Highlights & Basics
- Acetaminophen overdose may occur after an acute single ingestion of a large amount of acetaminophen or acetaminophen-containing medication, or repeated ingestion of an amount exceeding recommended dosage.
- Patients are often asymptomatic or have only mild gastrointestinal symptoms at initial presentation. Untreated acetaminophen poisoning may cause varying degrees of liver injury over the 1 to 4 days following ingestion, including fulminant hepatic failure.
- Rarely, massive overdose may initially present with coma and severe metabolic acidosis. Presentation with coma may also occur if a combination preparation of acetaminophen and opioid is taken in overdose, or after an overdose of multiple drugs.
- Hepatotoxicity is extremely rare in patients treated with acetylcysteine within 8 hours of an acute acetaminophen overdose. The efficacy of acetylcysteine decreases subsequent to the first 8 hours following an acute acetaminophen overdose, with a corresponding stepwise increase in hepatotoxicity with increasing treatment delays beyond 8 hours.
Quick Reference
History & Exam
Key Factors
attempted self-harm
repeated over-the-counter analgesic use for pain relief
asymptomatic presentation
nausea, vomiting, or abdominal pain
right upper quadrant pain and tenderness
jaundice
confusion, decreased consciousness level, and/or asterixis
Other Factors
Diagnostics Tests
1st Tests to Order
serum acetaminophen level
serum AST and ALT
Other Tests to consider
arterial pH and lactate level
metabolic panel or serum electrolytes with BUN and creatinine
serum prothrombin time and INR
serum salicylate level
ethanol level
blood glucose level
lipase level
serum phosphate
alpha-fetoprotein
Treatment Options
acute
acute single ingestion
<4 hours since ingestion
4-8 hours since ingestion
8-24 hours since ingestion
>24 hours since ingestion or time unknown
repeated supratherapeutic acetaminophen ingestion: with symptoms or signs of hepatotoxicity
acetylcysteine
supportive care
antiemetic
evaluation for liver transplant
Definition
Vignette
Common Vignette 1
Common Vignette 2
Other Presentations
Epidemiology
Etiology
Pathophysiology
Diagnostic Approach
Overall clinical picture
Special clinical considerations
Laboratory tests
- For acute acetaminophen overdose, specific management is dependent on the serum acetaminophen level relative to the time of ingestion.
- A timed serum acetaminophen level is drawn at least 4 hours after ingestion to risk-stratify likelihood of liver injury and the need for acetylcysteine treatment.[26]
- The serum level is plotted on the Rumack-Matthew nomogram to determine whether treatment with antidote (acetylcysteine) is required.Rumack-Matthew nomogram
- This nomogram was developed by plotting timed acetaminophen concentrations from acetaminophen overdose patients on a graph, and drawing a line to discriminate those who did and those who did not develop hepatotoxicity (defined as aminotransferase levels >1000 IU/L).
- The line connects a point at 150 micrograms/mL at 4 hours after ingestion and 4.7 micrograms/mL at 24 hours after ingestion and is termed the "treatment line." It is 25% more conservative than the nomogram as originally developed.
- Acetylcysteine treatment is started if the acetaminophen level falls on or above the line.
- The nomogram is not applicable in the following circumstances: unknown time of ingestion, repeated supratherapeutic ingestions, late presenting patients, and those with evidence of hepatotoxicity despite undetectable or therapeutic acetaminophen level. Some have suggested that co-ingestants that may delay gastrointestinal absorption (e.g., anticholinergic medications such as diphenhydramine) may also limit the nomogram, but there are no systematic studies to support this. Providers should use their discretion and consider the possibility of delayed absorption in patients with anticholinergic symptoms.
- Levels are done initially and repeated in the course of patient management (usually every 12 hours). The degree of derangement in laboratory results depends on the time of presentation relative to the time of acetaminophen overdose.
- These are used to monitor severity of hepatic failure and assist in patient stratification for optimal benefit in orthotopic liver transplantation.
- A prolonged INR is a poor prognostic sign.[1]
- Renal injury may occur in the absence of significant hepatotoxicity, and is relatively common with significant hepatotoxicity.
- Serum salicylate level should be considered in patients who have ingested substances in an attempt at self-harm.
- Ethanol level and blood glucose level should be obtained in any patient with altered mental status.
- Elevated lipase consistent with pancreatitis may occur, especially in patients with alcohol dependence.
- Phosphate and alpha-fetoprotein may be helpful for prognostication for patients with acute liver failure as a supplement to the King's College Criteria.[36]
Risk Factors
History & Exam
Tests
Differential Diagnosis
Shock liver
Differentiating Signs/Symptoms
- Shock liver occurs in the setting of sustained hypotension or low-flow state in the liver, which is unusual in acetaminophen overdose.
