Acetaminophen overdose

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Patients often present with a history of self-harm by ingestion. Most patients will state in the history that they have ingested acetaminophen or an acetaminophen-containing combination product. Some patients will not be certain which tablets or pills they have taken, and witness corroboration may be important. Others may be unaware that the preparations ingested in overdose contained acetaminophen. Brand name products are periodically reformulated; for example, some manufacturers that have traditionally made nonsteroidal anti-inflammatory (NSAID)-containing products have begun to manufacture products that contain acetaminophen. When possible, clinicians should make every attempt to verify the exact ingredients in the products the patient is taking. Patients with painful conditions may have taken repeated over-the-counter analgesics for pain relief, resulting in supratherapeutic ingestion of acetaminophen.[15][16][18][36] It is essential to attempt to establish the timing of the overdose as this will affect subsequent patient management.

Acetaminophen overdose should be suspected in anyone who has taken an overdose of any substances or who has self-harmed in any way. It is equally important to seek evidence of other substance ingestion in patients who have presented with acetaminophen overdose. All patients suspected of having an overdose should have a serum level of acetaminophen checked.

Overall clinical picture

Patients who present within the first 24 hours after ingestion of a potentially toxic dose of acetaminophen may be asymptomatic. Early nonspecific signs that may be present in the first 24 hours include anorexia, malaise, nausea, vomiting, or vague abdominal pain.[5] Patients may present with reduced consciousness level or coma if they have ingested a combined preparation of acetaminophen and an opioid, have co-ingested alcohol or other drugs that cause depressed mental status, or who present after a high-risk ingestion (>30 g or an acetaminophen concentration above the high-risk line on the nomogram).[1]

In a small percentage of patients, toxicity progresses and clinical signs of hepatic injury become apparent. Patients may manifest right upper quadrant pain and tenderness, hepatomegaly, nausea, vomiting, and jaundice. Serum aspartate aminotransferase (AST) elevation usually begins around 24 hours to 36 hours post ingestion.[51][52]

Liver injury usually becomes maximal at 72-96 hours and, dependent on the severity of the ingestion, may be characterized by massive elevation of serum AST and alanine aminotransferase (ALT) activity, hyperbilirubinemia, and prolongation of the prothrombin time. Nephrotoxicity occasionally occurs during this timeframe. Although most patients will recover, some may progress to have fulminant hepatic failure with encephalopathy, coma, renal failure (hepatorenal syndrome), and rarely, hemorrhage.[53][54][55][56][57] Abnormalities of prothrombin time, glucose, lactate, creatinine, pH, and phosphate, are more important markers of prognosis than the degree aminotransferase elevation.[58][59] Liver biopsies and post-mortem studies reveal extensive centrilobular hepatic necrosis without inflammatory changes.[60][61][62][63]

Renal injury is rare, and when it occurs, serum creatinine typically begins to rise soon after serum aminotransferase activity has peaked. It is rare for patients to present with isolated renal injury (<1% of cases); however, renal injury is common in patients with significant hepatotoxicity and hepatic failure, occurring in 25% and 53% of cases, respectively.[6][7][8]

Early presentation with coma and severe metabolic acidosis without hepatotoxicity is also rare and is associated with massive overdose (serum acetaminophen level >800 micrograms/mL).[54][55]

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 medications that induce CYP2E1, and people dependent on alcohol. However, clear evidence supporting increased risk is lacking.

