Acetaminophen Toxicity

Acetaminophen Toxicity – 14 Interesting Facts

  1. Acetaminophen toxicity can be classified as acute (one-time single ingestion) or chronic (repeated supratherapeutic ingestions); most common cause of acute liver failure in the United States 
  2. Acetaminophen is primarily toxic to the liver but can cause dysfunction of other organ systems such as renal system, central nervous system, and metabolic system 
  3. A single acute ingestion of greater than 7.5 to 10 g in an adult or 150 to 200 mg/kg in children is potentially toxic 
  4. Unintentional overdoses can occur in patients taking multiple acetaminophen-containing products or taking more than the recommended dose 
  5. Initially, most patients will be asymptomatic or have nonspecific complaints early after an acute toxic ingestion 
  6. Severe poisoning can progress to fulminant hepatic failure, coma, and death 
  7. Early involvement of a local poison center, consulting medical toxicologist, and/or a local liver transplant center can facilitate appropriate and timely diagnosis and treatment 
  8. Diagnosis of acute toxicity is confirmed by a serum acetaminophen concentration plotted on the Rumak-Matthew nomogram
  9. All patients presenting after an unknown overdose require an acetaminophen concentration as part of their evaluation 
  10. Correct interpretation of acetaminophen concentrations must consider numerous factors including timing of ingestion, classification of acute or chronic exposure, and other laboratory measurements 
  11. Acetylcysteine is the preferred treatment of both acute and chronic acetaminophen toxicity and is extremely effective if initiated within 8 hours of an acute ingestion; charcoal administration is adjunct for most acute ingestions presenting within 12 to 24 hours 
  12. Hemodialysis may be indicated for massive ingestions or for renal failure 
  13. Prognosis is poor when signs of hepatic failure develop without liver transplant(eg, acidemia, renal failure, coagulopathy, encephalopathy) 
  14. Liver transplant may be necessary for patients at high risk for developing fulminant hepatic failure despite acetylcysteine therapy 

Pitfalls

  • Failure to obtain a complete medication history can lead to delayed diagnosis, as acetaminophen is contained in numerous OTC and prescription medications
  • Failure to recognize potential toxicity from repeated supratherapeutic ingestions, especially in those at increased risk (eg, elderly patients, those who misuse alcohol), can lead to missed diagnosis in patients with chronic pain or on multiple acetaminophen-containing products 
  • Failure to recognize that patients may be asymptomatic early after an acute toxic ingestion can lead to delay in definitive diagnosis, treatment, preventable liver failure, and increased mortality 
  • Failure to consider toxicity in patients presenting with subtle manifestations of toxicity (eg, nausea, vomiting, abdominal pain) while taking OTC preparations containing acetaminophen may lead to delay in definitive diagnosis, treatment, preventable liver failure, and increased mortality 
  • Failure to recognize acetaminophen poisoning in patients with signs of hepatic injury or dysfunction and an undetectable acetaminophen concentration delays treatment resulting in increased morbidity and mortality 
  • Do not use nomogram for patients without acute toxicity presenting within 24 hours; nomogram is inaccurate for diagnosis of chronic/subacute ingestion 
  • Failure to repeat acetaminophen concentrations in cases of coingestion with anticholinergic agents and opioids or extended-release preparations can lead to missed diagnosis, as a delayed rise in acetaminophen concentration that may occur in these scenarios 
  • Failure to begin antidote therapy before reaching critical 8-hour time point after acute ingestion while awaiting laboratory confirmation of potential toxicity can lead to increased preventable hepatotoxicity; begin acetylcysteine before the 8-hour postingestion mark (when antidote is most effective) and discontinue further treatment if not indicated 
  • Delay in acetylcysteine administration to ensure administration of charcoal can result in increased risk of hepatotoxicity; administration of oral acetylcysteine concomitant with enteral charcoal gastrointestinal decontamination is safe and effective given lack of contraindications 
  • Avoid halting IV infusion for mild reactions to acetylcysteine, which are common; treat moderate to severe reactions with brief period of infusion discontinuation and symptomatic therapy before restarting infusion at a lower rate 
  • Failure to recognize signs of worsening hepatic function (eg, coagulation study results, metabolic acidosis, encephalopathy) and risk for poor prognosis (eg, positive King’s College criteria) without liver transplant can lead to delay in referral to a liver transplant center and increased mortality 

Clinical Clarification

  • Acetaminophen toxicity results from ingestion of acetaminophen-containing products in doses higher than therapeutic recommendations; toxicity can be acute or chronic
    • A single acute ingestion greater than 7.5 g in an adult or 150 mg/kg in children is potentially toxic (toxicity more commonly occurs with a single ingestion of more than 200-250 mg/kg) 
    • Repeated supratherapeutic ingestions may cause chronic toxicity in certain patient populations such as those with chronic alcohol use disorder, nutritional deficiencies, or prior weight-loss surgery, those taking medications or herbal preparations that affect enzyme activity, or febrile children 
  • Acetaminophen poisoning primarily results in liver toxicity; additional organ systems may be affected (eg, renal system, central nervous system) 
    • Acetaminophen concentrations greater than 150 mcg/mL 4 hours after an acute ingestion are potentially toxic
  • Manifestations of toxicity at presentation are largely dependent on chronicity of exposure
    • Acute (one-time) ingestions may present in distinct clinical phases; without treatment, initial gastrointestinal symptoms may be followed by liver toxicity, possibly multiorgan failure, and death 
    • Chronic poisoning (repeated supratherapeutic ingestions) often presents with signs of liver toxicity
  • Acetaminophen poisoning is the most common cause of acute liver failure in the United States 

Classification

  • Based on chronicity of exposure
    • Acute poisoning
      • One-time single ingestion occurring within a 4-hour period
      • Classified into 4 clinical phases of toxicity 
        • Phase I: gastrointestinal phase
          • 0 to 24 hours after ingestion
        • Phase II: hepatic injury
          • 24 to 72 hours after ingestion
          • Liver enzymes begin to rise 
        • Phase III: hepatic necrosis and multiorgan failure
          • 72 to 96 hours after ingestion
          • Phase of maximal liver injury; may be associated with development of jaundice, encephalopathy, severe metabolic acidosis, and coagulopathy 
        • Phase IV: recovery
          • 4 to 14 days after ingestion
        • Renal injury may evolve during phase II, III, or IV of toxicity 
    • Chronic or subacute poisoning 
      • Ingestion(s) occurring over a prolonged period that extends beyond 4 hours 
      • Caused by multiple supratherapeutic acetaminophen doses without clear clinical phases
      • Often presents with otherwise unexplained signs of liver toxicity

Clinical Presentation

History

  • Ingestion history
    • Acute ingestions are single, one-time events
      • Ingestions greater than 7.5 g in an adult or 150 mg/kg in children are potentially toxic 
      • May be result of intentional suicide attempt or unintentional overdose
      • Establishing exact time of ingestion can be difficult but important, given that time since ingestion heavily influences treatment decisions
      • IV acetaminophen overdoses are typically (10-fold) administration errors and are expected to follow a course similar to that of acute oral ingestions 
    • Chronic ingestions are repeated supratherapeutic doses that can occur over any period 
      • Most commonly are unintentional 
      • Presentation is typically delayed without a clear overdose history
      • History of chronic pain or unintentional use of multiple acetaminophen-containing products may be elicited
  • Acetaminophen formulation
    • Acetaminophen is contained in more than 100 products and is frequently combined with other medications that can have their own toxicity 
    • Presence of coingestants in combination products can alter clinical presentation
  • Acute exposure symptoms
    • Classically, occurs in 4 phases; however, course is often variable and may be influenced by multiple factors (ie, dose, formulation, coingestions, preexisting liver disease)
      • Phase I: gastrointestinal phase 
        • Patients are often asymptomatic 
        • Symptoms, if present, are nonspecific and may improve over the first 24 hours 
          • Anorexia
          • Nausea
          • Vomiting
          • Abdominal pain
          • Malaise
          • Diaphoresis
        • Nonspecific symptom manifestations do not reliably predict subsequent hepatotoxicity 
          • However, increased episodes of vomiting at first presentation may be a marker for subsequent hepatotoxicity
        • Patients with massive exposures (serum levels of 800-1000 mcg/mL) may show early obtundation and coma 
          • Central nervous system symptoms are not common early in the course of disease, except when associated with massive overdose 
          • Early central nervous system symptoms raise the concern for coingestions (eg, opioids) and other medical causes (eg, meningitis, central nervous system catastrophe) for mental status depression 
    • Phase II: hepatic injury 
      • Patients may be asymptomatic or have right upper quadrant pain developing by day 2 or 3 
      • Decreased urine output due to dehydration, renal damage, and/or antidiuretic effects of acetaminophen 
    • Phase III: hepatic necrosis and multiorgan failure 
      • Right upper quadrant pain
      • Jaundice
      • Oliguria
      • Encephalopathy or coma
      • Death will typically occur during this phase
    • Phase IV: recovery with resolution of symptoms
  • Chronic exposure symptoms
    • Symptoms are similar to those in acute overdose 
      • Frequently patients present later in the course of illness with signs of liver toxicity (eg, right upper quadrant pain, jaundice, vomiting, confusion, elevated liver function test results) 
      • More commonly, history does not demonstrate clear phases; likely secondary to later presentation
    • Patients are more likely to have risk factors for hepatotoxicity, particularly patients with chronic alcoholism, children during intercurrent febrile illness, and patients taking enzyme-inducing medications 