Differentiating Tests
- Serum acetaminophen level will be negative. However, this is not a definitive differentiating test. By the time liver failure develops, it would be unlikely for the acetaminophen level to be detectable.
Acute hepatitis A
Differentiating Signs/Symptoms
- There may be a history of travel to an endemic region, foodborne outbreak, close contact with an infected person, or men who have sex with men.
Differentiating Tests
- Hepatitis A IgM positive.
Acute hepatitis B
Differentiating Signs/Symptoms
- There may be a history of travel to an endemic region, intravenous drug use, contact with an infected person, or men who have sex with men.
Differentiating Tests
- Hepatitis B core antigen positive.
- Hepatitis B surface antigen will be positive 2 to 10 weeks after exposure.
Other hepatotoxins
Differentiating Signs/Symptoms
- An important differentiating factor is an exposure history such as exposure to mushrooms (e.g., Amanita phalloides) or herbal preparations (e.g., cascara, chaparral, comfrey, kava, ma-huang).
- Medications and other exposures include anesthetic agents (e.g., halothane), industrial chemicals (e.g., carbon tetrachloride, trichloroethylene, paraquat), ACE inhibitors, anabolic steroids, aspirin, calcium-channel blockers, ibuprofen, isoniazid, ketoconazole, methotrexate, naproxen, phenytoin, statins, or valproic acid.
Differentiating Tests
- Serum acetaminophen level will be negative. However, this is not a definitive differentiating test. By the time liver failure develops, it would be unlikely for the acetaminophen level to be detectable.
Mononucleosis
Differentiating Signs/Symptoms
- Presents with fever, pharyngitis, adenopathy, and fatigue.
Differentiating Tests
- Atypical lymphocytosis, elevated aminotransferases, positive heterophile antibodies ("Monospot").
Criteria
- Unknown time of ingestion.
- Repeated supratherapeutic ingestions.
- Late presenting patients.
- Those with evidence of hepatotoxicity despite undetectable or therapeutic acetaminophen levels.
- Grade 1: trivial lack of awareness; euphoria or anxiety; shortened attention span; plus impaired performance.
- Grade 2: lethargy or apathy; minimal disorientation to time and place; inappropriate behavior; subtle personality changes; impaired performance in subtraction.
- Grade 3: somnolence but with responsiveness to verbal stimuli; marked confusion; gross disorientation about time and place.
- Grade 4: coma.
Screening
Treatment Approach
Initial management
- All patients should receive general supportive care. This may include symptomatic treatment such as antiemetics for nausea, physiological support such as with intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses. Supportive care must be tailored to each specific patient and is essential to good outcomes.
- An attempt should be made to establish exact timing and amount of acetaminophen ingested. A serum acetaminophen level should be drawn 4 hours after ingestion or as soon as possible in patients presenting after 4 hours. At the same time, blood should be taken for aspartate aminotransferase (AST)/alanine aminotransferase (ALT), electrolytes and blood urea nitrogen (BUN), serum creatinine, arterial pH and lactate, and prothrombin time/international normalized ratio (INR).
- Activated charcoal can be considered if the patient presents within 2 hours of acute single acetaminophen ingestion, and if he or she is alert and willing to drink the solution.[2] Evidence (very low quality) suggests that activated charcoal is the best choice to reduce absorption of acetaminophen.[42] Patients receiving activated charcoal at a median 2 hours post-ingestion of a large dose of acetaminophen (≥40 g) had significantly lower acetaminophen concentrations (measured ≥1 hour after charcoal) than those who did not.[43] Patients should not be forced to take activated charcoal, nor should they be intubated or have nasogastric tubes placed solely to facilitate activated charcoal administration in the absence of other indications for these procedures.
- Specific management is determined by the type of overdose (acute or repeated supratherapeutic ingestion) and also the time elapsed since ingestion. Timely consultation with a medical toxicologist is recommended.
Acute single overdose
- Unknown, or ≥200 mg/kg acetaminophen.
- Unknown, or ≥10 g or ≥200 mg/kg acetaminophen (whichever is less).
- The patient is unconscious (and there is reasonable suspicion of acetaminophen toxicity)
- The patient presents 8 hours or more after ingestion, or there is uncertainty as to the timing of the overdose
- Serum acetaminophen level is not available within an 8-hour post-ingestion time window
- Co-ingestants that may delay acetaminophen absorption are suspected (e.g., anticholinergics)
- The patient presents with hepatotoxicity, possibly from acetaminophen, even with undetectable acetaminophen concentration.
