Paracetamol (Acetaminophen) Poisoning Evidence Based Review

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1 Paracetamol (Acetaminophen) Poisoning Evidence Based Review Context Deliberate self harm is a common reason for presentation to the ED, with paracetamol poisoning being one of the most common methods used in the UK. Paracetamol poisoning accounts for over 40% of poisoning admissions and deaths per annum. Legislation introduced in September 1998 has reduced pack sizes of paracetamol and aspirin to 16 (32 from a pharmacy). There is some evidence of a reduction in serious overdoses since this change. Death may result from hepatic necrosis, renal and respiratory failure, major haemorrhage and coma. These conditions take between two and three days to develop. Renal failure may occur in the absence of liver impairment. Pathophysiology Paracetamol is rapidly absorbed, with an absorption half-time of only 30 minutes (just five minutes for paediatric elixir), and enters cells by passive diffusion. It is metabolised down three pathways. The predominant pathway is glucuronadation, with sulphation playing a smaller role. The products of these pathways are harmlessly excreted in the urine, along with 5% of the ingested paracetamol. In children, sulphation plays a greater part in paracetamol metabolism than it does in adults. This means that children are less prone to toxicity, but there is insufficient research to prove how much of a difference there truly is. The metabolic pathway causing the problems in overdose is where cytochrome p450 subtype 2E1 (CYP2E1) metabolises paracetamol to N-acetyl-p-benzoquinone imine (NAPQI) in the liver. This extremely reactive compound is produced from approximately 5% of ingested paracetamol and is usually disposed of harmlessly by reaction with glutathione to form mercapturic acid, which is subsequently excreted in the urine. With a large enough paracetamol overdose, the glutathione donor groups stored in the liver are depleted to such a level that the NAPQI starts to bond with and destroy vital cellular structures. Lipids are peroxidated, proteins change conformation and mitochondria are unable to produce ATP effectively. Instead, hydrogen peroxide and oxygen free radicals are formed. Kupffer macrophages are activated by cytokines, which are released by the damaged hepatocytes. In turn, the Kupffer macrophages release various interleukins (IL-1, 6, 8 and 10) and TNFα. IL-6 triggers apoptosis of the hepatocytes while IL-10, on the other hand, stimulates hepatocyte regeneration (if enough survive). The resultant hepatic necrosis and failure leads to jaundice and hepatic coma, failure of production of clotting factors leading to bleeding, and vast quantities of inflammatory mediators that cause a systemic inflammatory response to evolve.

2 High risk groups These can be divided into two groups: Glutathione depletion Chronic excess alcohol HIV/AIDS Malnutrition e.g. anorexia nervosa Cystic fibrosis Cytochrome enzyme induction Chronic excess alcohol Anticonvulsants St. John s Wort Rifampicin It is accepted for the purposes of generalisation and simplicity that these patients can only tolerate approximately half the dose of paracetamol in excess that a low risk patient can. Toxic ingestion In the event of overdose, the likelihood of serious hepatic injury can be estimated by knowing the amount taken and the weight of the patient. Ingested dose Likelihood of serious toxicity <150 mg/kg Unlikely >250 mg/kg Likely (potentially fatal) Therefore, for a 70 kg man, 150 mg x 70 kg = 10.5 g = 21 tablets constitute a significant overdose. In the UK, the standard dose for paracetamol tablets is 500 mg, but it is important to be aware that some compound preparations may contain different amounts, e.g. 325 mg in coproxamol. Tylenol 8 hour and Tylenol Arthritis, both from the USA, contain a rapid release 325 mg dose and a slow release 325 mg dose in the same tablet. Many patients present having taken their overdose with alcohol or in a distressed state, so it may be difficult to get an accurate history of the amount ingested. In these cases one should consider erring on the side of caution and assume a higher dose than stated. Presentation < 24 hours - may be asymptomatic or have nausea, vomiting +/- abdominal pain - abdomen is often tender in epigastrium or right upper quadrant > 24 hours - may have mild jaundice > 48 hours - deep jaundice - bleeding - encephalopathy

