Recommendations
Key Recommendations
The main goal of treatment is to prevent or minimize liver injury following acetaminophen overdose. The decision to start treatment with acetylcysteine will depend on the clinical scenario (e.g., time of presentation after the overdose) and, in many cases, the serum levels of acetaminophen and/or liver enzymes. These serum levels can also be used to determine the duration of treatment.[75] If required, the treatment of choice is acetylcysteine.[76] If started within 8 hours of an acute ingestion, hepatotoxicity is extremely unlikely.
Initial management
All patients should receive general supportive care. This may include symptomatic treatment such as antiemetics for nausea; appropriate physiologic support such as intubation and ventilation or vasoactive infusions for blood pressure support, management of coagulopathy, or renal support for hepatorenal syndrome if present; 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.
Empiric acetylcysteine may need to be initiated in certain circumstances (see Acute single overdose for details).
In patients with an unknown time of ingestion, who present very late (>24 hours after overdose), who require treatment with acetylcysteine, or who appear sick, 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). In well-appearing patients who present earlier after overdose, these blood tests may not be necessary and generally do not help determine whether the patient needs treatment with acetylcysteine.
Activated charcoal can be considered if the patient presents within 4 hours of acute single acetaminophen ingestion, and if they are alert and willing to drink the solution.[1][77] Evidence (very low quality) suggests that activated charcoal is the best choice to reduce absorption of acetaminophen.[76] 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.[78] 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
An acute acetaminophen overdose in adults, in terms of Food and Drug Administration (FDA)-labeled therapeutic dosing, is minimally defined as a cumulative dose of acetaminophen >4 g ingested over 8 hours or less (some authors use a period of 4-24 hours).
For a single acute ingestion of acetaminophen, patients (all ages) should be transferred to the emergency department for evaluation and consideration of acetylcysteine. If the estimated ingestion is unknown, >10 g, or ≥200 mg/kg acetaminophen (whichever is less), 2023 US and Canadian consensus guidelines recommend acetylcysteine should be started immediately, if waiting for testing will result in treatment starting more than 8 hours after ingestion.[1]
Acetylcysteine should also be started immediately or empirically if:
The patient is unconscious (and there is reasonable suspicion of acetaminophen toxicity)
Estimated ingestion is ≥30 g (high-risk ingestion)
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
The patient presents with hepatotoxicity, possibly from acetaminophen, even with undetectable acetaminophen concentration
In practice, the initial dose is typically administered as soon as the need for treatment becomes evident.[1]
Serum acetaminophen level should be checked 4 hours after ingestion, or as soon as possible in patients presenting more than 4 hours after ingestion.[1] If a patient presents within 4 hours of ingestion, the level is drawn when 4 hours have elapsed since the possible overdose. Levels drawn before 4 hours may be helpful in that a trend can be observed between the initial and 4-hour level. Further, an undetectable level between 1 and 4 hours post ingestion excludes a significant acetaminophen ingestion. Any detectable acetaminophen level drawn before 4 hours requires a follow-up 4-hour level for clinical decision-making. Once the 4-hour acetaminophen level is obtained, it should be plotted against the time since ingestion on the revised Rumack-Matthew nomogram. [Figure caption and citation for the preceding image starts]: Revised Rumack-Matthew nomogram for the acute ingestion of acetaminophenDart RC et al. JAMA Netw Open. 2023;6(8):e2327739; used with permission [Citation ends].
If the plot falls on or above the treatment line, the patient should be treated with acetylcysteine. If the plotted level falls below the treatment line, then toxicity is exceedingly rare, and further evaluation and acetylcysteine is not required. The latter patients require only supportive care.
Patients presenting between 4 and 8 hours after ingestion should have acetaminophen levels measured, and acetylcysteine given if the level is on or above the treatment line on the revised Rumack-Matthew nomogram.
Following administration of immediate or empiric acetylcysteine, 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 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 may be given orally or intravenously.[79][80] The oral route frequently causes nausea and vomiting and, owing to the ease of administration and widespread availability of intravenous acetylcysteine, may no longer be readily available at all centers. Though the approved oral regimen is 72 hours in duration, the course is often shortened by monitoring the serum acetaminophen level and liver enzyme levels.[81][82] The intravenous route is generally well tolerated, although there is a significant incidence of nonallergic anaphylactic reactions (NAARs, formerly referred to as anaphylactoid reactions). Newer acetylcysteine regimens aim to decrease the risk of these NAARs.[83] There is no difference in efficacy between the two routes.[4][84]
There are several different strategies for acetylcysteine administration.[1][85] In the UK, a shortened course of intravenous acetylcysteine, also referred to as the SNAP (Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning) regimen, has been validated as having similar efficacy as standard therapy for preventing liver injury and in the population studied.[86][87][88] If using an alternative regimen, it is recommended to use an approved or published intravenous or oral protocol that delivers a minimum of 300 mg/kg over 20-24 hours.[1] Abbreviated courses of oral acetylcysteine should be used with caution only in early-presenting, well-appearing patients with favorable laboratory studies.