Physical examination

  • Acute signs depend on phase of presentation and may include:
    • Phase I: gastrointestinal phase 
      • Physical examination findings are typically normal
        • Abdominal tenderness may be present
        • Diaphoresis is often present
        • Dehydration, if patient has significant emesis
      • Rarely, massive ingestions may result in early altered mental status (eg, confusion, lethargy, coma) 
    • Phase II: hepatic Injury 
      • Abdominal tenderness (right upper quadrant)
    • Phase III: hepatic necrosis and multiorgan failure 
      • Abdominal tenderness (right upper quadrant)
      • Jaundice and scleral icterus
      • Purpura and other clinical evidence of bleeding diathesis
      • Ascites
      • Tachycardia
      • Hypotension
      • Altered level of consciousness
        • Lethargy or coma
        • Grade 3 or 4 hepatic encephalopathy is associated with an increased risk of death 
    • Phase IV: recovery
  • Chronic acetaminophen toxicity can present with any of the signs of acute toxicity 
    • Characteristically presents later in course of illness with right upper quadrant hepatic tenderness and possibly jaundice

Causes and Risk Factors

Causes

  • Excessive acetaminophen consumption
    • Intentional or unintentional acute exposure (entire dose consumed within 8 hours) to a toxic dose 
      • Toxic dose likely to cause hepatotoxicity is at least 7.5 to 10 g in adult or 150 to 200 mg/kg in child older than 6 years 
      • Single acute ingestion of less than 200 mg/kg in child younger than 6 years is unlikely to cause toxicity 
      • Acute hepatotoxicity is highly likely with single ingestion over 250 mg/kg in children or 12 g in adults over a 24-hour period; toxicity is expected in almost all children ingesting more than 350 mg/kg 
      • Acute intentional overdose of 15 to 25 g may cause severe liver injury that results in fatality in up to 25% of adults 
      • Often patients are not aware they are taking multiple products containing acetaminophen with unintentional acute exposure
      • Unintentional IV formulation dosing errors (usually 10-fold) can occur, often by provider calculating dose in milligrams but administering solution in milliliters 
    • Chronic repeated ingestion of supratherapeutic doses 
      • Toxic doses that may cause hepatotoxicity are repeated overdoses in populations who are not at high risk
        • Adults and children older than 6 years 
          • At least 10 g or 200 mg/kg (whichever amount is less) in a 24-hour period or 
          • At least 6 g or 150 mg/kg (whichever amount is less) per 24-hour period for 48 hours or longer 
        • Children younger than 6 years 
          • 200 mg/kg or more in a single 24-hour period or 
          • 150 mg/kg or more per 24 hours for the past 48 hours or 
          • 100 mg/kg or more per 24 hours for the past 72 hours 
      • Toxic doses in high-risk patients may be different (eg, patients who are pregnant or those have prolonged fasting, chronic alcohol use disorder, or concomitant use of drugs or herbal products that affect enzyme metabolism) 
        • More than 4 g or 100 mg/kg (whichever amount is less) in a 24-hour period may result in toxicity in some high-risk patients 
        • Up to 50% of admissions for hepatotoxicity occur in those with specific risk factors for increased susceptibility to toxicity despite daily dosing that does not greatly exceed recommended dosing range 
      • Most unintentional overdoses occur from either: 
        • Consumption of higher than recommended doses to treat an underlying condition (eg, chronic pain) or
        • Consumption of multiple acetaminophen-containing products
  • Sources of exposure
    • OTC products
      • Acetaminophen is available in numerous formulations 
        • Tablets (325, 500, or 625 mg)
        • Extended-release tablets (650 mg)
        • Chewable tablets (80 or 160 mg)
        • Elixirs (160 mg per 5 mL)
        • Rectal suppositories (120, 325, or 650 mg)
      • Acetaminophen is also commonly combined with other OTC medications 
        • Other analgesics
          • Aspirin (eg, Excedrin)
          • Ibuprofen (eg, Maxigesic)
        • Antihistamines
          • Diphenhydramine (eg, Tylenol PM, Excedrin PM)
        • Antitussives and expectorants
          • Dextromethorphan (eg, DayQuil Cold and Flu, Tylenol Cold Nighttime)
          • Guaifenesin (eg, DayQuil Severe Cold and Flu, Sudafed Triple Action)
    • Prescription products (single-agent and combination)
      • Acetaminophen is restricted by the FDA to a maximum of 325 mg per unit dose as of 2014 
      • Commonly combined with an opioid
        • Codeine (eg, Tylenol #3, Tylenol #4)
        • Hydrocodone (eg, Norco, Vicodin)
        • Oxycodone (eg, Percocet, Endocet)
        • Tramadol (eg, Ultracet)
      • Combined with other medications
        • Caffeine and butalbital (eg, Fioricet)
      • IV acetaminophen (10 mg/mL)
  • Pharmacology 
    • Absorption
      • Standard-release acetaminophen is rapidly absorbed from the gastrointestinal tract; concentrations typically peak within 90 minutes for therapeutic dosing 
      • May be prolonged in overdose, but complete absorption is assumed by 4 hours; peak serum concentrations usually occur by 4 hours in overdose 
      • Extended-release products and drugs that delay gastric emptying time (eg, anticholinergics, opiates) may prolong absorption, resulting in later peak serum concentration beyond 4 hours; however, total amount absorbed is unaffected 
    • Distribution
      • Acetaminophen has a small volume of distribution with minimal protein binding
      • Therapeutic concentration range is 10 to 20 mcg/mL 
    • Metabolism
      • Acetaminophen undergoes extensive hepatic metabolism 
        • Most of a therapeutic dose is conjugated to glucuronidated and sulfated metabolites 
        • Smaller percentage undergoes oxidation primarily by CYP2E1 (CYP-2A1 and CYP3A4 to a lesser extent) to the highly reactive and toxic intermediate NAPQI (N-acetyl-para-benzoquinone imine) 
          • NAPQI is detoxified by glutathione stores in the liver 
      • Acetaminophen has dose-related hepatotoxicity 
        • Sulfation and glucuronidation pathways are saturated at toxic dose level, resulting in increased amounts of toxic metabolite NAPQI formation
        • Glutathione stores are eventually depleted and NAPQI binds to hepatocytes, causing oxidative cellular injury and hepatocellular necrosis
        • Zone 3 hepatocytes are most vulnerable to injury, leading to characteristic centrilobular pattern of hepatocellular necrosis
    • Elimination
      • Acetaminophen metabolites and a small amount of unmetabolized acetaminophen are eliminated by the kidneys
      • Typical half-life is 2 to 4 hours but can be over 4 hours if liver dysfunction is present 
  • Factors influencing toxicity
    • Delayed absorption may lead to a delayed peak concentration; however, total amount of drug absorbed is unaffected. Factors that may lead to delayed absorption include: 
      • Antihistamines or drugs with anticholinergic properties
      • Opioids
      • Food 
      • Extended-release preparations
    • Alteration in effective metabolism of drug
      • Excessive cytochrome P450 activity
        • May be caused by CYP2E1 induction by enzyme-inducing agents such as ethanol, antituberculosis medications (eg, isoniazid), anticonvulsants (eg, phenobarbital), or St. John’s wort 
        • Garlic or germander may increase cytochrome P450 activity 
      • Decreased hepatic glucuronidation capacity or decreased hepatic sulfation capacity 
        • May result from chronic alcohol use
      • Depleted glutathione stores 
        • Leads to rapid unopposed NAPQI accumulation 
          • NAPQI causes hepatocellular damage and liver failure 
          • Zone 3 of the liver is primarily affected, owing to increased activity of CYP2E1, leading to the characteristic centrilobular necrosis 
        • May be seen at baseline in patients with a poor nutrition status and in patients taking certain medications (eg, trimethoprim-sulfamethoxazole) 

