CLINICAL EFFECTS 9.1 Acute poisoning 9.1.

1 Ingestion Paracetamol poisoning usually occurs in four stages: Stage I (0-24 hours) During this stage, the patient may be asymptomatic or experience gastrointestinal effects including anorexia, nausea and vomiting. Pallor, diaphoresis and malaise may also be present. Stage II (24-72 hours) Patients may be asymptomatic. They may experience right upper quadrant pain during this phase. Laboratory evidence of paracetamol poisoning may begin to occur. This includes increases in hepatic transaminases including AST and ALT, prolongation of the PT and increases in bilirubin. Stage III (72-96 hours) Fulminant hepatic toxicity may occur. This includes significant increases in transaminases and bilirubin as well as significant prolongation of PT. Liver biopsy will reveal a centrilobular necrosis. Elevations in serum creatinine and BUN may also occur during this phase. Decreases in cholesterol, glucose and albumin are also observed. There may be laboratory evidence of a metabolic acidosis. Clinical presentation often includes nausea and vomiting, right upper quadrant abdominal pain, jaundice and coagulation defects followed by hepatic encephalopathy and coma. Renal failure and cardiac involvement may occur during this stage. Death is due to hepatic failure and is usually preceded by an acidosis and oliguria. Stage IV (96 hours - 2 weeks) Resolution of hepatic dysfunction occurs in those patients who do not die or require liver transplant during Phase III. MANAGEMENT 10.1 General principles Following provision of necessary supportive care management of paracetamol toxicity involves gastric decontamination for recent exposures, laboratory analysis to determine the degree of toxicity, administration of specific antidotes such as N-acetylcysteine and more involved supportive care in those patients who experience hepatic and multi-system toxicities. 10.2 Life supportive procedures and symptomatic/specific treatment Symptomatic and supportive care should be provided. Laboratory Analysis: If a child has ingested more than 150mg/kg or an adult has ingested more than 150 mg/kg or 7.5g and over, a blood paracetamol concentration should be measured 4 hours after the ingestion. If a potentially toxic paracetamol ingestion has occurred and the time of the ingestion is unknown, a blood paracetamol concentration should be measured immediately upon presentation. Once the paracetamol

concentration is available, assess the risk of the patient developing toxicity by comparing the plasma paracetamol concentration to the time after ingestion using the treatment nomogram (see Figure 1, Section 1.4, of the Antidotes for poisoning by Paracetamol). Some centres treat at half the level if the patient is in a high risk group. If a paracetamol concentration is not available within 8 hours of the ingestion, then initiate treatment without awaiting the level. Stop treatment if their paracetamol level is non-toxic. Other essential laboratory studies that should be obtained in the patient who has a toxic paracetamol serum concentration: hepatic transaminases including AST and ALT, PT and INR, bilirubin, blood glucose, serum creatinine and BUN. In patients with signs of serious toxicity the following should also be obtained: arterial blood gas, albumin, cholesterol, complete blood count and a complete coagulation profile. 10.3 Decontamination Syrup of ipecac can be used to induce emesis in children if a potentially toxic exposure has occurred within 30 minutes. In adults gastric lavage may be used if the ingestion is massive and has occurred within 1 hour. Activated charcoal adsorbs acetaminophen. The paediatric dose is 1 gram/kg and the adult dose of is 25 to 50g. 10.5 Antidote treatment 10.5.1 Adults N-Acetylcysteine (please also see Antidotes for poisoning by Paracetamol): N-acetylcysteine (NAC) is the antidote of choice for paracetamol toxicity. NAC acts as a glutathione substitute, increases glutathione synthesis and increases sulphate conjugation of acetaminophen. Available Products: Intravenous and oral NAC areavailable as both a 10% and 20% solution. A 10mLampoule of NAC 10% contains 100 mg/mL i.e. 1g of NAC total. A 10mL ampoule of NAC 20% contains 200 mg/mL i.e. 2g of NAC in total. Adult Dose - Intravenous Infusion: Administer aloading dose of 150 mg/kg body weight in 200 mLs of 5%dextrose by slow intravenous (IV) infusion over 15minutes. Then administer 50 mg/kg by IV infusion in 500mLs of 5% dextrose over 4 hours followed by 100 mg/kg in 1 litre of 5% dextrose over the next 16 hours. If necessary, NAC can be administered in saline although its stability in saline is thought to be less than 24 hours. At the end of antidote treatment a blood sample should be taken for determination of INR, plasma creatinine concentration and blood gases. If they are normal and the patient is asymptomatic the patient may be discharged. If INR and/or plasma creatinine are raised then the patient requires further monitoring and more acetylcysteine should be given at a rate of 150 mg/kg over 24 hours. Adult Dose - Oral and Nasogastric Administration: Administer a loading dose of 140 mg/kg body weight. Four hours after administration of the loading dose,initiate a maintenance dose of 70 mg/kg administered every four hours for 17 doses. The NAC solution should be diluted to a 5% solution in soda pop, juice or water prior to oral and nasogastric administration. Oral NAC should be administered as a cold solution through a covered container and straw in order to increase palatability. It is

