DESCRIPTION
This document refers to immediate-release acetaminophen (paracetamol) formulations. Click the following link for information regarding modified-release formulations. |
SUBSTANCE NAME
Acetaminophen (Paracetamol) |
SUBSTANCE CLASS
Para-Aminophenol Derivative
|
INTERVENTION CRITERIA
This document refers to immediate-release acetaminophen (paracetamol) formulations. Click the following link for information regarding modified-release formulations. |
Ingestion - Ingestions of 10 g or 200 mg/kg (whichever is less) acetaminophen (paracetamol) Also investigate if: - Exposure occurred with intent to self-harm, regardless of the reported dose - The dose or timing of ingestion is uncertain - The patient is symptomatic |
Time of Ingestion Unknown |
Repeated Supratherapeutic Exposure |
Ingestion - Ingestions of 10 g or 200 mg/kg (whichever is less) acetaminophen (paracetamol) over a single 24-hour period; - Ingestions of 12 g or 300 mg/kg (whichever is less) for the preceding 48 hours; - Ingestions of more than 4 g per day or 60 mg/kg (whichever is less) per 24-hour period for more than 48 hours in those who also have symptoms indicating possible liver injury (e.g. nausea, vomiting, or abdominal pain) Also investigate if: - Exposure occurred with intent to self-harm, regardless of the reported dose - The dose or timing of ingestion is uncertain - The patient is symptomatic |
No observation is required for those patients with ingested doses or serum acetaminophen (paracetamol) determinations below the intervention levels unless there is intent for self-harm or the reported dose is thought to be inaccurate. However, clinical review is warranted should nausea, vomiting, or abdominal pain occur after discharge, particularly if within 24 to 48 hours after the ingestion. |
Medical observation and treatment should continue for any patient above the intervention level until criteria for discharge are met. |
Investigation and Initial Management |
Decontamination Administer activated charcoal to co-operative adults if within 2 hours of overdose of immediate release solid formulations. If at least 30 g is ingested administer activated charcoal to co-operative adults if within 4 hours of overdose.  2 to 8 hours post-ingestion Ingestion by well children without any underlying illness < 6 years of age of liquid acetaminophen (paracetamol) Measure: Serum acetaminophen (paracetamol) concentration at least 2 hours post-ingestion: Ingestion of standard release or liquid formulations Measure: Alanine aminotransferase (ALT) (Baseline ALT measurement) - If the serum acetaminophen (paracetamol) concentration is below the nomogram line, the patient does not require acetylcysteine; - If the serum acetaminophen (paracetamol) concentration is above the nomogram line, immediately commence a full course of acetylcysteine; - If the serum acetaminophen (paracetamol) concentration will not be available within 8 hours of ingestion, immediately commence a full course of acetylcysteine. This treatment can then be halted if the result subsequently returns below the nomogram line. - Additionally, if the acetaminophen (paracetamol) concentration is more than double the nomogram line, it is recommended that the second acetylcysteine infusion over 16 hours is doubled. Multiple or staggered acute ingestions over more than 2 hours with intent to self-harm require additional consideration and consultation with a medical toxicologist (at the bedside or through a Poison Center) is advised. 8 to 24 hours post-ingestion Measure: Serum acetaminophen (paracetamol) concentration Alanine aminotransferase (ALT) - If the serum acetaminophen (paracetamol) concentration is below the acetaminophen (paracetamol) treatment nomogram line and the ALT is less than 50 U/L, then the acetylcysteine infusion can be halted and no further medical treatment is necessary. - Additionally, if the acetaminophen (paracetamol) concentration is more than double the nomogram line, it is recommended that the second acetylcysteine infusion over 16 hours is doubled. If ALT is greater than 50 U/L then measure: BUN (Urea) Creatinine Electrolytes INR Blood glucose Phosphate Venous Blood Gas (pH and lactate in particular) Multiple or staggered acute ingestions over more than 2 hours with intent to self-harm require additional consideration and consultation with a medical toxicologist (at the bedside or through a Poison Center) is advised. 24 plus hours post-ingestion, or time of ingestion unknown Measure: Serum acetaminophen (paracetamol) concentration Alanine aminotransferase (ALT) International Normalized Ratio (INR) - If the serum acetaminophen (paracetamol) concentration is less than 10 mg/L (66 umol/L) and the ALT is less than 50 U/L, then the infusion can be halted and no further medical treatment is necessary. - If the serum acetaminophen (paracetamol) concentration is greater than 10 mg/L (66 umol/L) or the ALT is greater than 50 U/L, then complete the full course of acetylcysteine. If ALT is greater than 50 U/L then measure: BUN (Urea) Creatinine Electrolytes Blood glucose Phosphate Venous Blood Gas (pH and lactate in particular) |
