Topic Editor: Robert Giles, MBBS, BPharm
Review Date: 9/6/2012
Definition 
Acetaminophen (Tylenol®) or paracetamol (Panadol®) is a common over the counter analgesic and antipyretic. When taken in overdose, the result is hepatotoxicity, hepatic failure and potentially death. Toxicity may occur as a result of a single acute ingestion or chronic supratherapeutic dosing. Acute ingestions >150mg/kg (or 7-10 grams in adults) risk serious toxicity.
Description
- Acetaminophen is one of the most widely used over the counter medications. In most countries (non-U.S.), it is called paracetamol
- Acetaminophen is a common drug ingested in overdose
- Overdose may result from acute ingestion of a large quantity of acetaminophen at a single time, or repeated ingestion of a quantity that exceeds the recommended dosage
- Patients may initially be asymptomatic or present with only mild gastrointestinal (GI) symptoms. Failure to provide prompt treatment of an overdose may lead to liver injury over the following 1-4 days
- Pathophysiology
- Acetaminophen is rapidly absorbed from the stomach and small intestine, reaching a peak plasma level within an hour
- In normal circumstances, acetaminophen is metabolized in the liver by conjugation to form glucoronides or sulfates which are renally excreted
- High acetaminophen levels cause the liver conjugation pathway to be overloaded and acetaminophen is metabolized alternatively to form a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI)
- NAPQI is inactivated by glutathione; however, once glutathione stores are exhausted NAPQI accumulates. NAPQI is hepatotoxic and causes hepatic necrosis
- Hepatotoxicity can largely be prevented by the administration of the antidote N-acetylcysteine (NAC) within 8 hours of ingestion
Epidemiology
Incidence/Prevalence
- The American Association of Poison Control Centers reported 36,370 acetaminophen overdoses treated in health care facilities in 2009, with 125 deaths
- Approximately half of the overdoses treated in health care facilities occurred with combination acetaminophen products
- The incidence of acetaminophen overdose in developing countries is much lower than in the US or UK
- Acetaminophen was the most common cause of acute liver failure in the US from 1998-2003 with almost 50% of acetaminophen related liver failure cases occurring due to unintentional overdose
Age
- Children are more likely to have accidental ingestion of acetaminophen, usually as a sole ingestion
- Adults are more likely to have deliberate ingestion of acetaminophen, most commonly in combination with one or more other drugs
- Adults are also more likely to have chronic overdose with unknowing overusing acetaminophen at doses beyond recommended, not realizing the risks
Gender
- No gender variation is reported in acetaminophen overdose cases
Risk factors
- Frequent analgesic use
- Heavy alcohol consumption
- Long-term use of drugs that induce cytochrome P450 (CYP450) systems
- Low levels of glutathione (e.g. Malnutrition, chronic disease)
- Psychiatric illness, including depression, personality disorder and prior episodes of self-harm
- Underlying liver disease
Etiology
Acetaminophen overdose may occur due to:
- Self-harm or attempted suicide: Ingestion of a large quantity of acetaminophen at once or over a period of time
- Therapeutic error: Chronic supratherapeutic doses of acetaminophen
- Dosing error: Parents may administer incorrect doses to children
- Unsupervised ingestion: Common among children 6 years of age
[Outline]
History
- Stage 1 (24 hours)
- Anorexia, nausea, vomiting, diaphoresis and malaise. Some patients are asymptomatic
- Stage 2 (18-72 hours)
- Right upper quadrant abdominal pain
- Stage 1 symptoms may resolve
- Stage 3 (72-96 hours)
- Sustained nausea, vomiting and abdominal pain. Somnolence, confusion, and coma may be seen in severely poisoned patients
- May have spontaneous bleeding (due to prolonged INR from hepatic failure)
Physical findings on examination
- Stage 1 (24 hrs)
- Stage 2 (18-72 hours)
- Right upper quadrant tenderness
- Hypotension, tachycardia
- Stage 3 (72-96 hours)
- Right upper quadrant tenderness
- Jaundice, bleeding, confusion, coma, death
- Stage 4 (4 days to 3 weeks)
- Symptoms and organ failure may wholly or partially resolve in patients surviving stage 3
[Outline]
Blood test findings
- Serum acetaminophen levels
- For serum acetaminophen levels to be interpreted, a well-defined history of time of ingestion is required
- A serum acetaminophen level should be measured at least 4 hours post ingestion. This level is plotted against time on a Rumack-Matthew nomogram to define the potential for hepatotoxicity. If the level falls above the line then treatment with NAC should be commenced. If the level falls below the line then the overdose is unlikely to be toxic, and no treatment is needed
- Some authorities recommend a lower treatment line in patients who are more prone to hepatotoxicity (e.g. alcoholic or malnourished patients)