Risk factors and/or associations

Age
  • Metabolism of acetaminophen is somewhat age-dependent
    • Older patients are at higher risk than children for developing hepatotoxicity 
    • Children younger than 5 years are at lower risk of hepatotoxicity for a given acute supratherapeutic dose than older children and adults 
Sex
  • Pregnant women are a high-risk group
    • Acetaminophen is the most common drug overdose in pregnancy, likely because it is one of the most common medications administered during pregnancy 
Genetics
  • Genetic factors that may increase risk for hepatotoxicity
    • Gilbert syndrome 
      • Patients exhibit enhanced susceptibility to acetaminophen toxicity owing to inherited deficiency in glucuronidation
    • Polymorphisms in the cytochrome P450 system (mainly CYP2E1) may affect risk of acetaminophen toxicity 
Other risk factors/associations
  • Factors that may increase risk for hepatotoxicity, especially with repeated supratherapeutic dosing, include:
    • Chronic alcohol use disorder
      • Owing to preexisting liver damage and induction of the CYP2E1 enzyme 
      • Short courses of the maximum recommended daily dose of acetaminophen do not appear to be associated with increased risk 
    • Concomitant use of certain medications
      • Chronic medications and substances that induce certain hepatic enzymes
        • CYP2E1 inducers (eg, isoniazid, rifampin, phenobarbital, St. John’s wort) 
        • CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, St. John’s wort, rifampin, grapefruit juice)
        • Unspecified inducers include garlic and germander 
      • Medications that deplete glutathione
        • Chronic opioid therapy 
        • Zidovudine and trimethoprim-sulfamethoxazole (eg, in patients who are HIV-positive) 
    • Poor nutritional status
      • Often caused by depleted glutathione stores
        • Nutritional deficiencies or malnutrition 
          • Alcohol use disorder (in particular) 
          • HIV infection 
          • Cystic fibrosis 
        • Prolonged fasting 
          • Particularly in patients who misuse alcohol
          • Children in a fasting state during intercurrent febrile illness
        • Prior weight-loss surgery 
    • Chronic liver disease in patients who actively misuse alcohol 
      • Patients with chronic liver disease who do not regularly consume alcohol are not at increased risk with therapeutic dosing 
    • Dosing pattern 
      • Increased frequency of dosing
      • Prolonged duration of excessive dosing
  • Findings that increase risk of poor prognosis and death include:
    • Metabolic acidosis after IV fluid resuscitation 
    • Lactic acid level greater than 3.5 mmol/L at any time or greater than 3 mm/L after resuscitation 
    • Hyperphosphatemia detected between 48 and 72 hours after overdose 
    • Hepatic synthetic dysfunction marked by increase in prothrombin time and INR 
    • Renal dysfunction marked by rise in creatinine level 
    • Development of grade 3 or 4 hepatic encephalopathy 
    • Hypoglycemia 
    • Rapidly rising AST and/or ALT levels (doubling within 8 hours) and developing AST and/or ALT levels greater than 1000 units/L within 20 hours of acetylcysteine treatment 

