
  • Time of overdose >4 hours
  • Staggered overdose (in staggered overdoses, level not interpretable except to confirm ingestion)
• U& E Creatinine; to look for renal failure and have a baseline
• Liver function tests: ALT >1000iu/L indicates severe liver damage
• Glucose; hypoglycaemia is common in hepatic necrosis and capillary blood glucose should be checked hourly
• Clotting screen; PT is best indicator of severity of liver failure and the INR should be checked 12 hourly
• FBC
• Arterial blood gas; acidosis can occur at a very early stage, even when the patient is asymptomatic. It is seen in up to 10% patients with acute liver failure.

Specific up-to-date information is available online from Toxbase³

• The benefit of gastric lavage is unclear^4,5; consider emptying the stomach (gastric lavage) if >7.5g has been taken within 1 hour.
• Consider giving activated charcoal (dose = 50g [Child: 1g/kg] orally or via ng tube) if:
  • 150 mg/kg or 12g of paracetamol (whichever is the smaller) in total has been taken within 1 hour
  • Unknown ingestion time, or less than 1 hour (sometimes extended if gastric mobility reduced by other co-ingestants)
• Regularly monitor urine output, blood glucose hourly, U&E, LFT's and INR 12 hourly
• After you have the 4 hour Paracetamol level, decide whether the patient is at high risk of severe liver damage. Follow treatment line A or B as necessary.
  
  
  
  
  
• Start N-acetylcysteine (NAC) if Paracetamol level at 4 hours above the treatment line.
  However Start treatment with NAC immediately ⁶ - do not wait for the level - if any of the following are present:
  • If more than 150 mg/kg (or 12g in an adult) of paracetamol has been ingested.
  • Or the overdose is staggered.
  • Or the patient is a late presenter (>15hrs post ingestion) having allegedly taken a significant overdose.

If the patient has taken a significant overdose (based on the history), but the initial Paracetamol level is below the treatment line then repeat the level four hours later as there can be delayed absorption.
Refer to ICU if fulminant liver failure, those treated with NAC to the medical team and all parasuicides to the psychiatric team.

NAC is believed to work by a number of protective mechanisms. It acts as a precursor for glutathione, promoting normal conjugation of any remaining paracetamol, and also supplies thiols that function as antioxidants. Its protective effect is greatest when administered within 12 hours of ingestion. Therapy with NAC has been shown to decrease mortality in late-presenting patients with fulminant hepatic failure.
Treatment must be started within 8 hours of ingesting if maximum protection is to be obtained.

• < 5% of patients develop an allergic reaction to NAC (rash, Bronchospasm and hypotension).
• If they do then the rate of the infusion should be slowed down.
• If the patient has had previous allergic reactions to NAC then consider giving intravenous hydrocortisone and chlorphenamine prior to starting the infusion.
• An alternative is methionine,⁷ but absorption may be unreliable if there is vomiting or activated charcoal administration. Also methionine is less effective unless given early on. Give 2.5g methionine po every 4 hours for 4 doses (Child <6yrs give 1g po every 4 hours for 4 hours) if within 12 hours of overdose.

Treatment usually continues for the duration once NAC is started regardless of the plasma levels. This usually takes 24 hours.
Prior to discharge it is sensible to re- check the INR, renal and liver function tests.
Patient's should be advised to return if vomiting occurs after discharge.

The treatment of patients presenting more than 24 hours after ingestion is controversial.

• Measure INR, creatinine, ALT and venous blood acid/base balance or bicarbonate.
• If any of these is abnormal discuss with your nearest national poisons information centre (0870 600 6266).

Paracetamol overdose is the commonest drug taken in overdose during pregnancy.⁹The resulting toxic metabolites can cross the placenta and lead to hepatocellular necrosis of maternal and fetal liver cells.
NAC can bind the toxic metabolites in the mother and fetal circulation as it crosses the placenta. NAC appears to be safe during pregnancy and therefore should be administered.

• Encephalopathy or raised ICP. Signs of CNS oedema include BP >160/90 (sustained) or brief rises (systolic >200mmHg), bradycardia, decerebrate posture, extensor spasms, poor pupil responses. ICP monitoring can help.
• INR >2.0 at or before 48h or >3.5 at or before 72h (so measure INR every 12h). Peak elevation occurs around 72 - 96h. LFTs are not good markers of hepatocyte death.
• Renal impairment (creatinine >200 µmol/L). Monitor urine flow. Daily U&E and serum creatinine (use haemodialysis if >400 µmol/L).
• Blood pH <7.3 (lactic acidosis results in tissue hypoxia).
• Systolic BP <80mmHg despite adequate fluid resuscitation.
• Hypoglycaemia.
• Metabolic acidosis (pH <7.3 or bicarbonate < 18).

The mortality from severe liver failure is <5% with good supportive care.
Although liver transplantation only has a limited application,³ patients must be identified as early as possible, preferably on the second day.
Current data indicates a poor prognosis if:

• An arterial pH <7.30 (hydrogen ion concentration >50 nmol/L) on or after day 2 post overdose (found in ~70% of cases with a poor prognosis).
• A combination of a prothrombin time of more than 100 seconds (INR 6.7), plasma creatinine >300micromol/L and grade 3 or 4 hepatic encephalopathy (only a 17% survival rate).
• An increase in prothrombin time between day 3 and day 4 after overdose.

Liver transplantation is probably contra-indicated in patients with severe hypotension, severe cerebral oedema and serious infection.