Repeated supratherapeutic ingestion
- Obtain acetaminophen, AST, and ALT levels; treat with acetylcysteine.
- >4 g or >100 mg/kg acetaminophen ingestion (whichever is less) per 24 hours.
- ≥10 g or ≥200 mg/kg acetaminophen (whichever is less) over a single 24-hour period
- ≥6g or ≥150 mg/kg acetaminophen (whichever is less) per 24-hour period for the preceding 24 hours or longer.
- ≥200 mg/kg acetaminophen over a single 24-hour period
- ≥150 mg/kg acetaminophen per 24-hour period for the preceding 48 hours
- ≥100 mg/kg acetaminophen per 24-hour period for the preceding 72 hours or longer.
Modified-release preparations
Monitoring and endpoints for acetylcysteine treatment
- Most patients will be treated for a minimum of 21 hours. Whenever shorter treatment is considered, the case should be discussed with a medical toxicologist.
- Prior to discontinuing acetylcysteine the patient should be asymptomatic AND have the following laboratory tests repeated and documented undetectable or normal: serum acetaminophen (undetectable), serum AST or ALT, prothrombin time or INR, electrolytes, BUN, and creatinine (normal). Additional laboratory tests may be indicated depending on the clinical scenario.
- Acetylcysteine is indicated beyond 21 hours in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55]
- Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level. One exception that may be considered is resolving transaminitis, where the transaminases should be down-trending and under 1000 IU/L.[41] In these cases, consultation with a medical toxicologist is essential, especially prior to discontinuing therapy.
- The standard duration of therapy for oral acetylcysteine is 72 hours.
- Prior to discontinuing acetylcysteine the patient should be asymptomatic AND have the following laboratory tests repeated and documented undetectable or normal: serum acetaminophen (undetectable), serum AST or ALT, prothrombin time or INR, electrolytes, BUN, and creatinine (normal). Additional laboratory tests may be indicated depending on the clinical scenario.
- Acetylcysteine should be extended beyond 72 hours in patients with continued evidence of renal injury or liver injury/dysfunction, or other sequelae of acetaminophen toxicity. Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level. One exception that may be considered is resolving transaminitis, where the transaminases should be down-trending and under 1000 IU/L).[41] In these cases, consultation with a medical toxicologist is essential, especially prior to discontinuing therapy.
- Early termination (<72 hours) can be considered in patients who are asymptomatic and have a normal laboratory profile and undetectable acetaminophen level. This should only be done in consultation with a medical toxicologist.
Time-sensitive treatment issues
- For patients who present later than 8 hours after ingestion
- When serum acetaminophen concentrations cannot be determined within 8 hours
- If the exact timing of the ingestion is uncertain.
Fulminant liver failure
- Arterial lactate concentration >3.5 mmol/L after fluid resuscitation OR
- Arterial pH <7.3, and lactate >3.0 mmol/L after fluid resuscitation OR
- Prothrombin time (PT)/INR >100 seconds/6.0 seconds AND encephalopathy grade 3 or more AND creatinine >3.3 mg/dL (292 micromol/L) within 24 hours AND a normal arterial pH.
Treatment-related adverse effects
Usual treatment unavailable
Treatment Options
acute single ingestion
<4 hours since ingestion
acetylcysteine
Primary Options
- acetylcysteine
children and adults: 150 mg/kg intravenous infusion over 1 hour, followed by 50 mg/kg infusion over 4 hours, then 100 mg/kg infusion over 16 hours; OR 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for 72 hours
- acetylcysteine
Comments
- Acetylcysteine should be started immediately if the patient is unconscious (and there is reasonable suspicion of acetaminophen toxicity), or if co-ingestants that may delay acetaminophen absorption are suspected (e.g., anticholinergics).
- For a single acute ingestion of acetaminophen, patients should be transferred to the emergency department if the estimated ingestion is: unknown; ≥200 mg/kg (patient <6 years of age); or ≥10 g or ≥200 mg/kg (whichever is less, patient >6 years).[2]
- The serum acetaminophen level should be checked 4 hours after ingestion.[2] If a patient presents within 4 hours of ingestion, the level is drawn when 4 hours have elapsed since the possible overdose.
- Once the 4-hour acetaminophen level is obtained, it should be plotted against the time since ingestion on the Rumack-Matthew nomogram.Rumack-Matthew nomogram If the plot falls on or above the treatment line, the patient should be treated with acetylcysteine. It can be given either orally or intravenously.[42] [50]
- If the plotted acetaminophen level falls below the treatment line on the Rumack-Matthew nomogram, there is no risk of liver damage. Acetylcysteine is not required, or it can be discontinued.
