Acetaminophen (Paracetamol) toxicity: Clinical sciences

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Introduction0:00–1:01

Acetaminophen toxicity is the most common cause of acute liver failure in the United States. Acetaminophen, also known as paracetamol or N-acetyl-para-aminophenol or APAP for short, is a medication commonly used to treat pain and fever in children and adults.Normally, acetaminophen is metabolized in the liver, but if consumed in large amounts, the toxic byproduct of acetaminophen metabolism called NAPQI can lead to hepatotoxicity, which can eventually result in liver failure.
The management of acetaminophen toxicity is based on the amount of time that has passed since the drug was ingested, either within 4 hours, 5 to 24 hours, or longer than 24 hours ago.If a patient presents with signs and symptoms suggestive of acetaminophen toxicity, the first step is to perform an ABCDE assessment to determine if the patient is stable or unstable.

ABCDE Assessment1:01–1:42

If the patient is unstable, stabilize the airway, breathing, and circulation. This means that you might need to intubate the patient.
Next, obtain IV access and put the patient on continuous vital sign monitoring, including heart rate, blood pressure, and pulse oximetry.
Finally, if needed, don’t forget to provide supplemental oxygen.Alright, now let’s go back to the ABCDE assessment and discuss how to manage stable patients.
If the patient is stable, first perform a focused history and physical exam. The patient will typically report acetaminophen ingestion, as well as loss of appetite, fatigue, and malaise.

Stable branch1:42–6:06

Additionally, they might report abdominal pain, nausea, vomiting, and confusion. The physical exam might reveal tachycardia, right upper quadrant abdominal tenderness, and altered mental status.Now, here’s a high-yield fact!
In adults, acute ingestion of 12 grams of acetaminophen or 150 milligrams per kilogram is considered a toxic dose. But, keep in mind that patients might be asymptomatic for hours after ingesting acetaminophen, so a lack of symptoms doesn’t mean the patient won’t have acetaminophen toxicity.
Generally speaking, clinical manifestations of acetaminophen toxicity can be subdivided into 4 main stages! Stage I of acetaminophen toxicity covers the first 24 hours after the ingestion, and typically presents with non-specific findings like pallor and diaphoresis, as well as gastrointestinal manifestations like nausea and vomiting.
In this stage, there’s still no liver injury, so labs are usually normal. Next up is stage II, which occurs between 24 and 72 hours after the ingestion, and is associated with initial damage to the liver!
In this stage, the symptoms from stage I typically resolve, but, your patient could develop right upper abdominal pain and hepatomegaly.
Regarding labs, as hepatocytes start to die off, they begin to release AST and ALT in the bloodstream! Additional lab findings that are supportive of hepatic dysfunction include elevated bilirubin levels, as well as prolonged PT and INR.
Next up is stage III, which occurs between 72 and 96 hours after ingestion! In this stage, there’s significant damage to the liver, which in some cases can even lead to fulminant hepatic failure.
Some patients may experience hepatic encephalopathy, which is characterized by altered mental status and confusion. In extreme cases, patients may even progress to a state of coma!
Lab findings reveal hepatic injury and dysfunction, including metabolic acidosis, abnormal PT and INR, as well as hypoglycemia, and findings of renal failure, such as elevated creatinine.
Finally, there’s stage IV, which begins on day 4 of the overdose and can last up to 4 weeks. Stage IV is a period of recovery, during which the patient’s liver function may gradually improve, leading to a subsiding of symptoms.
However, it's important to note that certain patients who have experienced extensive liver damage or delayed medical intervention might face lasting sequelae, such as the development of liver failure or the need for a transplant.
Let’s follow this with a clinical pearl! In the context of evaluating for liver failure, prolonged PT/INR is referred to as synthetic dysfunction, meaning, the liver’s failing at its role of producing proteins involved in the clotting cascade.
Thus, a commonly used phrase you might hear in the clinical setting is "AST and ALT are elevated, but there's no synthetic dysfunction".
What this means is that, although there’s elevated levels of AST and ALT, which are markers of liver damage, the liver's ability to synthesize clotting proteins as indicated by the PT/INR is not yet affected.
On the flip side, if labs reveal synthetic dysfunction, you’re facing severe liver damage or liver failure. Based on these history and physical findings, you should suspect acetaminophen toxicity.
Next, it’s essential to assess the amount of time that has elapsed since the ingestion, since longer post-ingestion times are associated with a higher risk of hepatotoxicity and liver failure.First, let’s start with patients that are presenting within 4 hours after the ingestion.