Diagnostic Procedures

Primary diagnostic tools

  • Diagnosis is suggested by patient history, physical examination, and laboratory testing 
    • Do not delay antidote treatment beyond 8 hours after acute ingestion while waiting for laboratory confirmation 
    • Obtain acetaminophen concentration as close to 4 hours after ingestion as possible for acute exposure or on arrival for chronic exposure 
    • Initial ancillary testing approach for acute exposure 
      • Obtain AST level when acetaminophen concentration is above treatment line or presenting manifestations suggest hepatic injury
      • Obtain INR and levels of electrolytes, glucose, and BUN/creatinine if there are marked elevations in AST level or if patient appears very ill
    • Additional testing approach for chronic exposure 
      • Obtain AST level in all patients; consider full liver function testing panel
      • Obtain INR and levels of electrolytes, glucose, and BUN/creatinine if there are marked elevations in AST level or if patient appears very ill
  • Evaluation after acute overdose with known time of ingestion
    • Ideal concentration to plot on Rumack-Matthew nomogram is at 4 hours after ingestion 
    • Confirm potential for toxicity using nomogram after a single acute ingestion up to 24 hours after ingestion of an immediate-release product 
      • Nomogram cannot be applied in up to 50% of overdose scenarios presenting for evaluation (eg, repeated supratherapeutic ingestions, acute overdose of a sustained-release product, unknown time of ingestion, presentation 24 hours after ingestion)
    • Elevated serum acetaminophen concentration plotted on the Rumack-Matthew nomogram confirms diagnosis of potential acute hepatotoxicity 
      • Hepatotoxicity is defined as AST level exceeding 1000 units/L 
      • Risk for toxicity may be excluded if immediate-release acetaminophen concentration is negligible within 1 to 4 hours after ingestion 
    • Recommendations to determine treatment threshold for toxicity are highly variable between regions; consult regional medical toxicologist or poison control center for specific recommendations
      • Possible risk for hepatotoxicity or treatment line (150 line) on nomogram
        • Acetaminophen concentration lies above line between 150 mcg/mL at 4 hours and 5 mcg/mL at 24 hours, set by FDA to provide a 25% treatment safety margin below the probable toxicity (200) line 
          • Created to account for patients with unknown risk factors for increased toxicity and often inaccurate historical determination of ingestion time
          • Note: if there is any concern about time of ingestion and patient is close to treatment line, antidote treatment is recommended
        • Diagnose treatment threshold for possible toxicity when concentration falls above this line in the United States, Australia, and New Zealand, even in the absence of clinical or laboratory evidence for toxicity at the time of presentation 
      • Probable risk for hepatotoxicity line (200 line) on nomogram 
        • Acetaminophen concentration lies above line between 200 mcg/mL at 4 hours and 25 mcg/mL at 16 hours after ingestion, indicating risk for developing severe hepatotoxicity (defined as AST level exceeding 1000 units/L)
        • Without treatment, approximately 60% incidence of severe hepatotoxicity and 5% risk of mortality occurs when concentration lies above probable toxicity (200) line
      • High risk for hepatotoxicity line (300 line) on nomogram 
        • Without treatment, approximately 90% incidence of severe hepatotoxicity and 24% risk of mortality occurs when concentration lies above high risk for toxicity (300) line
  • Evaluation with an unknown time of acute ingestion or window for ingestion spans more than 24 hours 
    • Diagnosis of toxicity requires consultation with a medical toxicologist to assist with diagnostic recommendations
    • Obtain both acetaminophen concentration and AST level
    • Diagnose treatment threshold for possible toxicity either if AST level is elevated or if acetaminophen level is detectable
    • Exclude potential for toxicity if both of the following are true: AST level is within reference range and acetaminophen level is undetectable
  • Evaluation after acute ingestion of sustained-release preparation and coingestant that delays gastric motility (eg, opioid, anticholinergic)
    • Diagnosis of toxicity may require consultation with a medical toxicologist to assist with diagnostic recommendations
    • Obtain initial postingestion concentration between 4 and 6 hours; retest in another 4 to 6 hours after initial concentration if the first plots below treatment line 
    • Consider patients to be above treatment threshold if either concentration falls above treatment line 
    • Consider patients to be above treatment threshold, and possibly affected by toxicity until worsening toxicity is excluded during an empiric course of antidote treatment, if history suggests ingestion less than 200 mg/kg 
  • Evaluation after IV overdose
    • Limited experience exists with diagnostic strategies to approach parenteral overdose 
    • Consider patients to be above treatment threshold, and possibly affected by toxicity until worsening toxicity is excluded during a course of antidote treatment, for either of the following:
      • Parenteral dose of administered acetaminophen exceeding 60 mg/kg in children 
      • Concentration above a parallel treatment line beginning at 50 mcg/mL at 4 hours 
  • Evaluation after repeated supratherapeutic dosing
    • Diagnosis of chronic toxicity may require consultation with a medical toxicologist to assist with diagnostic recommendations 
      • Most patients at risk for developing significant chronic toxicity present with risk factors that predispose to hepatotoxicity (eg, those who chronically misuse alcohol, infants with febrile illness receiving supratherapeutic dosing, patients taking enzyme-inducing mediation, malnourished or fasting patients) 
    • Obtain acetaminophen concentration and liver function test results; consider prothrombin time and INR testing 
      • Undetectable acetaminophen concentration does not exclude chronic toxicity; nomogram cannot be used to assess for chronic toxicity
    • Diagnosis of treatment threshold for possible toxicity includes:
      • Concentrations considered by most experts to place patients at risk for hepatotoxicity, even if liver function test results are within reference range at presentation, such as: 
        • Supratherapeutic concentrations greater than 20 mcg/mL in patients without increased risk factors for toxicity
        • Concentrations greater than 10 mcg/mL in patients with increased risk factors for toxicity
      • Patients with history of excessive acetaminophen ingestion and elevated ALT levels, despite undetectable acetaminophen concentration 
    • Exclude worsening toxicity during a course of antidote treatment with clinical and laboratory monitoring in patients who meet treatment threshold for potential hepatotoxicity 
    • Exclude asymptomatic patients from significant toxicity risk and consider below treatment threshold when acetaminophen concentration is undetectable or less than 10 mcg/mL and ALT level is within reference range 
  • Obtain additional baseline ancillary laboratory testing at time of initial diagnosis for most patients with concern for significant ingestion, hepatotoxicity, or potential for hepatotoxicity
    • Ancillary testing includes electrolyte level with phosphate, liver function testing with bilirubin level, BUN/creatinine levels, prothrombin time/INR, and confirmatory levels of coingestants, if suspected 
    • Urinalysis with microscopic evaluation if renal injury is apparent
    • Ancillary testing is particularly important for patients with repeated supratherapeutic dosing and patients presenting more than 8 hours after acute ingestion 
    • Assess and monitor for possible need for liver transplant with a validated tool such as King’s College criteria in patients with severe hepatotoxicity 
  • Obtain routine screening laboratory tests in patients with intentional ingestion to assess for occult coingestion and potential factors that may modify treatment decisions
    • Glucose level in patients with mental status depression
    • Urine pregnancy test in women of child-bearing age
    • ECG to assess for conduction abnormalities requiring intervention 
    • Assess renal panel for presence of anion gap
  • Serum acetaminophen concentration
    • Therapeutic dosing results in peak acetaminophen concentration less than 30 mcg/mL about 30 to 90 minutes after dose and less than 10 mcg/mL by 4 to 6 hours after dose 
    • A detectable concentration will confirm an exposure 
      • Diagnosis of treatment threshold (need for antidote treatment) is informed by all of the following:
        • Formulation ingested (eg, immediate- versus extended-release) and presence of coingestants that delay gastric emptying (eg, opioids, anticholinergics)
        • Time since ingestion
        • Presence of related abnormal laboratory results (eg, liver function tests)
        • Acetaminophen concentration plotting on nomogram
    • An undetectable concentration may be present in some patients who manifest significant toxicity in certain clinical scenarios, including: 
      • Chronic acetaminophen toxicity
      • Delayed presentation after an acute ingestion
        • Increased transaminase levels presenting after 24 hours from a single ingestion are suggestive of acetaminophen toxicity 
      • Initially unexplained cause for liver failure
        • Up to 18% of patients who present with unexplained liver failure are found to have occult acetaminophen toxicity 
    • Indications for serial acetaminophen concentration testing include:
      • Acetaminophen concentration obtained less than 4 hours from a single acute ingestion requires additional testing, obtained 4 hours after the initial value was determined 
        • Retest at 4 to 6 hours after the initial concentration and plot both values on the Rumack-Matthew nomogram
      • Coingestion of acetaminophen with medications that slow gastrointestinal motility (eg, opioids, anticholinergic agents) may have delayed peak concentrations 
      • Concentrations of extended-release acetaminophen measured less than 8 hours after ingestion may be misleading 
        • Retest at 4 to 6 hours from the initial concentration and plot both values on the Rumack-Matthew nomogram
    • Other indications for obtaining acetaminophen concentration include the following: 
      • All suicidal patients after intentional ingestion 
      • All patients with other possible medication ingestions 
      • Patients with indeterminate cause of hepatitis or acute liver failure 
    • False-positive results may be noted with hyperbilirubinemia
      • Colorimetric methods of measuring acetaminophen may result in false-positive results in the presence of elevated direct bilirubin level (greater than 8-10 mg/dL) 
      • Diluting samples by a factor of 2 or confirming values using a nonenzymatic assay can correct a false-positive result 
    • Negative result can occur when patients present late, outside of positive testing window, despite acetaminophen-induced hepatotoxicity 
  • Hepatic function panel
    • Elevation of aminotransferase (AST and ALT) and/or bilirubin levels may be indicative of hepatic injury 
      • Usually occurs between 24 and 36 hours of an acute overdose, but may be as early as 12 hours 
      • Elevation of AST and/or ALT levels will be greater than 1000 units/L in patients with significant hepatotoxicity 
      • Degree of aminotransferase elevation roughly correlates with degree of hepatotoxicity 
      • Development of marked elevation in aminotransferase (often greater than 3000 units/L) is characteristic 
      • AST level can exceed 10,000 units/L; AST level is frequently elevated more than ALT level 
      • Maximal liver injury often occurs between 3 and 5 days after ingestion; may be associated with jaundice, intractable metabolic acidosis, coagulopathy, and encephalopathy 
      • Elevated AST level precedes laboratory markers of hepatic dysfunction (eg, increased prothrombin time/INR, hyperbilirubinemia, hypoglycemia, acidosis) 
    • Isolated abnormalities of the hepatic function panel results may be indicative of acetaminophen toxicity, even in the absence of a detectable acetaminophen concentration, given a positive history of acetaminophen ingestion or chronic exposure 
    • Total serum bilirubin levels greater than 8 mg/dL may be associated with false-positive serum acetaminophen concentrations 
  • Serum electrolyte, BUN, creatinine, and glucose measurements
    • Hypoglycemia 
      • Can occur in patients who develop liver failure
      • Associated with increased mortality from acetaminophen toxicity
    • Elevated anion gap 
      • May follow large acute, delayed acute, or chronic supratherapeutic ingestions
      • May be caused by increase in lactic acid or 5-oxoproline metabolic byproduct 
    • Renal dysfunction
      • Serum creatinine level greater than 3.3 mg/dL is suggestive of a poor prognosis 
      • May occur early in acute ingestion and rarely precedes hepatotoxicity
      • More common in phase III of acute ingestions or in chronic toxicity
    • Hyperphosphatemia
      • Serum phosphate level greater than 1.2 mmol/L at 48 to 72 hours after overdose is associated with an increased risk of death 
  • Coagulation studies
    • Markers of hepatic synthetic function
    • INR greater than 6.5 or prothrombin time greater than 100 seconds is suggestive of a poor prognosis 
    • Prothrombin time that continues to rise above 4 seconds after overdose and peak prothrombin time of at least 180 seconds impart an approximately 90% mortality rate without liver transplant 
    • Acetylcysteine antidote, and possibly acetaminophen itself, may cause a slight elevation in prothrombin time and INR 
      • Mean increase in INR is approximately 1.36 
      • Avoid confusing a mild increase in INR without other signs of liver injury early after acute overdose secondary to antidote with an increasing INR 24 hours after ingestion, which suggests true worsening of hepatic synthetic function 
    • Treatment with fresh frozen plasma or exogenous clotting factors alters interpretation of prothrombin time/INR by causing improvement in laboratory values without true improvement in hepatic synthetic function 
    • Treatment with vitamin K followed by improvement in synthetic liver function implies presence of remaining viable liver tissue 
  • Arterial or venous blood gas measurements 
    • Metabolic acidosis (pH less than 7.3) after IV fluid resuscitation is associated with decreased survival
  • Serum lactate measurement 
    • Lactic acidosis can develop
      • Early after massive overdose, before onset of hepatotoxicity owing to NAPQI mitochondrial inhibition 
      • Later in course (after day 2) in patients developing acute liver failure as a result of tissue hypoxia and diminished hepatic clearance of lactate 
    • Lactic acid level greater than 3.5 mmol/L at any time or greater than 3 mm/L after resuscitation is associated with increased mortality 
  • Serum ammonia measurement
    • Elevated level may be a marker of hepatic encephalopathy 
  • Serum amylase measurement
    • Levels are frequently elevated in patients with severe toxicity associated with acute liver failure; however, clinical pancreatitis is rare 
  • Acetaminophen-cysteine protein adducts 
    • Specific serum marker for hepatic injury secondary to acetaminophen
    • May help diagnose acetaminophen-related hepatotoxicity in patients with delayed presentation after overdose when acetaminophen levels are undetectable 
    • Not routinely available at most institutions