- Acetylcysteine is indicated beyond standard duration of therapy (21 hours) in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55] Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level.
supportive care
Comments
- May include physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses.
- Supportive care must be tailored to each specific patient and is essential to good outcomes.
antiemetic
Primary Options
- ondansetron
children: 0.1 mg/kg intravenously as a single dose, maximum 4 mg/dose; adults: 4-8 mg intravenously as a single dose
- ondansetron
Comments
- Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment. It can be treated with an antiemetic (e.g., ondansetron).
- If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic is administered and oral acetylcysteine dose is re-administered.
- One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on anaphylactoid reactions and was associated with an increase in serum aminotransferase levels.[63]
activated charcoal
Primary Options
- charcoal, activated
children: 1 g/kg orally/nasogastrically as a single dose; adults: 50 g orally/nasogastrically as a single dose
- charcoal, activated
Comments
- Activated charcoal may be considered in a cooperative patient presenting within 2 hours of acute single acetaminophen ingestion; charcoal may decrease the need for acetylcysteine when given within 2 hours of ingestion.
- Evidence (very low quality) suggests that activated charcoal is the best choice to reduce absorption of acetaminophen.[42] Patients receiving activated charcoal at a median 2 hours post-ingestion of a large dose of acetaminophen (≥40 g) had significantly lower acetaminophen concentrations (measured ≥1 hour after charcoal) than those who did not.[43]
4-8 hours since ingestion
acetylcysteine
Primary Options
- acetylcysteine
children and adults: 150 mg/kg intravenous infusion over 1 hour, followed by 50 mg/kg infusion over 4 hours, then 100 mg/kg infusion over 16 hours; OR 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for 72 hours
- acetylcysteine
Comments
- Acetylcysteine should be started immediately if the patient is unconscious (and there is reasonable suspicion of acetaminophen toxicity), or if co-ingestants that may delay acetaminophen absorption are suspected (e.g., anticholinergics).
- Patients presenting between 4 and 8 hours after ingestion should have acetaminophen levels measured as soon as possible.
- Acetylcysteine should be started if the serum acetaminophen level will not be available within an 8-hour post-ingestion time window, or if it is available within 8 hours of ingestion and the plot falls on or above the treatment line on the Rumack-Matthew nomogram.
- It can be given either intravenously or orally.[50]
- If the plotted acetaminophen level falls below the treatment line on the Rumack-Matthew nomogram, there is no risk of liver damage. Acetylcysteine is not required, or it can be discontinued.
- Acetylcysteine is indicated beyond standard duration of therapy (21 hours) in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55] Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level.
supportive care
Comments
- May include physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses.
- Supportive care must be tailored to each specific patient and is essential to good outcomes.
antiemetic
Primary Options
- ondansetron
children: 0.1 mg/kg intravenously as a single dose, maximum 4 mg/dose; adults: 4-8 mg intravenously as a single dose
- ondansetron
Comments
- Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment. It can be treated with an antiemetic (e.g., ondansetron).
- If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic is administered and oral acetylcysteine dose is re-administered.
- One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on anaphylactoid reactions and was associated with an increase in serum aminotransferase levels.[63]
8-24 hours since ingestion
acetylcysteine
Primary Options
- acetylcysteine
children and adults: 150 mg/kg intravenous infusion over 1 hour, followed by 50 mg/kg infusion over 4 hours, then 100 mg/kg infusion over 16 hours; OR 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for 72 hours
- acetylcysteine
Comments
- Acetylcysteine should be started immediately if patient presents >8 hours after ingestion. It can be given either intravenously or orally.[50]
- Acetaminophen levels should be measured as soon as possible.
- For patients with acetaminophen levels that plot on or above the treatment line on the Rumack-Matthew nomogram, the patient should have acetylcysteine continued.
- If the plotted acetaminophen level falls below the treatment line on the Rumack-Matthew nomogram, the patient is asymptomatic, and there is no evidence of renal injury or liver damage/dysfunction (normal laboratory tests), acetylcysteine may be discontinued.
- Acetylcysteine is indicated beyond standard duration of therapy (21 hours) in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55] Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level.
supportive care
Comments
- May include physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses.
- Supportive care must be tailored to each specific patient and is essential to good outcomes.
antiemetic
Primary Options
- ondansetron
children: 0.1 mg/kg intravenously as a single dose, maximum 4 mg/dose; adults: 4-8 mg intravenously as a single dose
- ondansetron
Comments
- Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment. It can be treated with an antiemetic (e.g., ondansetron).
- If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic is administered and oral acetylcysteine dose is re-administered.