3 Antidotes There are two commonly used antidote treatments, both of which work by being precursors to glutathione and replenish hepatic stores. Glutathione binds to the toxic metabolite, NAPQI, to form inactive mercapturic acid, which is excreted renally. This prevents NAPQI from binding to other, more important, molecules. N-acetyl cysteine has the advantage of being a free-radical scavenger, independent of the above. In the UK, the standard treatment is N-acetyl cysteine given intravenously. The infusion regime involves three fluid bags. The first is a loading dose with 150 mg/kg in 200 ml of 5% dextrose over 15 minutes, followed by 50 mg/kg in 500 ml over four hours, and then finally 100 mg/kg diluted to 1 l over 16 hours. The volumes of diluent are reduced in children to avoid fluid overload. N-acetyl cysteine is generally well tolerated, but 5% of patients receiving it will suffer an anaphylactoid reaction with flushing, itching, wheeze and vomiting. The patient may already be vomiting from the paracetamol. The patient usually responds well to slowing or stopping the infusion temporarily and administration of an antihistamine. It normally only occurs during the loading dose bag. Anaphylactoid reactions are not a contra-indication to further treatment with N-acetyl cysteine, but patients who attend frequently with overdoses may refuse it as it makes them feel unwell. In the USA, N-acetyl cysteine is administered orally in similar doses. The second-line treatment in the UK is methionine. This has the disadvantage of being an oral drug in a situation where the patient is often vomiting due to the toxic effects of the paracetamol. Its efficacy has not been studied in the same depth as N-acetyl cysteine. A course for an adult consists of four doses of 2.5 g at four-hourly intervals. Methionine is incorporated in some paracetamol preparations by law in some countries to prevent fatal overdose. It is available in the UK over the counter in this combination, but is not popular as it remains expensive and causes nausea and vomiting. Timing of ingestion changes management The first priority with any poisoned patient is the ABC approach. Paracetamol is present in many codeine-containing compound analgesics, where the codeine may cause significant respiratory and central nervous system depression. These patients may need airway manoeuvres +/- naloxone. Other co-ingestants, such as antidepressants, may require more urgent management for similar reasons. The following management algorithms for the ED assume that these factors have been addressed. If in doubt, contact your local poisons information service. < 4 hours in adults consider 50 g oral activated charcoal if: - patient presents within one hour of ingestion and - they have taken >150 mg/kg or 12 g in total wait until four hours post-ingestion to take blood for a paracetamol level

4 treat patient with IV N-acetyl cysteine if level >1.3 mmol/l if low risk or >0.65 mmol/l if high risk < 4 hours in children consider oral activated charcoal if: - patient presents within one hour of ingestion and - they have taken >150 mg/kg or 12 g in total dose of charcoal is 1 mg/kg in infants or g in children under 12 years if it is certain that the child has taken less than 150 mg/kg, they may safely be discharged and the parents reassured if there is doubt, or the child has definitely taken >150 mg/kg, they should be investigated and treated as for adults above By measuring the amount remaining in a bottle that a child has drunk from, it is possible to calculate the maximum possible dose taken. Paracetamol elixir comes in two concentrations: 120 mg/ 5 ml and 250 mg/ 5 ml. The largest bottle sizes of Calpol are 200 ml of low strength mixture and 100 ml of high strength mixture. Therefore, the maximum any bottle can contain is 250/5 x 100 = 5 g. Hence, a child over approximately 35 kg can drink an entire bottle without reaching the 150 mg/kg threshold. 4-8 hours (all patients) measure paracetamol level immediately if result will be available before eight hours post-ingestion, all patients can wait for result before starting treatment if result will be more than eight hours post-ingestion AND dose taken >150 mg/kg (or 12 g total), start N- acetyl cysteine while waiting for result treat patient with IV N-acetyl cysteine if levels above the treatment line are relevant to patient s risk group if below treatment line and already started N-acetyl cysteine, stop the infusion 8-15 hours (all patients) take blood for paracetamol level, INR, U&E and LFT if >150 mg/kg (or 12 g total) taken, start N-acetyl cysteine while waiting for the paracetamol level if paracetamol level is below the treatment line for high risk group and creatinine, INR and alanine transferase are all normal, the N-acetyl cysteine can be discontinued. If not, admit for full course of treatment with N-acetyl cysteine hours (all patients) take blood for paracetamol level, INR, U&E, bicarbonate and LFT start N-acetyl cysteine infusion unless you are absolutely certain that the amount taken does not exceed 150 mg/kg (or 12 g total) the nomogram for prediction of liver damage is less accurate after 15 hours, so admit patient for a full course of N-acetyl cysteine > 24 hours (all patients) take blood for INR, U&E, bicarbonate/venous blood gases and LFTs paracetamol level is irrelevant at this stage as it will all have been excreted or metabolised if any of the blood tests are abnormal, the case should be discussed with the local liver unit treatment with N-acetyl cysteine may be suggested by the liver unit

5 Staggered overdose or time unavailable take blood for INR, U&E and LFTs paracetamol level is not relevant, but often taken to confirm ingestion if more than 150 mg/kg taken, or suspected, commence N-acetyl cysteine infusion and admit for full course of treatment if all blood tests are normal 24 hours after last ingestion then significant toxicity is unlikely and infusion can be stopped King s College transplantation criteria 1. Arterial ph < Lactate >3.0 mmol/l (despite fluid resuscitation) 3. Creatinine >300 µmol/l 4. INR >6.5 or PT >100 seconds 5. Grade 3 or 4 hepatic encephalopathy Psychiatric involvement Current NICE guidelines suggest that all children and most adults who have self-harmed should be admitted for a period, followed by a psychosocial assessment by a mental health professional.