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Accident and Emergency Medicine, Ninewells Hospital, Dundee

              Paracetamol Poisoning

Poisoning

          There are basically two types of poisoning, non-intentional and intentional.  Non-intentional poisoning can be industrial, agricultural or domestic and involves exposure to intrinsically harmful substances.  Domestic non-intentional poisoning is very common in young children under the age of five, with the main culprits being household chemicals such as bleach or organophosphates (weedkillers).  Intentional poisoning occurs after exposure to substances only harmful in excess.  The age groups most at risk are the 15 - 19 year olds coping with adolescence.  Although a patient can theoretically overdose on whatever is at hand, and during my four weeks in A&E I saw Anadin Extra, Temazepam, right through to Beta-blockers and Metformin, there are certain drugs that seem to be favoured.  Paracetamol, is by far the leader, however the Compound Analgesics are catching up, after that Tricyclic antidepressants, Ibuprofen, Opioids, Benzodiazepines and Barbiturates.  Alcohol should also always be considered as it is often taken to wash down the overdose and can affect the management of a patient.  As I stated previously Paracetamol (Acetaminophen) is the most common drug taken in overdose, and therefore is the topic of my essay.

Paracetamol Poisoning

          Paracetamol is metabolised in the liver by Cytochromes P450, with a percentage metabolised into toxic intermediates.  Glutathione then conjugates these into Mercapturic Acid.  If the dose is large enough, the glucuronidation pathways are disrupted or if there is underlying liver damage Glutathione stores cannot cope and the unconjugated toxic metabolites react with proteins causing hepatic cell damage and death.  Signs and symptoms are as follows:

·        In 1^st 24 – 48 hrs patient may appear well – however nausea and vomiting may occur, especially if taken with alcohol

·        48 – 72 hrs: Anorexia

                         Nausea and vomiting

                         Right subcostal pain – indicator of hepatocellular necrosis.  

Surprisingly, the majority of people make a complete recovery, even after substantial overdoses, the liver healing with complete resolution, without fibrosis.  Conversely, hepatocellular damage can occur with as little as 20 – 30 tablets, about 150mg/kg.  Those with chronic alcohol consumption have a lower toxic threshold as they have increased levels of cytochromes P450 that metabolise the toxic intermediates faster than glutathione stores can keep up with.  Concomitant drugs such as Isoniazid, Phenytoin and Zidovudine can also lower the toxic dose threshold.  Isoniazid and Phenytoin increase the metabolism of paracetamol, and Zidovudine competes for glucuronidation pathways.  If severe liver damage and failure occurs it does so usually within 3 days and is associated with:

·        Repeated vomiting

·        Jaundice

·        Hypoglycaemia

·        Coagulopathy

·        Encephalopathy

·        ALT > 2000

Death occurs about 4 – 18 days later, usually from cerebral oedema and sepsis.

Management in A&E

Firstly, and most importantly:

·        Airway

·        Breathing

·        Circulation

The majority of paracetamol overdose patients present early and are therefore conscious and breathing normally.

If the patient is unconscious the airway must be protected and tracheal intubation may be required.  There is a risk of aspiration of stomach contents if the patient vomits. 

In all patients if a significant ingestion or suspicion of significant ingestion has occurred, the following guidelines are used in A&E:

1.     If within 1 hour of ingestion, gastric lavage can be carried out.  However this treatment is becoming increasingly unfashionable, as there is no direct evidence that it improves the patient’s outcome and it carries with it the risk of pulmonary aspiration of stomach contents.

2.     If within 4 hours, patients can be given 50gm of activated charcoal.  This procedure is more efficient at preventing absorption of poisons toxic in small amounts, eg Tricyclic Antidepressants.

3.     Patients should be admitted to the short stay ward.

4.     At 4 hours post ingestion, or on arrival to the department if greater than 4 hours post ingestion, plasma paracetamol levels should be obtained.  At this time Paracetamol and Salicylate levels should be requested and liver function tests should be done.

5.     When the Paracetamol level is known, it should be plotted on an individual nomogram for each patient.                                   

If below the treatment line, then no further action is required.

If the patient is in a “High Risk” group i.e someone taking enzyme inducing drugs such as Carbamazepine, Phenytoin, Phenobarbitone or Rifampicin, or if they are malnourished such as chronic alcoholics, anorexics or known to be HIV positive, then the threshold for treatment is the “High Risk” treatment curve on the nomogram:

   If the patient’s paracetamol level requires treatment they should   

   receive IV N Acetylcysteine (Parvolex) at the regime stated below the    

   nomogram.  N Acetylcysteine is a precursor of Glutathione, which increases Glutathione levels in the liver, therefore increasing the rate of conjugation of the toxic intermediates.