- One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on anaphylactoid reactions and was associated with an increase in serum aminotransferase levels.[63]
evaluation for liver transplant
Comments
- Laboratory criteria are helpful when evaluating patients for liver transplantation due to acetaminophen hepatotoxicity. However, patients with significant hepatotoxicity should be referred to a liver transplant facility as early as possible, ideally before metabolic acidosis, coagulopathy, and encephalopathy occur.
- Referral for liver transplant is indicated if: arterial lactate concentration >3.5 mmol/L after fluid resuscitation; OR arterial pH <7.3, and lactate >3.0 mmol/L after fluid resuscitation; OR PT/INR >100 seconds/6.0 seconds AND encephalopathy grade 3 or more AND creatinine >3.3 mg/dL (292 micromol/L) within 24 hours AND a normal arterial pH.[36] [57]
>24 hours since ingestion or time unknown
acetylcysteine
Primary Options
- acetylcysteine
children and adults: 150 mg/kg intravenous infusion over 1 hour, followed by 50 mg/kg infusion over 4 hours, then 100 mg/kg infusion over 16 hours; OR 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for 72 hours
- acetylcysteine
Comments
- Acetylcysteine should be started immediately if patient presents >24 hours after ingestion. It can be given either intravenously or orally.[50]
- Acetaminophen levels should be measured as soon as possible.
- For patients with detectable acetaminophen levels, or any indication of renal injury or liver injury/dysfunction, acetylcysteine is continued. If there is no detectable acetaminophen, and no evidence of renal injury or liver damage/dysfunction (normal laboratory tests), and the patient is asymptomatic, acetylcysteine may be discontinued.
- Acetylcysteine is indicated beyond standard duration of therapy (21 hours) in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55] Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level.
supportive care
Comments
- May include physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses.
- Supportive care must be tailored to each specific patient and is essential to good outcomes.
antiemetic
Primary Options
- ondansetron
children: 0.1 mg/kg intravenously as a single dose, maximum 4 mg/dose; adults: 4-8 mg intravenously as a single dose
- ondansetron
Comments
- Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment. It can be treated with an antiemetic (e.g., ondansetron).
- If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic is administered and oral acetylcysteine dose is re-administered.
- One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on anaphylactoid reactions and was associated with an increase in serum aminotransferase levels.[63]
evaluation for liver transplant
Comments
- Laboratory criteria are helpful when evaluating patients for liver transplantation due to acetaminophen hepatotoxicity. However, patients with significant hepatotoxicity should be referred to a liver transplant facility as early as possible, ideally before metabolic acidosis, coagulopathy, and encephalopathy occur.
- Referral for liver transplant is indicated if: arterial lactate concentration >3.5 mmol/L after fluid resuscitation; OR arterial pH <7.3, and lactate >3.0 mmol/L after fluid resuscitation; OR PT/INR >100 seconds/6.0 seconds AND encephalopathy grade 3 or more AND creatinine >3.3 mg/dL (292 micromol/L) within 24 hours AND a normal arterial pH.[36] [57]
repeated supratherapeutic acetaminophen ingestion: with symptoms or signs of hepatotoxicity
acetylcysteine
Primary Options
- acetylcysteine
children and adults: 150 mg/kg intravenous infusion over 1 hour, followed by 50 mg/kg infusion over 4 hours, then 100 mg/kg infusion over 16 hours; OR 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for 72 hours
- acetylcysteine
Comments
- Discussion with a medical toxicologist is strongly advised.
- Acetylcysteine should be started immediately. It can be given either intravenously or orally.[50]
- Acetaminophen levels should be measured as soon as possible.
- Acetylcysteine is indicated beyond standard duration of therapy (21 hours) in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55] Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level.
supportive care
Comments
- May include physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses.
- Supportive care must be tailored to each specific patient and is essential to good outcomes.
antiemetic
Primary Options
- ondansetron
children: 0.1 mg/kg intravenously as a single dose, maximum 4 mg/dose; adults: 4-8 mg intravenously as a single dose
- ondansetron
Comments
- Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment. It can be treated with an antiemetic (e.g., ondansetron).
- If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic is administered and oral acetylcysteine dose is re-administered.
- One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on anaphylactoid reactions and was associated with an increase in serum aminotransferase levels.[63]
evaluation for liver transplant
Comments
- Laboratory criteria are helpful when evaluating patients for liver transplantation due to acetaminophen hepatotoxicity. However, patients with significant hepatotoxicity should be referred to a liver transplant facility as early as possible, ideally before metabolic acidosis, coagulopathy, and encephalopathy occur.