Functional testing

  • King’s College criteria for acetaminophen-induced acute liver failure 
    • Helps to predict patients at high risk of death from fulminant hepatic failure 
      • Overall positive predictive value ranges from 70% to 95%; negative predictive value ranges from 40% to 90% 
    • Indications include any of the following:
      • Arterial pH less than 7.3 or blood lactate level greater than 3 mg/dL (0.33 mmol/L) after adequate volume resuscitation, irrespective of the grade of encephalopathy
      • Blood lactate level exceeding 3.5 mg/dL (0.39 mmol/L) after early volume resuscitation
      • Either of the following:
        • Grade 3 or 4 encephalopathy with prothrombin time greater than 100 seconds
        • INR greater than 6.5 with creatinine level above 3.4 mg/dL

Treatment Goals

  • Decrease further gastrointestinal absorption of acetaminophen (gastric decontamination) 
  • Detoxify and prevent formation of toxic acetaminophen metabolite, N-acetyl-para-benzoquinone imine (NAPQI) 
  • Prevent or treat hepatic failure 
  • Identify patients who may require liver transplant early and expedite transport to tertiary care facility capable of rescue procedure

Admission criteria

Any patient requiring acetylcysteine antidote therapy 

  • Acute overdoses with serum acetaminophen concentration above Rumack-Matthew nomogram treatment line
  • Any patient with signs of hepatic injury or dysfunction (elevation in AST, ALT, INR, or bilirubin level)

Patients with stated or suspected self-harm or malicious ingestions may require psychiatric admission after appropriate treatment of possible toxicity 

  • Routine testing of these patients with a serum acetaminophen concentration is recommended even in the absence of a stated history of ingestion
Criteria for ICU admission
  • Findings consistent with significant toxicity require ICU level of care 
    • Acute hepatic failure (eg, decreased level of consciousness, coagulopathy, acidosis) 
    • Acute renal failure or dialysis requirement 
    • Rising markers of hepatic synthetic dysfunction (eg, INR/prothrombin time, lactate level) 

Consider early referral to a liver transplant center for patients with evidence of functional hepatic impairment including: 

  • Rapidly rising coagulation study results
  • Renal failure
  • Metabolic acidosis refractory to resuscitation
  • Altered mental status (grade 3 or 4 hepatic encephalopathy)

Recommendations for specialist referral

  • Consult a medical toxicologist or poison center in all suspected cases of poisoning for further diagnostic and treatment recommendations 
  • Consult a liver transplant specialist for patients with the following findings for further diagnostic and treatment recommendations: 
    • Rising hepatic transaminase levels
    • Evidence of multiorgan failure (eg, cerebral edema, renal failure, coagulopathy)
    • Worsening prognostic markers (eg, elevations in creatinine, lactate, or phosphate levels; elevated prothrombin time/INR; metabolic acidosis)
  • Consult a psychiatrist in cases of suicidal intent for further diagnostic and treatment recommendations once medically cleared from toxicity

Treatment Options

Early consultation with a medical toxicologist is important to guide individualized therapy informed by patient’s clinical condition 

  • Early consultation with a liver transplant team is important when patients meet or are close to meeting criteria for potential liver transplant (eg, King’s College criteria); early psychiatric consultation can facilitate early transplant eligibility 
  • Historical accounts of precise ingestion time are notoriously unreliable or inaccurate
    • Use earliest possible time of ingestion when reliable history is unavailable 
    • Safest option is to begin empiric treatment with antidote when time of ingestion is in doubt and exclude potential for toxicity before discontinuing treatment 
  • Base antidote treatment decision largely on maximum possible dose ingested, patient risk factors for toxicity, serum acetaminophen concentration, and liver function test results 

Gastrointestinal decontamination 

  • Single-dose activated charcoal
    • Reduces absorbed dose from gastrointestinal tract after acute overdose 
    • Administer to patients presenting within 2 hours of overdose; consider delayed treatment up to 4 hours in cases of coingestants that prolong gastric emptying and extended-release preparations 
    • Do not delay treatment with acetylcysteine beyond 8 hours in cases of acute acetaminophen ingestion so that activated charcoal can be administered 
    • Charcoal may be given simultaneously with acetylcysteine 
      • Charcoal administration does not alter efficacy of acetylcysteine oral dosing; no adjustment of dosing is required with concomitant charcoal and acetylcysteine oral administration 
    • Contraindications include risk for aspiration (eg, significantly altered mental status, intractable vomiting), bowel obstruction (eg, ileus, mechanical obstruction), and coingestion of a corrosive or proconvulsant (eg, bupropion, tricyclic antidepressants)
    • Prioritize administration of acetylcysteine if administration of only 1 agent is feasible based on clinical status of patient 

Antidote

  • Acetylcysteine
    • Highly effective in preventing hepatotoxicity in most patients after acute overdose if administered within 8 to 10 hours 
      • Efficacy decreases if administered after 8 hours 
    • Aids in recovery and improves prognosis in patients with established hepatotoxicity 
    • Route of therapy
      • Optimum route of therapy is controversial 
      • Oral and IV administration have similar efficacy 
      • Decision between routes is individualized; base decision on availability, presence of vomiting, and ability to tolerate oral acetylcysteine 
      • IV dosing is preferred for patients with acute liver failure and patients with contraindications to oral regimen (eg, coma, refractory vomiting, pancreatitis, bowel ileus or obstruction) 
      • Longer duration of oral dosing (72 hours) may be more effective than shorter IV duration (20 hours) at reversing hepatotoxicity when treatment is delayed beyond 10 hours of ingestion 
    • Mechanisms of action 
      • Directly reduces NAPQI to acetaminophen
      • Repletes glutathione stores
      • Enhances sulfation pathway of metabolism 
      • Increases nonspecific antioxidant activity
    • Acute overdose indications
      • Known time of ingestion
        • Less than 8 hours 
          • Consider starting treatment if serum acetaminophen concentration is above the treatment line (possible toxicity, 150 line) on the Rumack-Matthew nomogram 
          • Begin therapy if serum acetaminophen concentration is above the probable toxicity line (200 line) on the Rumack-Matthew nomogram 
          • Efficacy decreases when therapy is started 8 hours or more after an acute overdose 
          • Start immediate treatment and discontinue if acetaminophen concentration will not be available before 8 hours 
        • More than 8 hours 
          • Immediately begin empiric therapy pending a full laboratory evaluation for hepatic injury and possible toxic acetaminophen concentrations
      • Unknown time of ingestion
        • No universally accepted approach exists; options include:
          • Consult medical toxicologist for treatment recommendations
          • Initiate therapy if there is a detectable serum acetaminophen concentration or if there are abnormalities in other ancillary laboratory markers (eg, elevations in AST and/or ALT [greater than laboratory reference range], prothrombin time/INR, and bilirubin levels) 
          • Initiate empiric acetylcysteine immediately; discontinue if acetaminophen concentration is undetectable and liver function test results are within reference range 
    • Chronic toxicity indications 
      • Treatment is indicated for:
        • Asymptomatic patients with supratherapeutic acetaminophen concentration greater than 20 mcg/mL without risk factors for increased potential for toxicity 
        • Asymptomatic patients with acetaminophen concentration greater than 10 mcg/mL in those with significant risk factors, especially chronic alcohol use disorder 
        • Elevated AST or ALT level with a history of ingesting more than 4 g acetaminophen per day 
        • Abnormality in other laboratory markers (eg, prothrombin time/INR, bilirubin level) in the context of repeated supratherapeutic doses with no other explained cause for abnormality 
        • Patients with hepatic failure thought to be as a result of acetaminophen toxicity 
      • Acetylcysteine administration is associated with an increased rate of transplant-free survival compared with placebo; however, acetylcysteine may be less effective in chronic toxicity compared with acute toxicity 
    • Duration of antidote therapy
      • Optimum duration of therapy is controversial 
      • Protocols are in place for administration of IV and oral dosing routes; however, acetylcysteine should not be discontinued at the end of dosing protocol in certain situations, especially with findings associated with worsening liver injury 
        • Treatment beyond typical protocol duration is indicated when patients have any of the following: 
          • Evidence of hepatotoxicity (ie, elevated hepatic transaminase levels)
          • Positive predictors of poor prognosis (eg, decreased pH; increased phosphate, lactate, or creatinine levels; increased prothrombin time/INR)
          • Persistent acetaminophen concentration detected by laboratory testing
        • When treatment is indicated beyond typical protocol, reevaluate monitoring parameters (minimally, acetaminophen concentration and liver function tests) every 12 hours to determine whether further continuation of therapy is required 
      • Discontinue treatment when all of the following parameters are met: 
        • Undetectable serum acetaminophen concentration
        • Improving hepatic transaminase levels (according to most experts, decrease of more than 50% from peak measurement or 3 consecutive decreasing values, all below 1000 units/L)
        • Improving prognostic markers (eg, creatinine, lactate, pH, prothrombin time/INR, phosphate)
    • Monitor for adverse effects of acetylcysteine treatment
      • Rate-dependent anaphylactoid reactions can occur with IV administration 
      • Vomiting is common with oral administration, but can also occur with IV route

