Today we discuss massive acetaminophen ingestion. I nabbed an amazing toxicologist for the discussion…
Emily Austin, MD
Emily Austin is a toxicologist at the Ontario Poison Centre. She completed her training at the U of T Clinical Pharmacology and Toxicology Royal College sub-specialty program. She is also an emergency medicine physician at St. Michael's Hospital in Toronto, Ontario.
Massive Ingestion is Defined By
1 tablet or 500 mg/kg
30 gms in the presence of co-ingestants
Over 250-500 APAP level
Signs of Mitochondrial Toxicity
Presentation
Altered mental status within ~4 hours of ingestion
Elevated Lactate
Signs of Liver injury at ~12 hour mark
Labs for Suspected Massive
Send VBG, Lactate, LFTs, PT/PTT, and Phosphate in addition to standard APAP/ASA
Repeat the APAP level at least every 4 hours
Intial INR elevation may not be from liver failure simply from an interaction to NAPQI (to below 2)
From EM Cases: In the setting of a single acute acetaminophen ingestion such as this case, an early rise in INR is not actually indicative of hepatotoxicity. Both acetaminophen and its toxic metabolite NAPQI interfere with Vitamin K dependent coagulation factors and therefore lead to a transiently elevated INR (typically under 2). This will resolve without any specific management and does not affectthe standard indications for starting NAC. Additionally,high levels of circulating acetaminophen may also interfere with the INR lab assay leading to falsely elevated INR.
Both of these reasons for elevated INR are distinct from a case where acetaminophen toxicity leads to fulminant hepatic failure and there is subsequent INR elevation. In cases of acetaminophen and fulminant hepatic failure, INR will rise 2-3 days after the acute ingestion and be accompanied by elevated transaminases and other markers that fit a clinical picture of fulminant hepatic failure.
Very early presentation of patients with significantly elevated paracetamol levels can be associated with marked metabolic acidosis and elevated lactate, but only mild elevation of transaminase levels and minimal, if any, coagulopathy. This is a separate entity to the later ALF that may develop. This clinical syndrome is considered as a direct drug effect, relating to functional mitochondrial standstill, and resolving with falling paracetamol levels. These patients should be treated with appropriate fluid resuscitation, N-acetylcysteine (NAC), and may need renal replacement therapy (RRT) to treat the acidosis. In these cases, other compounding aetiologies should also be sought such as salicylate, tricyclic or methanol ingestion. [EASL Guidelines on Liver Failure]
Hendrickson RG advocates there should be higher doses at 300, 450, and 600 on the nomogram [2019 Clin Tox 10.1080/15563650.2019.1579914]
Fomepizole for Massive APAP
Fomepizole inhibits the CYP2E1 pathway, thus preventing conversion of APAP into NAPQI
Still at the level of case series
15 mg/kg
Talk to your toxicologist
Link et al. Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series, Clinical Toxicology, 2022;60:4, 472-477, DOI: 10.1080/15563650.2021.1996591
If the [APAP] more than 1000 mg/L (6620 μmol/L) and NAC is NOT administered (1D)
If the patient presents with altered mental status, metabolic acidosis, with an elevated lactate, and an [APAP] is more than 700 mg/L (4630 μmol/L) and NAC is NOT administered (1D)
If the patient presents with an altered mental status, metabolic acidosis, an elevated lactate, and an [APAP] is more than 900 mg/L (5960 μmol/L) even if NAC is administered (1D)
In adults, an acute ingestion of more than 150 mg/kg or 12 g of acetaminophen is considered a toxic dose and poses a high risk of liver damage. In children, acute ingestion of 250 mg/kg or more poses significant risk for acetaminophen-induced hepatotoxicity.
The recommended practice is to administer acetylcysteine until stopping criteria are met. A high-risk ingestion is defined as ingestion of at least 30 g of acetaminophen or an acetaminophen concentration above the high-risk line on the nomogram (Figure 2).
The majority of patients survive acetaminophen toxicity with supportive care such as intravenous fluids and anti-nausea medication, activated charcoal, if used within one hour after ingestion, and antidotal therapy, including N-acetylcysteine (Acetadote®, Mucomyst®).
The results of the acetaminophen test appear in micrograms per milliliter (mcg/mL): A blood level of acetaminophen in the range of 10 to 20 mcg/mL is considered safe. A blood level of acetaminophen higher than 200 mcg/mL 4 hours after ingestion means there is risk for liver damage.
The initial signs and symptoms of acetaminophen overdose are non-specific and include nausea, vomiting, and diffuse abdominal pain. These symptoms may progress to include right-sided abdominal pain, jaundice, and confusion. In severe cases, liver failure, kidney problems, coma and death can occur.
Regardless of whether acetaminophen toxicity occurs because of a single overdose or after repeated supratherapeutic ingestion, the progression of acetaminophen poisoning can be described in four sequential phases: preclinical toxic effects (phase one), hepatic injury (phase two), hepatic failure (phase three), and ...
Hepatic injury generally starts 24 to 72 hours after the ingestion with marked elevations in serum ALT and AST (often to above 2000 U/L), followed at 48 to 96 hours by clinical symptoms: jaundice, confusion, hepatic failure and in some instances death. Evidence of renal insufficiency is also common.
Patients develop mitochondrial dysfunction very early (usually within <12 hours of ingestion), before any liver damage occurs. This may cause early development of lactic acidosis and altered mental status.
Call 911 or poison control (800-222-1222) right away if you suspect you, your child, or someone you know took too much Tylenol. It's critical to seek medical assistance as soon as possible. Early treatment is associated with lower mortality rates in both children and adults.
The antidote to acetaminophen overdose, N-acetylcysteine (NAC), is most effective when given within 8 hours of ingesting acetaminophen and can prevent liver failure, if given early enough, by replenishing the stores of glutathione in the liver to detoxify NAPQI.
If you have no significant health conditions and only take Tylenol at recommended doses, then it is typically out of your system within 12 to 24 hours after your last dose. If you've been taking more than the recommended doses of Tylenol, it could take a few days for your body to clear it.
Acetaminophen in overdose can seriously damage the liver. If the damage is severe, a liver transplant may be necessary in order to save someone's life. The antidote to acetaminophen overdose is N-acetylcysteine (NAC). It is most effective when given within eight hours of ingesting acetaminophen.
Patients presenting more than 24 hours after ingesting toxic doses of acetaminophen may manifest symptoms including nausea, vomiting, jaundice, abdominal pain, and hypotension.
In adults and adolescents, hepatotoxicity may occur following ingestion of greater than 7.5 to 10 grams (g) (eg, 24 regular-strength or 15 extra-strength caplets or tablets) over a period of 8 hours or less. Fatalities are infrequent especially when treated with acetylcysteine (0.3% of treated cases).
The common method used to derive the TI is to use the 50% dose-response points, including TD50 (toxic dose) and ED50 (effective dose). For example, if the TD50 is 200 and the ED50 is 20 mg, the TI would be 10. A clinician would consider a drug safer if it had a TI of 10 than if it had a TI of 3 (Figure 1).
Toxic units are derived by scaling a measured compound concentration to its inherent effect concentration in a standard test system (STS, e.g., acute LC50 for Daphnia magna). In this way, the effect of single chemicals can be compared with each other or added to an overall effect.
Dividing the weight by 2, the acetaminophen dose is 6 mL. The ibuprofen dose is likewise 6 mL. Using this formula, acetaminophen is dosed at 16 mg/kg and ibuprofen at 10 mg/kg, provided that the children's concentrations are used.
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