- The Rumack-Matthew nomogram should not be used for chronic poisonings, staggered overdoses or if the time of ingestion is unknown
- Liver function tests
- Clotting parameters
- Prothrombin time (PT) and international normalized ratio (INR) levels are significant prognostic indicators of hepatic dysfunction, liver failure and mortality, and should be evaluated every 12 hours. Prolonged PT and elevated INR should eventually occur with significant hepatotoxicity
- Serum NAPQI adducts
- Concentration of serum NAPQI adducts correlate with acetaminophen-induced hepatic damage. Peak values of Serum NAPQI adducts parallel ALT and AST levels and maybe useful in evaluating the patient with liver failure of unknown etiology
- Serum electrolytes, blood urea nitrogen (BUN) and creatinine
- Monitoring of electrolytes, BUN and creatinine may be helpful in evaluating renal function and severity of hepatic failure. Elevated serum creatinine level predicts mortality. A high anion Gap may be evident in early phases of poisoning
- Serum lactate and arterial pH
- Acidemia and elevated lactate levels are useful for assessment of hepatotoxicity and are an important predictor of mortality
- Serum glucose
- Serum glucose level should be monitored regularly since hypoglycemia is common in hepatic necrosis
Other laboratory test findings
- Urinalysis
- Presence of proteinuria and hematuria is suggestive of acute tubular necrosis
- Urine toxicology testing can be useful in looking for other co-ingested drugs
[Outline]
General treatment items
- Gastric decontamination
- Activated charcoal effectively adsorbs acetaminophen in the GI tract. Studies have demonstrated decreased elevation in transaminases and decreased hepatic injury if used early in overdose
- Charcoal should be administered only in the event a potentially toxic quantity of acetaminophen has been ingested
- It may be effective if administered up to four hours post ingestion however some guidelines suggest use only if the presentation is within the first hour. It is indicated for a longer period post ingestion when an extended release preparation of acetaminophen was ingested
- Use of activated charcoal is contraindicated in non-intubated patients who are sedated or are unable to protect their airway
- N-Acetylcysteine administration
- N-Acetylcysteine (NAC) is a specific antidote for acetaminophen overdose. It replenishes glutathione and promotes normal conjugation of the remaining acetaminophen
- If the first dose of NAC is given within 8 hours of acetaminophen ingestion it is extremely effective in preventing hepatotoxicity and liver failure
- For patients who present early, where serum acetaminophen levels are expected to be available within 8 hours of ingestion, NAC should only be commenced on confirmation of a toxic overdose
- Patients who present more than 8 hours post ingestion or whose blood results will not be available within 8 hours of ingestion should have NAC commenced while awaiting acetaminophen levels and liver function tests. Thereafter, a decision on whether NAC should be continued or ceased can be made after laboratory tests return
- Regardless of the time since ingestion, NAC may be effective in any patient presenting with evidence of hepatotoxicity due to acetaminophen [e.g. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT)]
- The pharmacokinetics of extended release acetaminophen preparations (e.g. Tylenol Extended Relief, Tylenol Arthritis, Tylenol 8 hr, or Panadol osteo) make the Rumack-Matthew nomogram difficult to interpret. Some authors suggest taking serial acetaminophen levels at 4 hours and 8 hours post ingestion. If either of these levels are above the treatment line or if the AST/ALT begin to rise then treatment should be commenced. NAC may be commenced while awaiting blood results if >200mg/kg has been consumed
- NAC is likely as effective orally as intravenously. Because of its sulfur content, it causes vomiting in one third of patients following oral administration. Antiemetics such as metoclopramide or ondansetron may be given but IV or nasogastric administration may be the preferred route of administration for NAC
- If activated charcoal is given concomitantly it will bind to and decrease the oral bioavailability of NAC. However, this decrease in bioavailability is considered inconsequential
- Management of fulminant hepatic failure
- NAC administration has been shown to decrease mortality
- Fulminant hepatic failure associated with acetaminophen poisoning may necessitate the need for liver transplantation following consultation with a hepatologist and transplant surgeon
- The King's College Criteria are one of several useful prognostic tools which have been proposed to determine the need for transplantation in patients with hepatic failure. The American Association for the Study of Liver Disease recommends caution in using any particular guideline.