Laboratory tests

Depending on the time of presentation relative to the time of acetaminophen overdose, laboratory investigation may show a measurable serum acetaminophen concentration, abnormal serum AST or ALT, abnormal prothrombin time or international normalized ratio (INR), renal dysfunction, or metabolic acidosis. Initial laboratory investigations should include:[53][54][55][56][57]

Serum acetaminophen levels

For acute acetaminophen overdose, specific management is dependent on the serum acetaminophen level relative to the time of ingestion.
A timed serum acetaminophen level is drawn at least 4 hours after ingestion to risk-stratify likelihood of liver injury and the need for acetylcysteine treatment.[2]
The serum level is plotted on the Rumack-Matthew nomogram to determine whether treatment with acetylcysteine is required.
This nomogram was developed by plotting timed acetaminophen concentrations from acetaminophen overdose patients on a graph, and drawing a line to discriminate those who did and those who did not develop hepatotoxicity (defined as aminotransferase levels >1000 IU/L).[2] The nomogram was later updated to contain a line that connects a point at 150 micrograms/mL at 4 hours after ingestion and 4.7 micrograms/mL at 24 hours after ingestion, termed the "treatment line.” This line is 25% lower than the original nomogram line and was added at the Food and Drug Administration’s request for additional safety during the first US open-label study.[1][3][64][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].
In 2023, the revised Rumack-Matthew nomogram was developed, containing only lines that guide clinical action.[1] As well as the “treatment line,” the revised Rumack-Matthew nomogram also contains a “high risk” line that connects a point at 300 micrograms/mL at 4 hours and 9.4 micrograms/mL at 24 hours after ingestion.[1][4][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].
Acetylcysteine treatment is started if the acetaminophen level falls on or above the treatment line.
The nomogram is not applicable in the following circumstances: unknown time of ingestion, repeated supratherapeutic ingestions, late presenting patients (patients presenting greater than 24 hours after ingestion), and those with evidence of hepatotoxicity despite undetectable or therapeutic acetaminophen level. Some have suggested that co-ingestants that may delay gastrointestinal absorption (e.g., anticholinergic drugs) may also limit the nomogram, but there are no systematic studies to support this. Some experts recommend obtaining a second acetaminophen concentration 4-6 hours after the first, if the first measurement is greater than 10 micrograms/mL.[1]

AST and ALT levels

Levels are done initially and repeated in the course of patient management (usually every 12-24 hours). The degree of derangement in laboratory results depends on the time of presentation relative to the time of acetaminophen overdose.
The acetaminophen-aminotransferase multiplication product, calculated by multiplying the serum acetaminophen concentration by the aminotransferase activity (AST or ALT, whichever is higher), can potentially complement early assessment of patients who are at low risk of hepatotoxicity.[65] Patients with a multiplication product greater than 10,000 mg/L × IU/L have a high likelihood of developing hepatotoxicity, especially if it is more than 8 hours post ingestion; patients with a multiplication product lower than 1500 mg/L × IU/L have a low likelihood of developing hepatotoxicity.[66][67][68]

Prothrombin time/INR, arterial pH, arterial lactate level, and metabolic panel with serum creatinine

These are used to monitor severity of hepatic failure and assist in patient stratification for optimal benefit in orthotopic liver transplantation (e.g., using the King’s College Criteria).[58][69] May not be indicated in early presenting, low-risk patients; AST abnormalities always precede evidence of hepatic synthetic dysfunction.
A prolonged INR is a poor prognostic sign.[5]
Renal injury may rarely occur in the absence of significant hepatotoxicity, and is relatively common with significant hepatotoxicity.

Other tests to consider

Serum salicylate level should be considered in patients who have ingested substances in an attempt at self-harm.
Ethanol level and blood glucose level should be obtained in any patient with altered mental status.
Elevated lipase consistent with pancreatitis may occur, especially in patients with alcohol-use disorder.
Phosphate may be helpful for prognostication for patients with acute liver failure as a supplement to the King's College Criteria. Elevated phosphate is associated with worse outcomes.[70]

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How to take a venous blood sample from the antecubital fossa using a vacuum needle.

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How to obtain an arterial blood sample from the radial artery.

Femoral artery puncture animated demonstration

How to perform a femoral artery puncture to collect a sample of arterial blood.

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Acetaminophen overdose

Approach

Overall clinical picture

Special clinical considerations

Laboratory tests