Treatment of established significant hepatotoxicity and acute liver failure

  • Immediately begin IV acetylcysteine regimen
  • Arrange for possible transportation to a liver transplant facility if patient presents with signs of acute liver failure or meets King’s College criteria for transplant
  • Supportive management is similar to cases not caused by acetaminophen, with the following caveat: 
    • Administration of fresh frozen plasma is only recommended for specific indications (eg, evidence of bleeding, risk of bleeding from concomitant trauma, prior invasive procedures) rather than abnormal INR value alone 

Intermittent hemodialysis is recommended only for severe toxicity and for patients who develop acute renal failure

  • Includes patients with massive overdose presenting with altered mental status, metabolic acidosis, or acetaminophen concentrations approaching 1000 mcg/mL 

Psychiatric evaluation is necessary for all patients with suspected intentional ingestions

Drug therapy

  • Activated charcoal
    • Activated Charcoal Oral suspension; Infants: 1 g/kg/dose PO. Dosages can be repeated PRN, q4h to q6h.
    • Activated Charcoal Oral suspension; Children: 1 to 2 g/kg/dose or 25 to 50 g/dose PO. Dosages can be repeated PRN, q4h to q6h.
    • Activated Charcoal Oral suspension; Adults and Adolescents: 5 to 10 times the estimated weight of the drug or chemical ingested or 50 to 100 g/dose. Dosages can be repeated PRN, q4h to q6h.
  • Acetylcysteine
    • Standard dosing
      • Oral therapy: inhalation solution (given PO) or effervescent tablets 
        • Consider pretreatment with antiemetic 
        • Acetylcysteine Nebulizer solution; Adults, Adolescents, and Children: 140 mg/kg PO, followed by 70 mg/kg/dose PO every 4 hours for 17 doses starting 4 hours after loading dose. Repeat any dose vomited within 1 hour of administration.
        • Maximum weight used for oral dosing is 110 kg 
        • Repeat any dose vomited within 1 hour of administration 
      • IV therapy
        • The only FDA-approved IV formulation is Acetadote 
          • Acetylcysteine Solution for injection; Infants and Children weighing 5 to 20 kg: 300 mg/kg total dose divided into 3 portions and given sequentially as a continuous infusion with no significant time between portions.Divide dose as follows: Loading Dose: 150 mg/kg in 3 mL/kg diluent IV over 1 hour; Second Dose: 50 mg/kg in 7 mL/kg diluent IV over 4 hours; Third Dose: 100 mg/kg in 14 mL/kg diluent IV over 16 hours. Ideally, initiate within 8 hours of APAP ingestion; infusions may be extended beyond 21 hours when the absorption and/or half-life of APAP is expected to be prolonged.
          • Acetylcysteine Solution for injection; Children and Adolescents weighing 21 to 40 kg: 300 mg/kg total dose divided into 3 portions and given sequentially as a continuous infusion with no significant time between portions. Ideally, initiate within 8 hours of APAP ingestion; infusions may be extended beyond 21 hours when the absorption and/or half-life of APAP is expected to be prolonged. Divide dose as follows: Loading Dose: 150 mg/kg in 100 mL diluent IV over 1 hour; Second Dose: 50 mg/kg in 250 mL diluent IV over 4 hours; Third Dose: 100 mg/kg in 500 mL diluent IV over 16 hours.
          • Acetylcysteine Solution for injection; Adults, Adolescents, and Children weighing more than 40 kg: 300 mg/kg total dose divided into 3 portions and given sequentially as a continuous infusion with no significant time between portions. Ideally, initiate within 8 hours of APAP ingestion; infusions may be extended beyond 21 hours when the absorption and/or half-life of APAP is expected to be prolonged. Divide dose as follows: Loading Dose: 150 mg/kg (Max: 15,000 mg) in 200 mL diluent IV over 1 hour; Second Dose: 50 mg/kg (Max: 5,000 mg) in 500 mL diluent IV over 4 hours; Third Dose: 100 mg/kg (Max: 10,000 mg) in 1000 mL diluent IV over 16 hours.
          • Maximum weight for IV dosing is 100 kg 

Body weightBag 1 (loading dose) 150 mg/kg in 3 mL/kg of diluent* infused over 1 hourBag 2 (second dose) 50 mg/kg in 7 mL/kg of diluent* infused over 4 hoursBag 3 (third dose) 100 mg/kg diluted in 14 mL/kg of diluent* infused over 16 hours
Loading doseDiluent volumeSecond doseDiluent volumeThird doseDiluent volume
5 kg**750 mg15 mL250 mg35 mL500 mg70 mL
10 kg1500 mg30 mL500 mg70 mL1000 mg140 mL
15 kg2250 mg45 mL750 mg105 mL1500 mg210 mL
20 kg3000 mg60 mL1000 mg140 mL2000 mg280 mL

Caption: *Dilute acetylcysteine in 1 of the following 3 solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water. **Recommended dosing for those less than 5 kg has not been studied.

Citation: Data from Cumberland Pharmaceuticals: Acetadote (acetylcysteine) injection [package insert]. Updated January 23, 2020. Accessed April 11, 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=472f158a-5ab9-4308-8e49-1116e6ea3d39

Body weightBag 1 (loading dose) 150 mg/kg in 100 mL of diluent* infused over 1 hourBag 2 (second dose) 50 mg/kg in 250 mL of diluent* infused over 4 hoursBag 3 (third dose) 100 mg/kg in 500 mL of diluent* infused over 16 hours
21 kg3150 mg1050 mg2100 mg
30 kg4500 mg1500 mg3000 mg
40 kg6000 mg2000 mg4000 mg

Caption: *Dilute acetylcysteine in 1 of the following 3 solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water.