- King's College Criteria for Acetaminophen induced acute liver failure
- Arterial lactate >3.5 following early fluid resuscitation OR
- pH 7.3 or lactate >3.0 following adequate fluid resuscitation OR
- INR >6.5 (Prothrombin time >100s) and Creatinine >3.4 mg/dL (300 µmol/L) in patients with Grade 3 or 4 hepatic encephalopathy
Medications indicated with specific doses
Antidotes
- Activated charcoal
- N-Acetylcysteine [IV]
- N-Acetylcysteine [Oral]
Antiemetics- Metoclopramide [IM/IV]
- Metoclopramide [Oral]
- Ondansetron [IM/IV]
- Ondansetron [Oral]
Dietary and Activity restrictions
- A special diet is not required unless there is evidence of severe hepatic injury
- Activity restriction is recommended only in cases of severe hepatic injury
Disposition
Admission criteria
- Acetaminophen levels that are potentially hepatotoxic and need NAC treatment
- Liver function abnormalities resulting from chronic or late presentations
- Attempted suicide using nontoxic dose, requiring psychiatric consultation
Discharge criteria
- Patients with a nontoxic ingestion who do not require NAC treatment and have been psychiatrically cleared (if indicated) may be discharged
[Outline]
Prevention
- From 2011, manufacturers in the US have limited the dose of acetaminophen in prescription drug products, including opioid combinations to 325 mg per dosage form
- All medications (including those containing acetaminophen) should be stored in childproof containers and kept out of reach of children
- Medications containing acetaminophen must not be mixed unless instructed to do so by a physician
- Healthcare professionals should guide patients on the correct dosage of acetaminophen
- Physicians should be aware that patients may already be taking other medications containing acetaminophen
Prognosis
- Patients treated with NAC within 8 hours of ingestion have an excellent prognosis. Hepatotoxicity and death are highly unlikely
- Patients who survive usually regain normal hepatic function with few sequelae
- Nearly 4% of patients with severe liver toxicity progress to hepatic failure; half of these cases are fatal or require liver transplantation
- Children 5 years have better outcomes than adults for acute acetaminophen poisoning due to better excretion of acetaminophen
- The Schiot score predicts the risk of hepatic encephalopathy (and hence need for transplantation) as a percentage based on 3 criteria
- Time between ingestion and start of acetylcysteine (NAC) infusion
- INR
- Platelet count
Pregnancy/Pediatric effects on condition
- Acetaminophen overdose has not been associated with an increased risk of congenital abnormalities in the developing fetus. Although there is a possibility of maternal and fetal hepatocellular necrosis, maternal and fetal outcomes are good after early treatment
- N-acetylcysteine is safe to administer during pregnancy
Synonyms/Abbreviations
Synonyms
- Acetaminophen poisoning
- Acetaminophen toxicity
- Paracetamol overdose
- Paracetamol poisoning
- Paracetamol toxicity
ICD-9-CM
- 965.4 Poisoning by aromatic analgesics, not elsewhere classified
ICD-10-CM
- T39.1 Poisoning by, adverse effect of and underdosing of 4-Aminophenol derivatives
[Outline]