6.     At 8 hours following ingestion a further paracetamol level and clotting factor, in particular Prothrombin time, should be taken.

Patients who present late to the department (8 – 24 hours) with significant ingestion i.e greater than 150mg/kg or when ingestion time is staggered should be commenced on Parvolex immediately and blood investigations taken appropriately.

Those patients presenting more than 24 hours after ingestion can also be given parvolex particularly if their investigations are abnormal and they are symptomatic.

7.  Patients who stay over night in the short stay ward are assessed the next morning in the ward round.The patient will also be seen by a psychiatric nurse who will arrange appropriate counselling and help.

Case study – Miss X

Miss X is a 17year old female who presented to A&E having taken 16 Paracetamol and 32 Ibuprofen.  This worked out to be 8g of Paracetamol.  She was asymptomatic on presentation, having been brought in about an hour after ingestion after her father realised she had ingested a large amount of tablets.  On examination there was evidence of deliberate self-harm.  She had a history of overdose with a previous attempt at 14 years old, and was on Fluoxetine, however her GP was in the process of changing her prescription and she had been without medication for about three days.  At 4 hours post ingestion her plasma Paracetamol and Salicylate levels were measured and found to be:

Paracetamol – 0.61 mmol/l

Salicylate – none detected

This was plotted on her individual nomogram and found to be below the treatment line and required no treatment with Parvolex.  Miss VM was admitted to the short stay ward overnight for observation.  In the morning she was assessed by the psychiatric nurse and I sat in on the session. 

Compound Analgesic Poisoning     

Compound Analgesic preparations contain a simple analgesic (usually Paracetamol) with an opioid component.  Therefore an overdose carries the added complications of opiate poisoning.  Examples of such preparations (of which there are many) include Co-proxamol, which contains 325mg of Paracetamol and 32.5mg of Dextropropoxyphene hydrochloride per tablet, and Solpadeine, which contains 500mg of Paracetamol, 8mg of Codeine phosphate and 30mg of caffeine per tablet.  Along with the signs and symptoms of paracetamol poisoning, the patient will also show signs of opiate poisoning:

·        Respiratory depression

·        Pin-point pupils

·        Vomiting

·        Circulatory failure

·        Coma

Management in A&E

As well as the management for Paracetamol poisoning discussed above, Naloxone may have to be administered if respiratory depression is severe.  This is a short acting Opioid antagonist that is administered IV and may be repeated several times without ill-effects.  This is sometimes the case as Naloxone has a shorter half-life than the Opiate.

Case Study – Mr Y

Mr Y is a 58year old male who presented to A&E having taken approximately 30 – 40 tablets of Solpadeine about 10 hours previously.  He had been drinking alcohol prior to the overdose.  On examination he was found to have a tender epigastrium and pin-point pupils.  His plasma Paracetamol and Salicylate levels were measured immediately and found to be:

Paracetamol -  0.39mmol/l

Salicylate – None detected

Although this was below the treatment curve, Mr GC had been drinking heavily for a period of time before his overdose and was therefore assessed using the “High Risk”curve, which he was above, and therefore was given Parvolex.  He had managed to survive respiratory depression overnight without the need for Naloxone.

Fulminant Hepatic Failure (FHF)

Fulminant hepatic failure is the rapid development of hepatocellular dysfunction and encephalopathy in a previously normal liver.  One of the most common causes is Paracetamol toxicity, where it usually develops in less than 1 week.  As little as 4g of Paracetamol in high-risk patients can cause FHF.  The clinical presentation is:

·        Nausea, vomiting, fatigue and malaise

·        Jaundice – due to impaired bilirubin elimination

·        Coagulopathy – due to decreased synthesis of factors I, II, V, VII, IX & X.

·        Hypoglycaemia – due to decreased glucose synthesis

·        Metabolic acidosis – due to decreased lactate uptake and anaerobic glycolysis producing lactate.

·        Encephalopathy – 4 stages:

1.     Insomnia, poor concentration

2.     Drowsiness, confusion, disorientation

3.     Sleepiness, incoherence

4.     Frank coma

·        Cerebral oedema – may be as a result of a disruption in the blood brain barrier by gut derived neurotoxins that escaped hepatic clearance, causing vasogenic oedema.

·        Infection – 33% are fungal

·        Multiple Organ Failure

·        Death

In patients with paracetamol poisoning, any one of the following features is serious:

1.     Prothrombin Time > 6.5

2.     Arterial pH < 7.3

3.     Serum Creatinine > 3.4 mg/dL

Management in A&E    

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Last updated: November 14, 2003.