Factors such as alcohol use, liver disease, CYP450 inducers, malnutrition, HIV infection, and cystic fibrosis may be perceived as associated with high risk. It has been suggested these be considered against the Rumack-Matthew nomogram, on the basis that agents that induce CYP2E1 or are known to deplete glutathione may exacerbate acetaminophen toxicity. However, clinical experience indicates that though these patients may be at higher risk from therapeutic excess, the decision to use acetylcysteine following an acute overdose should remain the same.[5][38]
Repeated supratherapeutic ingestion
Repeated supratherapeutic acetaminophen ingestion denotes ingestion of excess acetaminophen with intent to treat pain or fever (i.e., without self-harm intent). It may be accidental or intentional, and occurs in the setting of a reliable and accurate history.
Repeated supratherapeutic ingestion is defined as multiple episodes of acetaminophen ingestion over a period greater than 24 hours that results in any of the following:[1]
Findings consistent with acetaminophen toxicity (repeated vomiting, right upper quadrant abdominal tenderness, or mental status changes)
Ingestion period of 24-48 hours: >6 g/day or >150 mg/kg/day (whichever is less)
Ingestion period of greater than 48 hours: >4 g/day or >100 mg/kg/day (whichever is less)
In patients who report repeated supratherapeutic acetaminophen ingestion, obtain acetaminophen levels, AST, ALT, and creatinine. Management of repeated supratherapeutic acetaminophen ingestion is challenging, and discussion with a medical toxicologist is strongly advised for all patients.
For patients who present with symptoms or signs of hepatotoxicity, consider empiric treatment with acetylcysteine while awaiting laboratory results and any other necessary evaluation to exclude other differential diagnoses.
Acetylcysteine should be started if acetaminophen level is ≥20 micrograms/mL, or AST or ALT level is abnormal (unless abnormal aminotransferase level is baseline for the patient).[1] It can be given either orally or intravenously.[89]
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 should be extended beyond standard duration of therapy in patients with continued evidence of renal injury, liver injury/dysfunction, or other sequelae of acetaminophen toxicity.
Modified-release formulations
In a prospective observational study conducted in Australia, 116 patients (age >14 years) who ingested ≥10 g or 200 mg/kg (whichever is less) of modified-release acetaminophen experienced persistently elevated acetaminophen concentrations.[90] Many patients required prolonged treatment; some developed liver injury despite judicious administration of acetylcysteine.[90] The standard risk assessment and acetylcysteine infusion regimen employed following immediate-release acetaminophen overdose may not be appropriate in cases of modified-release acetaminophen toxicity.[91] Consultation with a medical toxicologist is recommended.[92]
It is important to note that the modified-release acetaminophen product in Australia differs from that available in the US, so these findings may not apply to the US modified-release formulations.
Modified-release acetaminophen formulations have been suspended in Europe because of the difficulty of managing overdose.[93]
Special clinical considerations
Certain subgroups of patients may be at higher risk of acetaminophen-induced hepatotoxicity. These include patients with glutathione deficiency from acute starvation (e.g., during a febrile illness) or chronic starvation (e.g., bulimia or anorexia nervosa), those with chronic debilitating illness, patients taking drugs that induce CYP2E1, and people dependent on alcohol. However, clear evidence supporting increased risk is lacking. Some have recommended lowering the treatment threshold for these patients; however, there is no definitive study to support this recommendation.
Rarely, hemodialysis is recommended in addition to treatment with acetylcysteine for patients with a very large ingestion of acetaminophen (e.g., concentration of 900 micrograms/mL or greater with acidosis or altered consciousness due to acetaminophen toxic effects); consult with a poison center or toxicologist.[1]
Monitoring and end points for acetylcysteine treatment
Intravenous acetylcysteine
Most patients should be treated for a minimum of 20-24 hours.[1] Whenever shorter treatment is considered (e.g., SNAP regimen), the case should be discussed with a medical toxicologist.
Prior to discontinuing acetylcysteine, the patient should be clinically well-appearing, AND have the following laboratory tests repeated: serum acetaminophen (<10 micrograms/mL), serum AST or ALT (normal for the patient or, if elevated, have decreased 25% to 50% from peak), INR (<2.0).[94] Additional laboratory tests may be indicated depending on the clinical scenario. For example, in patients who develop hepatotoxicity or are critically sick, consider obtaining creatinine, lactate, pH, and phosphate to monitor for multisystem organ dysfunction and assess potential need for hepatic transplant.