Repeated Supratherapeutic Exposure |
In patients meeting intervention criteria for repeated supratherapeutic ingestion Measure: Serum acetaminophen (paracetamol) concentration Alanine aminotransferase (ALT) -If serum acetaminophen (paracetamol) is < 20 mg/L (< 132 umol/L) and ALT < 50 U/L, then no medical treatment is necessary. -If serum acetaminophen (paracetamol) is > 20 mg/L(> 132 umol/L) or ALT > 50 U/L, then commence an acetylcysteine infusion. After commencement of the infusion measure serum acetaminophen (paracetamol) and ALT concentrations 8 hours after the previous measurement. -If serum acetaminophen (paracetamol) is < 10 mg/L (< 66 umol/L) and ALT < 50 U/L (or static), then the infusion can be halted and no further medical treatment is necessary. Otherwise continue the infusion and check serum acetaminophen (paracetamol) and ALT at 12 hourly intervals until: -Serum acetaminophen (paracetamol) is < 10 mg/L (< 66 umol/L) and ALT < 50 U/L (or static), then the infusion can be halted and no further medical treatment is necessary. |
Patients requiring intervention for acute acetaminophen (paracetamol) overdose should be managed in a medical facility able to rapidly determine serum acetaminophen (paracetamol) and provide acetylcysteine. Referral to an intensive care unit and/or liver transplant unit may be required in severe poisoning. |
TREATMENT
TREATMENT SUMMARY
This document refers to immediate-release acetaminophen (paracetamol) formulations. Click the following link for information regarding modified-release formulations. |
Decontamination with activated charcoal is recommended in cooperative adults within 2 hours of ingestion of (solid) immediate-release forms or within 4 hours of ingestion if greater than 30 g of acetaminophen (paracetamol) is ingested.   Following acute overdose, assessment of serum acetaminophen (paracetamol) concentration and use of the acetaminophen (paracetamol) treatment nomogram to determine requirement for the antidote acetylcysteine is required. If a concentration result is not available within 8 hours of ingestion, acetylcysteine should be commenced and further acetylcysteine treatment based on the results of the serum concentration plotted on the nomogram. Acetylcysteine is considered beneficial at any time post-ingestion. Acetylcysteine administration following repeated supratherapeutic/chronic ingestions is dependent on dose and investigations. In cases of massive acetaminophen (paracetamol) ingestion (serum concentrations greater than twice the nomogram line) doubling the final (16 hour) acetylcysteine infusion is recommended.  Following overdoses of greater than 50 g or 1 g/kg (whichever is less), acetaminophen (paracetamol) concentrations more than triple the nomogram line, patients with hepatotoxicity (ALT > 1,000 IU/L), or neonatal acetaminophen (paracetamol) poisonings consultation with a medical toxicologist (at the bedside or through a Poison Center) is advised.  |
Hemodialysis may be beneficial in severe poisoning with very high blood concentrations, particularly if acetylcysteine is unavailable.  Supportive care includes the continued use of acetylcysteine, monitoring of major organ function, and further management as indicated. Use of sedating drugs is not recommended due to their impact on the assessment of mental function/encephalopathy. Acute hepatic and renal failure are well recognized concerns. Most complications are a consequence of hepatic failure and rarely occur in its absence. Advice should be sought from a specialist liver transplant unit:  If The International Normalized Ratio (INR) is greater than 3 at 48 hours or 4.5 at any time after overdose Or Oliguria or creatinine is greater than 200 umol/L (2.2 mg/dL) Or Persistent acidosis (pH less than 7.3) or arterial lactate greater than 3 mmol/L Or Systolic hypotension with a blood pressure less than 80 mmHg, despite resuscitation Or Hypoglycemia Or Severe thrombocytopenia Or Encephalopathy of any degree, or any alteration of consciousness (Glasgow Coma Scale less than 15) not associated with co-ingestion of sedatives Early discussion with a liver transplant unit is essential. Advice may be given and a decision to transport dependent upon results. In general it is considered desirable to transport patients prior to development of grade 2 encephalopathy. |
EMERGENCY STABILIZATION
Emergency Stabilization Should Not Be Required |