important not to delay in treating a patient with a paracetamol overdose. Although NAC is useful up to 72 hours post ingestion,its efficacy decreases greatly if started more than 8 hours post ingestion (Makin et al., 1994, Prescott1983). Adverse effects of IV NAC: IV NAC may cause discomfort along the vein of administration, erythematous or urticarial rashes, nausea, vomiting, diarrhoea, headache, and tinnitus. For mild allergic reactions administer antihistamines and continue treatment. Anaphylactoid reactions, including bronchospasm (particularly in asthmatics) and hypotension have been reported in sensitive patients or if the initial infusion is given more rapidly than recommended. In such cases, stop the infusion immediately and give an antihistamine such as diphenhydramine or chlorpheniramine, adrenaline, corticosteroids, and bronchodilators as necessary. In some centres, if it is less than 8 hours after exposure, oral methionine (see below) is administered if activated charcoal has not been given. If more than 8 hours has passed since the overdose, these centres recommend resumption of the NAC infusion at the lowest rate (100mg/kg over 16 hours) with concurrent antihistamine and steroid treatment. Adverse Effects of Oral and Nasogastric NAC: The most common adverse effect following administration of oral NAC is vomiting. This is due to the noxious odour and taste of the product. Efforts to enhance palatability, as described above, should be taken. If a patient vomits the NAC dose within one hour of administration, the dose should be administered again. Efforts to prevent further episodes of vomiting should be taken. Antiemetics such as metoclopramide or ondansetron can be used. The anti-emetic dose of metoclopramide is 1 mg/kg. This can be mixed in 50 mL of 0.9% sodium chloride solution or 5% dextrose solution. It should then be administered intravenously over 30 minutes. Ondansetron, 150 g/kg, should be mixed in 50 mL of 0.9% sodium chloride solution or 50 mL of 5% dextrose solution. If emesis has occurred following oral NAC administration, a nasogastric or duodenal tube can be placed. If these interventions are not effective in preventing vomiting, intravenous administration of NAC should be initiated. Urticaria has also been observed after oral and nasogastric administration. NAC interference with paracetamol measurement: Laboratories using enzymatic kits for paracetamol measurements may find a reduction in the true paracetamol level when NAC has been administered. This applies ONLY when the analytic method has been modified for use on certain types of clinical analysers. When the kits are used manually, according to the manufacturer's instructions there is no interference. Methionine (please also see Antidotes for poisoning by Paracetamol): Some centres use methionine rather than NAC if the patient presents within 8 hours of ingestion, isconscious, not vomiting and if activated charcoal has not been given. Adult Dose: The adult dose is 2.5g orally every 4 hours for 4 doses (10g total). Children over 6 years of age should be treated with the adult dose. 10.5.2 Children

N-acetylcysteine (NAC) (please also see Antidotes for poisoning by Paracetamol): Paediatric Dose - Intravenous Infusion: In children who weigh greater than 20kg, administer an NAC loading dose of 150 mg/kg in 100 mLs of 5% dextrose over 15 minutes. Then administer 50 mg/kg in 250mLs of 5% dextrose over 4 hours followed by 100 mg/kg in 500mLs of 5% dextrose over the next 16 hours. For children who weigh less than 20 kg, administer the NAC doses listed for children greater than 6 years old and adjust the infusion volumes based on the daily fluid requirements of the child by weight. Paediatric Dose - Oral and Nasogastric Administration: Administer a loading dose of 140 mg/kg body weight. Four hours after administration of the loading dose, initiate a maintenance dose of 70mg/kg administered every four hours for 17 doses. The NAC solution should be diluted to a 5% solution in soda pop, juice or water prior to oral and nasogastric administration. Oral NAC should be administered as acold solution through a covered container and straw in order to increase palatability. Methionine Paediatric Dose: Children over 6 years of age should be treated with the adult dose. In children less than 6 years of age, the dose is 1 g administered orally every 4 hours for 4 doses (4g total). 10.6 Management discussion Activated charcoal does not significantly interfere with the absorption of NAC from the gastrointestinal tract. One complication associated with the concurrent administration of NAC and charcoal is an increased risk for vomiting. Criteria for Liver Transplant: If the patient has any of the following: evidence of acidosis, coagulopathy that does not respond to therapy or that persists as transaminases decrease, hypoglycaemia, renal failure, hypotension (mean arterial pressure less than 60mmHg) or encephalopathy, as they are all possible indications of irreversible hepatic toxicity and potential multi-system failure. Some centres will administer both oral or intravenous NAC in patients who present after 72 hours, including those patients who present with signs of hepatic toxicity.