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.[94]
Monitor acetaminophen concentration, AST, ALT, and INR every 12-24 hours or more frequently if indicated based on the clinical exam.
End points for treatment with acetylcysteine in such cases are the same as for those patients who meet stopping criteria at the 21-hour mark. Rather than peak and decline by 25% to 50%, some centers recommend acetylcysteine is continued until the transaminases are down-trending and under 1000 IU/L.[75] In these cases, consultation with a medical toxicologist is essential, especially prior to discontinuing therapy.
Oral acetylcysteine
The standard duration of therapy for oral acetylcysteine is 72 hours; however, there is evidence to shorten the duration in well-appearing patients with undetectable acetaminophen and favorable transaminases.[82][86][95] Patients who present early after acetaminophen overdose are the commonest subset to receive shortened course of oral acetylcysteine.
Prior to discontinuing acetylcysteine, the patient should be asymptomatic AND have the following laboratory tests repeated: serum acetaminophen (<10 micrograms/mL), serum AST or ALT (normal for the patient or, if elevated, have decreased from peak by 25% to 50%), INR <2.0. 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. End points for treatment with acetylcysteine in such cases are: a clinically well patient, serum acetaminophen (undetectable), serum AST or ALT (normal for the patient or, if elevated, have decreased from peak by 25% to 50%), INR <2.0. Rather than peak and decline by 25% to 50%, some centers recommend acetylcysteine is continued until transaminases are down-trending and under 1000 IU/L.[75] In these cases, consultation with a medical toxicologist is essential, especially prior to discontinuing therapy.
Time-sensitive treatment issues
Hepatic injury can be prevented in nearly all patients treated with acetylcysteine within 8 hours of an acute ingestion, regardless of the magnitude of the acetaminophen overdose.[4][96] Ideally, the need for acetylcysteine treatment should be based on a serum acetaminophen concentration determined within this 8-hour window.
Empiric acetylcysteine therapy should be initiated:
If the estimated ingestion is unknown, >10 g, or ≥200 mg/kg[1]
For patients who present later than 8 hours after ingestion
When serum acetaminophen concentrations cannot be determined within 8 hours[1]
If the exact timing of the ingestion is uncertain
Early treatment is important, as deaths are unlikely in patients treated prior to 16 hours following an acute overdose. Acetylcysteine also has some therapeutic effect for patients who present 10 to 24 hours after ingestion, although its efficacy diminishes as the time to treatment increases.[4] Intravenous acetylcysteine may be of benefit when rendered as late as 36 to 80 hours in patients presenting with fulminant hepatic failure, coagulopathy, and encephalopathy.[97][98]
Fulminant liver failure
Patients presenting with or progressing to fulminant hepatic failure should be treated with continuous intravenous acetylcysteine and receive an early referral to a liver unit and assessment of candidacy for orthotopic liver transplantation. Delayed referral can adversely affect outcome.[58][99]
Referral for liver transplant is indicated if:[58][99]
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
Other predictors of poor prognosis without transplant include:
Arterial lactate concentration >3.5 mmol/L after fluid resuscitation (<4 hours) OR lactate >3 mmol/L after full fluid resuscitation OR
Phosphate >3.75 mg/dL (>1.2 mmol/L) at 48-96 hours
Clinicians should have a low threshold for referral and not necessarily wait for these parameters to be met prior to deciding on referral.
Treatment-related adverse effects
Adverse drug events associated with intravenous acetylcysteine include nonallergic anaphylactic reactions (NAARs, formerly called anaphylactoid reactions). Symptoms seen with NAARs can include nausea, flushing, vomiting, rash, urticaria, pruritus, angioedema, dyspnea, wheezing, bronchospasm, tachycardia, hypotension, anaphylaxis, and death.[100][101][102][103]
Vomiting that occurs during intravenous acetylcysteine administration will not affect the efficacy of treatment, but it can be treated with an antiemetic (e.g., ondansetron). One randomized controlled trial found that while pretreatment with ondansetron was effective at decreasing vomiting, it had no effect on NAARs and was associated with an increase in serum aminotransferase levels.[104]
Adverse drug events associated with oral acetylcysteine include nausea and vomiting.[97] If vomiting occurs within 1 hour of oral acetylcysteine, an antiemetic (e.g., ondansetron) is administered and oral acetylcysteine re-administered.
Usual treatment unavailable
Acetylcysteine should be readily available in developed countries such as the US and the UK. In situations where it is not available, oral methionine may be an alternative option. In the absence of acetylcysteine and methionine, oral-gastric lavage and activated charcoal should be considered.[105] If no other options are available, hemodialysis may be instituted in patients presenting soon after an acute acetaminophen overdose, provided it can be initiated promptly and its benefits outweigh its risks.[106] In these situations, discussion with a medical toxicologist or poison center is recommended.
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