Emergency stabilization of patients following recent ingestion of acetaminophen (paracetamol), solely, is highly unlikely to be necessary. However, massive overdose may lead to early decline in level of consciousness and/or lactic acidosis.  Immediate attention should be given to the airways, assessment of blood glucose, and supportive care.  Definitive treatment is provided by the antidote acetylcysteine, with hemodialysis possibly indicated.  Carefully consider coingestant(s) or non-toxicological causes. |
DECONTAMINATION
Single Dose Activated Charcoal |
Gastrointestinal decontamination is not indicated in any pediatric (< 6 years old) patient following acetaminophen (paracetamol) overdose.  Gastrointestinal decontamination with activated charcoal is only indicated:  In co-operative adult patients If the formulation is a solid (e.g. tablets, capsules) If at least 10 g or 200 mg/kg (whichever is less) is ingested Within 2 hours of the overdose for immediate-release formulations If at least 30 g is ingested Within 4 hours of the overdose for immediate-release formulations Further decontamination with activated charcoal may be necessary for co-ingestants. Induction of emesis and gastric lavage are both contra-indicated. |
Single dose activated charcoal CHILD 1 to 2 g/kg orally ADULT 50 to 100 g orally |
ANTIDOTE(S)
Acetylcysteine is the treatment of choice for acetaminophen (paracetamol) overdose, and its intravenous use considered preferable.  When administered within eight hours of acetaminophen (paracetamol) ingestion it is almost completely effective in preventing death.  Use beyond this time is also beneficial and recommended.  |
Intra-venous acetylcysteine infusion is indicated as outlined in the following links: |
While acetylcysteine is recommended to be administered intravenously in 5% dextrose in water, 1/2 normal (0.45%) saline or normal saline (0.9%) may be substituted if necessary.  In children there is a risk of hyponatremia with 5% dextrose alone  and therefore normal (0.9%) saline should be used. CHILD  It is recommended that acetylcysteine dose for children be calculated for actual body weight. Children < 14 years old: 200 mg/kg in 7 mL/kg (up to 500 mL) of normal saline over 4 hours Followed by 100 mg/kg in 14 mL/kg (up to 1,000 mL) of normal saline over 16 hours Children 14 years and older: As per adults Closely monitor fluid and electrolyte balance. It is recommended that acetylcysteine dose for adults be calculated for actual body weight rounded up to the nearest 10 kg with a ceiling weight of 110 kg. Administer: 200 mg/kg in 500 mL of 5% dextrose over 4 hours Followed by 100 mg/kg in 1,000 mL of 5% dextrose over 16 hours |
In the case of large overdoses (those whose acetaminophen (paracetamol) concentration is more than double the nomogram line) it is recommended that the second infusion over 16 hours is doubled to 200 mg/kg.  Following very large overdoses of greater than 50 g or 1 g/kg (whichever is less) or acetaminophen (paracetamol) concentrations more than triple the nomogram line, even higher doses of acetylcysteine may be required and consultation with a medical toxicologist (at the bedside or through a Poison Center) is advised. |
Recommended investigations according to time from acetaminophen (paracetamol) ingestion to acetylcysteine treatment  At 2 hours before completion of the infusion, investigate as below: Time (hours) from ingestion to start of acetylcysteine | Investigations near the completion of acetylcysteine | Less than 24 hours | ALT* | Greater than 24 hours | ALT and INR# | Patients with an abnormal ALT | Repeat investigations 12 hourly including: UEC, LFTs, INR, BGL, and VBG |
ALT = alanine aminotransferase; BGL = blood glucose level; UEC = BUN (urea), electrolytes, and creatinine; LFTs = liver function tests; VBG = venous blood gases including pH and lactate. * NOTE: If the initial acetaminophen (paracetamol) concentration is more than double the nomogram line or a modifed release preparation was ingested, then repeat ALT and acetaminophen (paracetamol) concentration at the completion of acetylcysteine. # NOTE: Mild elevation in INR no greater than 2.0 may occur early in those without hepatic injury. This is due to direct inhibition of clotting factor production and activity, by paracetamol and acetylcysteine, respectively. |
Following completion of initial acetylcysteine, patients who have persistently high acetaminophen (paracetamol) concentrations > 10 mg/L (66 umol/L) or ALT is > 50 U/L and increasing (if baseline ALT was > 50 U/L) require acetylcysteine to be continued at the rate of the last infusion stage (100 mg/kg acetylcysteine over 16 hours). If the acetaminophen (paracetamol) concentration is above 100 mg/L (660 umol/L) following completion of initial acetylcysteine, consultation with a medical toxicologist (at the bedside or through a Poison Center) is advised for advice on optimum continued acetylcysteine dosing. Continue acetylcysteine until the patient is clinically improving, ALT is decreasing, INR is improving and < 2, and the acetaminophen (paracetamol) concentration is less than 10 mg/L (66 umol/L). |
