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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-systemtoxicities.

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 seeAntidotes forpoisoning 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 creatinineare 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

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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 seeAntidotes 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 seeAntidotes 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 NasogastricAdministration:

Administer a loading dose of 140 mg/kg body weight. Four hour

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 shouldbe 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.

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