- Referral for liver transplant is indicated if: arterial lactate concentration >3.5 mmol/L after fluid resuscitation; OR arterial pH <7.3, and lactate >3.0 mmol/L after fluid resuscitation; OR PT/INR >100 seconds/6.0 seconds AND encephalopathy grade 3 or more AND creatinine >3.3 mg/dL (292 micromol/L) within 24 hours AND a normal arterial pH.[36] [57]
repeated supratherapeutic acetaminophen ingestion: asymptomatic with hepatic risk factor, with acetaminophen ingestion >4 g/24 hours or >100 mg/kg/24 hours
acetylcysteine
Primary Options
- acetylcysteine
children and adults: 150 mg/kg intravenous infusion over 1 hour, followed by 50 mg/kg infusion over 4 hours, then 100 mg/kg infusion over 16 hours; OR 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for 72 hours
- acetylcysteine
Comments
- In patients with risk factors that may increase susceptibility to acetaminophen toxicity (alcohol dependence, glutathione deficiency, use of medications that induce hepatic enzymes, prolonged fasting), the dose of acetaminophen considered as a repeated supratherapeutic ingestion is >4 g/24 hours or >100 mg/kg/24 hours (whichever is less).[2]
- Discussion with a medical toxicologist is strongly advised.
- Acetylcysteine should be started immediately. It can be given either intravenously or orally.[50]
- Acetaminophen levels should be measured as soon as possible.
- For patients with detectable acetaminophen levels, or any indication of renal injury or liver injury/dysfunction, acetylcysteine is continued. If there is no detectable acetaminophen, and no evidence of renal injury or liver damage/dysfunction (normal laboratory tests), and the patient is asymptomatic, acetylcysteine may be discontinued.
- Acetylcysteine is indicated beyond standard duration of therapy (21 hours) in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55] Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level.
supportive care
Comments
- May include physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses.
- Supportive care must be tailored to each specific patient and is essential to good outcomes.
antiemetic
Primary Options
- ondansetron
children: 0.1 mg/kg intravenously as a single dose, maximum 4 mg/dose; adults: 4-8 mg intravenously as a single dose
- ondansetron
Comments
- Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment. It can be treated with an antiemetic (e.g., ondansetron).
- If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic is administered and oral acetylcysteine dose is re-administered.
- One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on anaphylactoid reactions and was associated with an increase in serum aminotransferase levels.[63]
evaluation for liver transplant
Comments
- Laboratory criteria are helpful when evaluating patients for liver transplantation due to acetaminophen hepatotoxicity. However, patients with significant hepatotoxicity should be referred to a liver transplant facility as early as possible, ideally before metabolic acidosis, coagulopathy, and encephalopathy occur.
- Referral for liver transplant is indicated if: arterial lactate concentration >3.5 mmol/L after fluid resuscitation; OR arterial pH <7.3, and lactate >3.0 mmol/L after fluid resuscitation; OR PT/INR >100 seconds/6.0 seconds AND encephalopathy grade 3 or more AND creatinine >3.3 mg/dL (292 micromol/L) within 24 hours AND a normal arterial pH.[36] [57]
repeated supratherapeutic acetaminophen ingestion: asymptomatic without hepatic risk factor
with acetaminophen ingestion ≥10 g/24 hours or ≥200 mg/kg/24 hours (>6 years of age) or ≥200 mg/kg/24 hours (<6 years of age)
acetylcysteine
Primary Options
- acetylcysteine
children and adults: 150 mg/kg intravenous infusion over 1 hour, followed by 50 mg/kg infusion over 4 hours, then 100 mg/kg infusion over 16 hours; OR 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for 72 hours
- acetylcysteine
Comments
- Discussion with a medical toxicologist is strongly advised.
- Acetylcysteine should be started immediately. It can be given either intravenously or orally.[50]
- Acetaminophen levels should be measured as soon as possible.
- For patients with detectable acetaminophen levels, or any indication of renal injury or liver injury/dysfunction, acetylcysteine is continued. If there is no detectable acetaminophen, and no evidence of renal injury or liver damage/dysfunction (normal laboratory tests), and the patient is asymptomatic, acetylcysteine may be discontinued.
- Acetylcysteine is indicated beyond standard duration of therapy (21 hours) in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55] Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level.
supportive care
Comments
- May include physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses.
- Supportive care must be tailored to each specific patient and is essential to good outcomes.
antiemetic
Primary Options
- ondansetron
children: 0.1 mg/kg intravenously as a single dose, maximum 4 mg/dose; adults: 4-8 mg intravenously as a single dose
- ondansetron
Comments
- Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment. It can be treated with an antiemetic (e.g., ondansetron).