Suspect acetaminophen toxicity6:06–6:26

In this case, the drug might still be undigested in the stomach, so proceed with gastric lavage and oral activated charcoal or cholestyramine.

0-4 hours post-ingestion6:26–7:18

Activated charcoal and cholestyramine can bind the acetaminophen in the gastrointestinal tract, prevent its absorption, and eventually help eliminate the medication from the body.
Next, wait until the fourth hour after ingestion to order labs, including APAP level and CMP. It’s important not to send the labs earlier, because medications take time to get absorbed, so the results within the first 4 hours won’t represent the true acetaminophen level in the bloodstream.
On the other hand, let’s look at a patient presenting 5 hours up to 24 hours after the ingestion. In this case, skip the initial management and immediately order APAP levels and CMP.

5-24 hours post-ingestion7:18–8:32

This is because gastric lavage, oral activated charcoal, and cholestyramine are not effective after 4 hours, since most of the acetaminophen has already been absorbed into the bloodstream.Now, let’s take a look at the lab results.
In all individuals that present within the first 24 hours of ingestion, the labs will typically reveal detectable APAP with or without elevated AST and ALT.
Once you get the results, plot the patient’s APAP levels on the Rumack-Matthew Nomogram, or RMN for short. If the APAP levels are below the treatment line, no further management is needed.
However, APAP levels above the treatment line are highly suggestive of acetaminophen toxicity, so you should proceed with further management!
Our last scenario is patients presenting after 24 hours, or an unknown amount of hours after ingestion. In this case, immediately check APAP levels and CMP!
If APAP levels are not detectable and AST and ALT are normal, you should consider an alternative diagnosis. On the flip side, regardless of APAP presence in the blood, if AST and ALT are elevated, diagnose acetaminophen toxicity and immediately proceed with management!Finally, let’s go over management.

>24 hours or unknown8:32–9:07

Start with medical therapy, primarily oral or intravenous N-acetyl cysteine, or NAC for short. Both routes are effective, but keep in mind that IV administration is preferred in patients who are vomiting; refusing oral administration; or those who have severe liver disease.
NAC is almost 100% hepatoprotective if you administer it within 8 hours of ingestion. Once you initiate the treatment, monitor labs periodically.

Management9:07–10:30

You can check the patient’s APAP levels, AST, and ALT, as well as prognostic markers, including PT, INR, bilirubin, lactate, creatinine, glucose, bicarbonate, and serum pH.
If you notice that prognostic markers are getting worse as you monitor them, there’s a high chance that the patient is going to develop acute liver failure.
In this case, you should consult your surgery team for possible liver transplantation. However, if prognostic markers are improving as you monitor, it indicates that your patient is getting better and going toward full resolution.Alright, as a quick recap… If you suspect acetaminophen toxicity, you should order labs, including APAP levels, AST and ALT, while also assessing time that has elapsed since the ingestion.
In individuals that present within 4 hours after ingestion, proceed with gastric lavage, oral activated charcoal or cholestyramine.
However, if your patient presents 5 to 24 hours after the ingestion, skip this initial management. In all individuals that present within 24 hours, labs will typically reveal detectable APAP with or without elevated AST and ALT.

Review10:30–11:39

Then, plot the patient’s APAP levels on the Rumack-Matthew Nomogram. If the APAP levels are below the treatment line, no further management is needed; while levels above the treatment line require management.
Finally, if the patient presents after 24 hours, or an unknown amount of time, if AST and ALT are elevated, regardless of APAP, diagnose acetaminophen toxicity and immediately proceed with management!
without elevated A ST and alt then plot the patient's A PP levels on the rheum ma Matthew nomogram If the APAP levels are below the treatment line no further management is needed while levels above the treatment line require management Finally if the patient presents after 24 hours or an unknown amount of time if a ST and alt are elevated regardless of A