Citation: Data from Cumberland Pharmaceuticals: Acetadote (acetylcysteine) injection [package insert]. Updated January 23, 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=472f158a-5ab9-4308-8e49-1116e6ea3d39

Body weightBag 1 (loading dose) 150 mg/kg in 200 mL of diluent* infused over 1 hourBag 2 (second dose) 50 mg/kg in 500 mL of diluent* infused over 4 hoursBag 3 (third dose) 100 mg/kg in 1000 mL of diluent* infused over 16 hours
41 kg6150 mg2050 mg4100 mg
50 kg7500 mg2500 mg5000 mg
60 kg9000 mg3000 mg6000 mg
70 kg10,500 mg3500 mg7000 mg
80 kg12,000 mg4000 mg8000 mg
90 kg13,500 mg4500 mg9000 mg
≥ 100 kg**15,000 mg5000 mg10,000 mg

Caption: *Dilute acetylcysteine in 1 of the following 3 solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water. **No specific studies have been conducted to evaluate the necessity of dose adjustments in patients weighing over 100 kg. Limited information is available regarding the dosing requirements of patients that weight more than 100 kg.

Citation: Data from Cumberland Pharmaceuticals: Acetadote (acetylcysteine) injection [package insert]. Updated January 23, 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=472f158a-5ab9-4308-8e49-1116e6ea3d39

    • Nebulizer solution given as IV (not FDA-approved) 
      • Acetylcysteine inhalation solution has been previously given intravenously when the commercial product was not available 
  • Modified protocols 
    • Various institution- and hospital-driven policies are in place for acute and chronic/subacute ingestion 
    • Depending on the individualized clinical scenario, development of hepatotoxicity, and detectable acetaminophen concentration, the length of therapy may be shortened 
    • Other treatment protocols and lengths of therapy can be used in consultation with medical toxicologist 
      • Shorter course (20-48 hours) of oral dosing may be used when serial acetaminophen concentration is less than 10 mcg/mL with no elevation in ALT level or INR after a minimum of 20 hours of treatment 
      • Shorter courses of IV dosing may be recommended when 16-hour ALT levels are within reference range and acetaminophen concentration is undetectable

Nondrug and supportive care

Volume resuscitation

  • Administer IV fluids for dehydration, metabolic acidosis, or persistent gastrointestinal fluid losses 

Liver dialysis has been described with success in individual cases but is not routinely deployed 

  • Can be considered in cases where there are contraindications to orthotopic liver transplant (eg, psychosocial comorbidities, unavailable donor liver)
Procedures
Intermittent hemodialysis

General explanation

  • Removal of non–protein-bound acetaminophen from the serum and correction of acid-base abnormalities
  • Acetaminophen can be removed owing to its low volume of distribution and minimal protein binding 
  • Preferred to intermittent hemoperfusion, continuous renal replacement therapy, and exchange transfusion techniques
  • Requires concurrent anticoagulation
  • Vascular access is obtained through a surgically created arteriovenous fistula (eg, radiocephalic, brachiocephalic), through an arteriovenous graft, or by using a central venous catheter
  • Continue administration of acetylcysteine at an increased rate during hemodialysis 

Indication

  • Severe acetaminophen poisoning
    • When acetylcysteine is being administered
      • Signs of mitochondrial dysfunction (eg, altered mental status, metabolic acidosis, elevated lactate level) and acetaminophen concentration greater than 900 mcg/mL
    • When acetylcysteine is not being administered
      • Acetaminophen concentration greater than 1000 mcg/mL
      • Signs of mitochondrial dysfunction (eg, altered mental status, metabolic acidosis, elevated lactate level) and acetaminophen concentration greater than 700 mcg/mL
  • Severe persistent electrolyte or acid-base abnormalities
  • Acute or chronic renal failure
  • Fluid overload greater than 10% normal body volume 

Contraindications

  • Severe hypotension
    • May preclude adequate removal of acetaminophen and correction of the acid-base status

Complications

  • Interference with acetylcysteine therapy
    • Up to 50% of acetylcysteine is removed by intermittent hemodialysis 
    • Double rate of acetylcysteine therapy during intermittent hemodialysis 
  • Vascular access complications (eg, infection, thrombosis, obstruction of the atrioventricular fistula, venous hypertension)
  • Infectious complications (eg, bacteremia, endocarditis, osteomyelitis)
  • Metabolic complications (eg, electrolyte abnormalities, hypoglycemia)

Interpretation of results

  • Sustained clinical and laboratory improvement indicates effective intermittent hemodialysis
Orthotopic liver transplant

General explanation

  • Surgical replacement of diseased liver with healthy donor liver
  • Performed at tertiary healthcare center with designated hemodialysis services

Indication

  • Numerous predictive scoring criteria have been developed to assess the need for liver transplant, including the King’s College criteria, APACHE II score, MELD score, and SOFA score 
  • King’s College criteria is most used
    • Any of the following findings constitute a positive criterion and impart less than 10% to 20% survival without transplant:
      • Arterial pH less than 7.3 or blood lactate level greater than 3 mg/dL after adequate volume resuscitation 
      • Lactate level greater than 3.5 mg/dL after early volume resuscitation 
      • Either of the following:
        • Grade 3 or 4 hepatic encephalopathy with prothrombin time greater than 100 seconds 
        • INR greater than 6.5 with creatinine level greater than 3.4 mg/dL 
  • Hyperphosphatemia is an additional strong predictor of mortality without transplant
    • Serum phosphate level greater than 1.2 mmol/L at 48 to 96 hours is predictive of death 

Contraindications

  • Severe recalcitrant hemodynamic instability at time of transplant
  • Unavailability of donor liver at time of transplant
  • Psychiatric contraindications
    • Likelihood of another suicide attempt is evaluated before transplant in cases of attempted suicide 

Complications

  • General surgical complications
  • Liver transplant rejection
  • Long-term complications from required posttransplant immunosuppressive therapy

Interpretation of results

  • Overall lower posttransplant survival rate may exist for patients requiring liver transplant compared with those who do not have acetaminophen-associated causes for liver transplant

Special populations

  • Pregnant women
    • Acetaminophen is the most commonly overdosed medication in pregnant patients 
    • Acetaminophen crosses the placenta and can be metabolized beginning at 18 weeks’ gestation 
    • Acetylcysteine crosses the placenta and is effective for treatment of acetaminophen toxicity during pregnancy 
    • Treatment is similar as for other populations with acetaminophen toxicity, except that decision strategy for acetylcysteine intervention may be more aggressive and IV form may be preferred (controversial) 
      • Some experts advocate beginning treatment immediately, before confirmed toxicity by laboratory values 
      • Some experts recommend IV acetylcysteine, especially in later stages of pregnancy 
    • Calculate acetylcysteine dose based on patient’s actual pregnant weight, up to a maximum of 110 kg 