Following repeated supratherapeutic ingestion of acetaminophen (paracetamol) and commencement of acetylcysteine infusion, measure serum acetaminophen (paracetamol) and ALT concentrations 8 hours after the previous measurement. If serum acetaminophen (paracetamol) is <10 mg/L (<66 umol/L) and ALT is less than 50 U/L or static, then the infusion can be halted and no further medical treatment is necessary. Otherwise continue the infusion and check serum acetaminophen (paracetamol) and ALT at 12 hourly intervals until: Serum acetaminophen (paracetamol) is <10 mg/L (<66 umol/L) and ALT is less than 50 U/L or static, then the infusion can be halted and no further medical treatment is necessary. |
Acetylcysteine should be administered to pregnant patients following the standard adult regimen. Transplacental transport of acetylcysteine is not thought to be clinically significant,  however, delay in initiation of acetylcysteine treatment is associated with increased incidence of spontaneous abortion and fetal death.  Acetylcysteine is not considered teratogenic.  |
Six to 23% of patients receiving IV acetylcysteine develop an anaphylactoid reaction.   These do not represent an immunological (allergic) reaction; rather, they are thought due to a direct dose-dependent effect on histamine release and generally occur within the first two hours of an infusion. History of previous anaphylactoid reaction to acetylcysteine does not contraindicate use. If there is concern of recurrence of the reaction the patient may be pre-treated 15 minutes before commencement of the infusion with an antihistamine.  Effects range from mild flushing to urticaria, angioedema, or bronchospasm. Hypotension may occasionally occur. Asthmatics appear more at risk. However, effects are usually easily managed and there is no reason to withhold acetylcysteine from any patient when indicated.  |
Hyponatremia has been reported in children if administered acetylcysteine in 5% dextrose following adult protocols for dilution of infused dose.  |
SIGNS AND SYMPTOMS
Hepatic damage is a common feature of acetaminophen (paracetamol) toxicity and further signs and symptoms become apparent if hepatotoxicity develops. As time after overdose progresses, signs and symptoms associated with acute hepatic failure including right upper quadrant tenderness, hypotension, acidosis, coagulopathy, encephalopathy, and hypoglycemia may develop.    Jaundice is not evident as an early sign but develops as hepatic failure progresses.  Additionally, an initial increase in INR can be seen in the first 24 to 48 hours which appears to result from an inhibition of the activation of vitamin K dependent coagulation factors.  Later, coagulopathy is typically a result of liver failure. Renal failure associated with acetaminophen (paracetamol) overdose may rarely appear acutely, or more usually over a period of days and in association with hepatotoxicity/failure.  Cardiovascular concerns are rarely an acute consequence of poisoning, but hypotension and myocardial injury may appear in patients with fulminant hepatic failure as part of multisystem organ failure.  |
Onset/Duration of Symptoms |
Acetaminophen (paracetamol) in the form of liquid formulations and oro-dispersable tablets are more quickly absorbed than standard tablets,  so may alter the onset of symptoms. |
Four phases of acute acetaminophen (paracetamol) toxicity have been described.  Phase 2 (24 to 72 hours after overdose): Previous symptoms subside. Right upper quadrant pain may appear indicating hepatic damage with associated raised hepatic transaminases. International Normalized Ratio (INR) increases. Renal function may begin to deteriorate, however blood urea may remain low due to decreased hepatic urea formation.   Phase 3 (72 to 96 hours after overdose): Continuing hepatic centrilobular necrosis with associated coagulation defects, hypoglycemia, metabolic acidosis, and jaundice. Renal failure and cardiac complications frequently occur. Hepatic encephalopathy and death may ensue.   Phase 4 (4 days to 2 weeks after overdose): If phase 3 is survived complete resolution of hepatic and renal function is usual.   |
Mild Acetaminophen (Paracetamol) Toxicity | Moderate Acetaminophen (Paracetamol) Toxicity | Severe Acetaminophen (Paracetamol) Toxicity | Malaise Nausea Vomiting Pallor Diaphoresis | Upper right quadrant pain Increased INR | Metabolic acidosis Hypoglycemia Jaundice Renal failure Fulminant hepatic failure Hepatic encephalopathy Coma |
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CHRONIC EFFECTS
Symptoms in chronic situations are broadly similar to acute ones. Heptotoxicity and its complications are the major concern.   |
Do Not Archive. This document is current on day of issue,
NZ: 21.Jan.2021 |