- If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic is administered and oral acetylcysteine dose is re-administered.
- One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on anaphylactoid reactions and was associated with an increase in serum aminotransferase levels.[63]
evaluation for liver transplant
Comments
- Laboratory criteria are helpful when evaluating patients for liver transplantation due to acetaminophen hepatotoxicity. However, patients with significant hepatotoxicity should be referred to a liver transplant facility as early as possible, ideally before metabolic acidosis, coagulopathy, and encephalopathy occur.
- Referral for liver transplant is indicated if: arterial lactate concentration >3.5 mmol/L after fluid resuscitation; OR arterial pH <7.3, and lactate >3.0 mmol/L after fluid resuscitation; OR PT/INR >100 seconds/6.0 seconds AND encephalopathy grade 3 or more AND creatinine >3.3 mg/dL (292 micromol/L) within 24 hours AND a normal arterial pH.[36] [57]
with acetaminophen ingestion >6 g or ≥150 mg/kg per 24-hour period for the preceding 24 hours or longer (>6 years of age)
acetylcysteine
Primary Options
- acetylcysteine
children and adults: 150 mg/kg intravenous infusion over 1 hour, followed by 50 mg/kg infusion over 4 hours, then 100 mg/kg infusion over 16 hours; OR 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for 72 hours
- acetylcysteine
Comments
- Discussion with a medical toxicologist is strongly advised.
- Acetylcysteine should be started immediately. It can be given either intravenously or orally.[50]
- Acetaminophen levels should be measured as soon as possible.
- For patients with detectable acetaminophen levels, or any indication of renal injury or liver injury/dysfunction, acetylcysteine is continued. If there is no detectable acetaminophen, and no evidence of renal injury or liver damage/dysfunction (normal laboratory tests), and the patient is asymptomatic, acetylcysteine may be discontinued.
- Acetylcysteine is indicated beyond standard duration of therapy (21 hours) in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55] Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level.
supportive care
Comments
- May include physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses.
- Supportive care must be tailored to each specific patient and is essential to good outcomes.
antiemetic
Primary Options
- ondansetron
children: 0.1 mg/kg intravenously as a single dose, maximum 4 mg/dose; adults: 4-8 mg intravenously as a single dose
- ondansetron
Comments
- Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment. It can be treated with an antiemetic (e.g., ondansetron).
- If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic is administered and oral acetylcysteine dose is re-administered.
- One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on anaphylactoid reactions and was associated with an increase in serum aminotransferase levels.[63]
evaluation for liver transplant
Comments
- Laboratory criteria are helpful when evaluating patients for liver transplantation due to acetaminophen hepatotoxicity. However, patients with significant hepatotoxicity should be referred to a liver transplant facility as early as possible, ideally before metabolic acidosis, coagulopathy, and encephalopathy occur.
- Referral for liver transplant is indicated if: arterial lactate concentration >3.5 mmol/L after fluid resuscitation; OR arterial pH <7.3, and lactate >3.0 mmol/L after fluid resuscitation; OR PT/INR >100 seconds/6.0 seconds AND encephalopathy grade 3 or more AND creatinine >3.3 mg/dL (292 micromol/L) within 24 hours AND a normal arterial pH.[36] [57]
with acetaminophen ingestion ≥150 mg/kg per 24-hour period for the preceding 48 hours (<6 years of age)
acetylcysteine
Primary Options
- acetylcysteine
children: 150 mg/kg intravenous infusion over 1 hour, followed by 50 mg/kg infusion over 4 hours, then 100 mg/kg infusion over 16 hours; OR 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for 72 hours
- acetylcysteine
Comments
- Discussion with a medical toxicologist is strongly advised.
- Acetylcysteine should be started immediately. It can be given either intravenously or orally.[50]
- Acetaminophen levels should be measured as soon as possible.
- For patients with detectable acetaminophen levels, or any indication of renal injury or liver injury/dysfunction, acetylcysteine is continued. If there is no detectable acetaminophen, and no evidence of renal injury or liver damage/dysfunction (normal laboratory tests), and the patient is asymptomatic, acetylcysteine may be discontinued.
- Acetylcysteine is indicated beyond standard duration of therapy (21 hours) in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55] Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level.
supportive care
Comments
- May include physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses.
- Supportive care must be tailored to each specific patient and is essential to good outcomes.
antiemetic
Primary Options
- ondansetron
children: 0.1 mg/kg intravenously as a single dose, maximum 4 mg/dose
- ondansetron
Comments
- Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment. It can be treated with an antiemetic (e.g., ondansetron).
- If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic is administered and oral acetylcysteine dose is re-administered.