Monitoring

  • Monitoring for patients requiring acetylcysteine treatment
    • Monitor serial acetaminophen serum concentrations
      • Half-life is typically 2 to 3 hours in overdose but may be prolonged to 4 hours with hepatic injury 
        • Longer apparent half-life may indicate ongoing absorption, decreased elimination and metabolism, or ongoing consumption
      • Check serial concentrations before discontinuing acetylcysteine 
        • Establish a clear downward trend of concentration before discontinuing acetylcysteine in patients who are not in high-risk group
        • Establish a concentration of less than 10 mcg/mL before discontinuing therapy in high-risk patients 
        • Establish an undetectable concentration in patients with significant hepatotoxicity or resolving acute liver failure before discontinuing therapy 
      • Note: hyperbilirubinemia (greater than 8 mg/dL) may result in false-positive acetaminophen concentration 
    • Monitor AST and ALT levels
      • Evaluate liver function test results daily if there is no evidence of hepatic injury
        • Establish presence of reference range ALT level in patients at high risk for hepatotoxicity before discontinuing acetylcysteine 
        • More frequent monitoring is required in patients with elevated liver function test results or signs of hepatic failure
          • Establish clear downward trend of ALT level in patients with significant hepatotoxicity or resolving acute liver failure before discontinuing acetylcysteine 
      • Obtain and monitor prothrombin time/INR at least daily in patients with elevated liver function test results 
    • Monitor for adverse effects of antidote administration
      • Oral acetylcysteine
        • Vomiting is common
          • Vomiting can be diminished by diluting antidote with soda or juice, administering in a covered container to avoid pungent odor, holding breath while drinking antidote, or via nasogastric administration 
          • About 5% of patients do not tolerate oral dosing and require IV administration 
      • IV acetylcysteine
        • Induces histamine release from mast cells and basophils 
        • Anaphylactoid reactions (eg, rash, itching, angioedema, bronchospasm, tachycardia, hypotension) develop in up to 20% of patients and are most common with loading dose 
          • Flushing alone or mild symptoms do not require specific intervention other than close clinical observation for worsening manifestations
          • Moderate to severe reactions (eg, urticaria, angioedema, hypotension, bronchospasm) require temporary halting of infusion and specific treatment aimed at particular manifestation before resuming infusion
            • Often a combination of diphenhydramine, corticosteroids, bronchodilators, and/or IV fluids is required
            • Restart infusion after specific treatment at a slower rate with continued close clinical monitoring
            • Consider switch to oral route of administration 
            • Severe reactions with bronchospasm and/or hypotension are rare 
        • Reactions are rate-dependent; diminishing initial infusion time from 15 minutes to 60 minutes does not compromise efficacy 
        • Life-threatening reactions may be more common in patients with severe atopy or asthma 
    • Observe clinically and with laboratory assessments for evidence of worsening toxicity and acute hepatic failure 
      • Monitor clinically for changes in mental status and urine output to assess for renal failure
      • Obtain serial measurements of ancillary laboratory values (eg, prothrombin time/INR, acid-base status, renal function, bilirubin) in patients with evidence of severe hepatotoxicity or patients at high risk for severe hepatotoxicity
      • Progression of hepatotoxicity or acute liver failure despite appropriate acetylcysteine treatment requires increased monitoring frequency of ancillary laboratory values
      • Note: acetylcysteine may cause a slight elevation in prothrombin time and INR 
  • Monitoring for patients with established hepatotoxicity (AST level greater than 1000 units/L) or elevated INR at presentation
    • Frequent and cautious clinical and laboratory monitoring is vital
    • Monitor liver synthetic function (prothrombin time/INR) and renal function (BUN/creatinine) every 6 to 12 hours 
    • Patients who develop signs of acute liver failure (eg, encephalopathy, coagulopathy, persistent acidosis) or meet King’s College criteria require expedient transfer to facility capable of liver transplant
  • Monitoring for patients with severe hepatotoxicity or acute liver failure
    • Close clinical and laboratory monitoring in an ICU setting is indicated; frequent monitoring for the following is crucial:
      • Hypoglycemia, acidosis, synthetic liver function, and renal failure 
      • Vital signs, neurologic status, and evidence of bleeding 
    • Arrange for expedient transportation to liver transplant facility
    • Continue acetylcysteine infusion until patient receives liver transplant or until liver dysfunction reverses (ie, ALT or AST levels have peaked and are improving, encephalopathy resolves, and INR is less than 1.5) with undetectable acetaminophen level 

Complications

  • Acute fulminant liver failure and death
    • Can result from severe acetaminophen hepatotoxicity
    • Acetaminophen toxicity is the most frequent cause of acute liver failure and liver transplant in the United States 
    • Most common direct cause of death is cerebral edema
      • Death from multisystem organ failure, hemorrhage, adult respiratory distress syndrome, and sepsis can occur
  • Renal insufficiency and failure
    • Often manifests as acute tubular necrosis (eg, elevations in BUN/creatinine levels, proteinuria, hematuria, granular casts in urine)
    • Up to 25% of patients with significant hepatotoxicity develop acute renal failure 
    • Up to 50% of patients who develop acute liver failure experience acute renal failure 
    • Onset is usually after hepatic injury is already apparent; maximal renal injury lags beyond peak in liver injury 
      • Most commonly develops 1 to 3 days after ingestion; worsens over 7 to 10 days, occasionally requiring renal replacement therapy 
      • Caused by local renal formation of toxic metabolite NAPQI 
    • Isolated renal toxicity without hepatic toxicity is rare 
    • May be more common with repeated excessive sustained-release preparations 
  • Central nervous system complications
    • Diffuse cerebral edema with brainstem herniation and encephalopathy can result from massive overdose 
    • Often secondary to severe increased anion gap acidosis produced by metabolites in massive overdose 
  • Pancreatitis
    • Elevated serum amylase level is common, especially in patients who develop acute liver failure
    • Clinical pancreatitis is rare (0.3%-5%) in patients with severe toxicity 
  • Myocardial damage
    • Can occur with massive overdose as part of multisystem organ failure secondary to fulminant hepatic failure 
  • Infectious complications
    • May develop as a result of liver failure
  • Fetal demise
    • Can occur without appropriate treatment of mother or in massive overdose

Prognosis

  • Acute overdose with appropriate treatment
    • Most patients with an acute overdose can be safely and effectively managed with acetylcysteine to prevent hepatotoxicity 
    • Prognosis is generally favorable in acute ingestions treated within 8 hours with acetylcysteine, as dictated by the Rumack-Matthew nomogram 
      • Hepatotoxicity occurs in less than 3% to 10% of patients after acute overdose when acetylcysteine is administered within 8 to 10 hours of ingestion 
      • Delay of acetylcysteine administration beyond 10 hours is associated with increased risk of hepatotoxicity 
    • Overall mortality is low
    • In rare cases, patients who progress to hepatic failure despite appropriate treatment are at increased risk of death without liver transplant
  • Chronic toxicity with repeated supratherapeutic ingestions or acute overdose with delayed presentation
    • Patients experience higher mortality rates compared with acute ingestion, likely related to presenting later in the course of illness 
      • Hepatotoxicity occurs with increased frequency (20%-30%) when administration of acetylcysteine is delayed more than 10 hours from ingestion 
    • Patients who present with or progress to severe hepatic dysfunction are at increased risk of death without liver transplant
  • Patients who develop hepatotoxicity (defined as AST level greater than 1000 units/L) 
    • Hepatotoxicity resolves spontaneously in over 90% of patients 
  • Patients who develop acute liver failure (ie, hepatotoxicity accompanied by encephalopathy, progressive coagulopathy, or persistent acidosis) 
    • Prognosis is generally better than other causes of acute liver failure not associated with acetaminophen 
    • Those who survive after hepatic injury or dysfunction suffer no long-term hepatic sequelae if liver transplant is avoided 
    • Up to 30% overall mortality is expected without liver transplant 
    • Death most commonly occurs during phase III (maximal liver injury phase)
    • Those with rapidly rising AST and/or ALT levels (doubling within 8 hours) or developing AST and/or ALT levels greater than 1000 units/L within 20 hours of acetylcysteine treatment are at increased risk of mortality 
    • Markedly elevated INR that continues to rise on day 4 after overdose marks a very poor prognosis 
    • Mortality rate up to 80% to 90% exists for patients with acute liver failure who meet King’s College criteria for transplant 
    • Overall lower posttransplant survival rate may exist for patients requiring liver transplant compared with those requiring transplant for other causes not attributed to acetaminophen 
      • Adherence to follow-up appointments and compliance with immunosuppressive regimens are lower in posttransplant acetaminophen overdose patients, irrespective of pretransplant psychiatric comorbidity
  • Patients who develop renal failure
    • Typically reversible and resolves completely if patient survives course of toxicity 
    • Recovery is often more protracted than recovery from hepatic toxicity 
    • Up to 50% mortality rate is associated with renal failure apparent at first presentation 
  • Children have a lower incidence of hepatotoxicity from acetaminophen exposures owing to multiple factors: 
    • Doses less than 200 mg/kg in children younger than 6 years are unlikely to result in toxicity 
    • Children have increased rates of glutathione production and repletion
    • Children have increased rates of sulfation as compared with adults
    • Exposures are usually acute and unintentional in nature with lower cumulative dose
    • Liquid acetaminophen formulations contain propylene glycol, which is a known CYP2E1 inhibitor 
  • Toxicity during pregnancy
    • Fetal outcome is generally favorable with successful treatment of pregnant mother 

Prevention

  • Prevent unintentional ingestion in children 
    • Keep medications safely stored in child-resistant packaging and out of reach of children
  • Educate patients regarding potential for unintentional overdose 
    • Review correct dosing of acetaminophen, especially in pediatric patients
    • Review the large list of OTC and prescription medications that contain acetaminophen with patients, particularly elderly patients and those with chronic pain
  • Consider recommending lower therapeutic dosing in patients at increased risk for toxicity (eg, patients who actively misuse alcohol) 

Sources

  • Alhelail MA et al: Clinical course of repeated supratherapeutic ingestion of acetaminophen. Clin Toxicol (Phila). 49(2):108-12, 2011 Reference
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