Acetaminophen overdose resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vidit Bhargava, M.B.B.S [2]

Definition

Acetaminophen overdose is the intentional or accidental ingestion of more than 7.5-10 g of acetaminophen in adolescents and adults. Acetaminophen overdose is acute if it occurs in ≤8 hours, while chronic acetaminophen overdose occurs following the repeated supratherapeutic ingestion of acetaminophen more than 8 hours ago.

Acetaminophen is available in the U.S. market under the following brand names:

• Tylenol
• Anacin-3
• Liquiprin
• Percocet
• Tempra
• Cold and flu medicines
• Aceta
• Actimin
• Apacet
• Aspirin Free Anacin
• Atasol
• Banesin
• Dapa
• Datril Extra-Strength
• Feverall
• Fibi
• Genapap
• Genebs
• Panadol

Toxic Dose

The toxic dose of paracetamol is highly variable. In individuals over 6 years of age, single doses above 200 mg/kg consumed over a single 24-hour period have a reasonable likelihood of causing toxicity. If an individual has consumed large quantities of paracetamol over a 48 hour period, a dose of above 6 grams or 150 mg/kg in the subsequent 24 hour period may cause toxicity.

Shown below is a table containing recommended maximum doses of paracetamol.

Patients	Maximum single dose	Minimum dosing intervals (hours)	Maximum dose in 24 hours
Adults	1 g	4	4 g
Children 6-12 years	500 mg	4	2 g
Children 1-5 years	240 mg	4	960 mg
Infants 3-12 months	120 mg	4	480 mg

Rumack Matthew nomogram

It is a graph that plots serum concentration of acetaminophen against time since ingestion. It helps to assess liver toxicity in terms of prognosis as well as guides a physician whether to proceed with N-acetylcysteine treatment or not. The graph starts from 4 hours after ingestion, when the maximal ingested dose is usually absorbed. Generally levels > 140-150 μg/mL at 4 hours after ingestion warrant treatment. It is useful only for making treatment decisions only in acute acetaminophen overdose. Below is an image depicting the 'Rumack Matthew nomogram':

Management

Shown below is an algorithm summarizing the approach to acetaminophen overdose.

Obtain a focused history: ❑ Time since last ingestion ❑ Number of tablets/other dosing form taken ❑ Frequency of dosage

Characterize the symptoms & examine the patient: Stage I: First 24 hours ❑ Asymptomatic ❑ Nausea & vomiting ❑ Diaphoresis ❑ Anion gap metabolic acidosis & coma (with massive doses) Stage II: 24 to 72 hours Clinical & lab features of hepatotoxicity ❑ Right upper quadrant tenderness ❑ Deranged LFT's, PT, Serum bilirubin Clinical & lab features of nephrotoxicity ❑ Oligouria, hematuria ❑ Deranged RFT's, proteinuria, hematuria, casts Stage III: 72 to 96 hours Signs of liver failure ❑ Hepatic tenderness ❑ Jaundice ❑ Impaired consciousness ❑ Asterixis ❑ Foetur hepaticus ❑ Hemorrhage Labs consistent with severe liver failure ❑ AST/ALT levels > 1000 mg/Dl ❑ Prolonged PT/INR ❑ Hypoglycemia ❑ Lactic acidosis ❑ Total bilirubin > 4.0 ❑ Renal failure ❑ Death from multiorgan system failure Stage IV: 4 days to 2 weeks ❑ Recovery

Order labs: ❑ Serum paracetamol concentration ( @4 hours and 16 hours) ❑ Liver function tests (LFT's) ❑ Prothrombin time (PT) or International normalised ratio (INR) Renal function tests (RFT's) ❑ Chart Rumack Matthew nomogram (not useful for chronic overdose)

Acute overdose (Single ingestion within a 4 hour period)

Chronic overdose (Multiple ingestions over more than 4 hours)

❑ Begin therapy within 8 hours of ingestion ❑ Gastric decontamination Activated charcoal 1g/Kg max 50 Kg ❑ Supportive care Fluid resuscitation Symptomatic treatment of nausea & vomiting If liver failure established consider for liver transplant (see box below)

Initiate N-acetlycysteine therapy if, one or more true: ❑ Acetaminophen concentration above nomogram line ❑ AST is elevated ❑ Serum acetaminophen concentration > 10 mcg/mL

Initiate N-acetlycysteine therapy if, one or more true: ❑ AST is elevated ❑ Serum acetaminophen concentration > 10 mcg/mL

N-acetylcysteine therapy: ❑ Oral: 140 mg/Kg loading dose followed by 70 mg/Kg 4 hourly for additional 17 doses OR ❑ IV: 150 mg/Kg in 200 cc D5W infused over 15 mins followed by 50 mg/Kg in 500 cc D5W infused over 4 hours then 100 mg/Kg in 1000 cc D5W over remaining 16 hours IV route is referred in following cases (High risk patients): ❑ Malnourished/eating disorders ❑ Failure to thrive in children ❑ AIDS ❑ Alcoholism ❑ Associated febrile illness ❑ Using drugs that induce CYP2E1 p450 system Carbamazepine/phenytoin/phenobarbital Rifampicin/rifabutin Efavirenz/nevirapine ❑ Abnormal renal or hepatic function at presentation Pregnancy

At the completion of therapy check for: ❑ AST < 100 mg/dL ❑ Serum acetaminophen levels < 10 mcg/mL

Yes

No

Resolution

Continue therapy. Use following as end points of treatment: ❑ Normalization of INR ❑ Resolution of encephalopathy ❑ Decreasing ALT

Criteria for possible liver transplantation: Arterial pH < 7.3 Hepatic encephalopathy grade III/IV Serum creatinine concentration > 300 μmol/L Prothrombin time > 100 secs Arterial lactate concentration > 3.5 mmol/L on admission or > 3.0 mmol/L 24 hours after paracetamol ingestion Discuss with transplant team when in doubt.

The following algorithm is based on guidelines from "Management of paracetamol poisoning" and "Acetaminophen toxicity and treatment" published by American college of emergency physicians.

Do's

• Measure serum acetaminophen concentrations between 4 and 16 hours post-ingestion. Values taken before 4 hours are not useful as it takes about 4 hours for maximal drug absorption. Likewise values taken after 16 hours are less useful as liver failure may have already occurred by than and the values might not reflect a true picture.
• Ketones on urinalysis and low blood urea concentration point towards malnourishment or starvation.
• Activated charcoal was found to be superior as compared to gastric lavage and substance induced emesis, though both of them are also somewhat useful.
• N-acetylcysteine is most beneficial within first 8 hours of ingestion, however it can be still used after that if liver damage is suspected.
• If a patient is vomiting, a trial of anti emetic may be done, however in such cases IV N-acetylcysteine is preferred.
• IV N-acetylcysteine may sometimes precipitate an anaphylactoid reaction, in such cases stop the infusion, treat with H1-antihistaminics and resume at a slower infusion rate.

Dont's

• Do not overlook acetaminophen in those who have signs suggestive of overdose with other agents.
• Do not rely on activated charcoal decontamination after 4 hours of ingestion, as it is found to be less reliable after that.
• Do not delay treatment with antidote, as the efficacy rapidly decreases after 8 hours.

References

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