- One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on anaphylactoid reactions and was associated with an increase in serum aminotransferase levels.[63]
evaluation for liver transplant
Comments
- Laboratory criteria are helpful when evaluating patients for liver transplantation due to acetaminophen hepatotoxicity. However, patients with significant hepatotoxicity should be referred to a liver transplant facility as early as possible, ideally before metabolic acidosis, coagulopathy, and encephalopathy occur.
- Referral for liver transplant is indicated if: arterial lactate concentration >3.5 mmol/L after fluid resuscitation; OR arterial pH <7.3, and lactate >3.0 mmol/L after fluid resuscitation; OR PT/INR >100 seconds/6.0 seconds AND encephalopathy grade 3 or more AND creatinine >3.3 mg/dL (292 micromol/L) within 24 hours AND a normal arterial pH.[36] [57]
with acetaminophen ingestion ≥100 mg/kg per 24-hour period for the preceding 72 hours (<6 years of age)
acetylcysteine
Primary Options
- acetylcysteine
children: 150 mg/kg intravenous infusion over 1 hour, followed by 50 mg/kg infusion over 4 hours, then 100 mg/kg infusion over 16 hours; OR 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for 72 hours
- acetylcysteine
Comments
- Discussion with a medical toxicologist is strongly advised.
- Acetylcysteine should be started immediately. It can be given either intravenously or orally.[50]
- Acetaminophen levels should be measured as soon as possible.
- For patients with detectable acetaminophen levels, or any indication of renal injury or liver injury/dysfunction, acetylcysteine is continued. If there is no detectable acetaminophen, and no evidence of renal injury or liver damage/dysfunction (normal laboratory tests), and the patient is asymptomatic, acetylcysteine may be discontinued.
- Acetylcysteine is indicated beyond standard duration of therapy (21 hours) in patients with continued evidence of liver injury/dysfunction, abnormalities in predictors of poor prognosis, or persisting presence of serum acetaminophen detected by laboratory testing.[55] Endpoints for treatment with acetylcysteine in such cases are asymptomatic clinical status and normal laboratory tests, including undetectable acetaminophen level.
supportive care
Comments
- May include physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, psychological care for mental illness, and education for those with accidental overdoses.
- Supportive care must be tailored to each specific patient and is essential to good outcomes.
antiemetic
Primary Options
- ondansetron
children: 0.1 mg/kg intravenously as a single dose, maximum 4 mg/dose
- ondansetron
Comments
- Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment. It can be treated with an antiemetic (e.g., ondansetron).
- If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic is administered and oral acetylcysteine dose is re-administered.
- One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on anaphylactoid reactions and was associated with an increase in serum aminotransferase levels.[63]
evaluation for liver transplant
Comments
- Laboratory criteria are helpful when evaluating patients for liver transplantation due to acetaminophen hepatotoxicity. However, patients with significant hepatotoxicity should be referred to a liver transplant facility as early as possible, ideally before metabolic acidosis, coagulopathy, and encephalopathy occur.
- Referral for liver transplant is indicated if: arterial lactate concentration >3.5 mmol/L after fluid resuscitation; OR arterial pH <7.3, and lactate >3.0 mmol/L after fluid resuscitation; OR PT/INR >100 seconds/6.0 seconds AND encephalopathy grade 3 or more AND creatinine >3.3 mg/dL (292 micromol/L) within 24 hours AND a normal arterial pH.[36] [57]
Emerging Tx
Risk stratification using mechanistic biomarkers
Prevention
Primary Prevention
Secondary Prevention
Follow-Up Overview
Prognosis
Monitoring
Complications
Citations
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Chiew AL, Gluud C, Brok J, et al. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2018 Feb 23;(2):CD003328.[Abstract][Full Text]
American College of Medical Toxicology. ACMT Position statement: duration of intravenous acetylcysteine therapy following acetaminophen overdose. J Med Toxicol. 2017 Mar;13(1):126-7.[Abstract][Full Text]
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Key Articles
Other Online Resources
Referenced Articles
Guidelines
Diagnostic
Summary
Guidelines to assist US poison center personnel in appropriate triage of patients with suspected ingestion of acetaminophen.Published by
American Association of Poison Control Centers
Published
2006
Treatment
Summary
Guidelines to assist US poison center personnel in management of patients with suspected ingestion of acetaminophen.Published by
American Association of Poison Control Centers
Published
2006
Credits
Patient Instructions
- It is important to emphasize the importance of avoiding inadvertent overdose caused by combination of acetaminophen-containing drugs.
- Patients with a history of intentional self-harm are referred for psychiatric evaluation once they are medically stable.