ACETAMINOPHEN is a safe and effective antipyretic analgesic when used correctly. In excessive amounts, however, it can cause kidney damage, irreversible liver damage, and death.
Sold under more than 50 brand names and found in more than 200 drug combinations, acetaminophen is one of the most common drugs involved in overdoses reported to the American Association of Poison Control Centers (AAPCC).1-3 In 2004, the AAPCC reported 419 deaths that involved an analgesic.4 Of these, 67 involved acetaminophen alone, 43 were related to acetaminophen plus at least one other substance, and 108 were associated with acetaminophen in a combination product, usually an opioid.4
Prompt treatment within 8 hours of an overdose is key to reducing hepatic injury and preventing death.1 But acetaminophen toxicity can be challenging to recognize at first for various reasons, including delayed onset of symptoms and an inaccurate patient history.
In this article, I'll use a case study to outline an effective strategy for accurately assessing an adult with acute acetaminophen overdose and managing her care.
Nadine Stewart, 29, arrives at the emergency department (ED) by ambulance. She's pale and complains of intermittent episodes of nausea after an intentional overdose of acetaminophen at home. Awake and oriented to person, place, and time, she tells you that she was depressed about her recent job loss and took 30 500-mg acetaminophen tablets (15 grams) about 3 hours ago. Ms. Stewart vomited twice at home and saw a few pill fragments in the emesis. She called 911 after she started to vomit. She says she hasn't taken any other medication or substances, except for her daily 10 mg of loratadine for seasonal allergic rhinitis. She has no known drug or food allergies.
Ms. Stewart's physical exam is unremarkable. Her vital signs are: BP, 122/82; pulse, 112; respirations, 18; and temperature, 99.4[degrees]F (37.4[degrees]C). She weighs 128 pounds (58 kg).
The paramedics established intravenous (I.V.) access in Ms. Stewart's left arm, and she's receiving 0.9% sodium chloride solution at 75 mL/hour. The ED physician orders 4 mg of I.V. ondansetron to treat Ms. Stewart's nausea and vomiting and orders the following lab work: a chemistry screen, liver function panel, urine drug screen, pregnancy test, and acetaminophen level. Because the treatment nomogram for acetaminophen overdose is based on serum acetaminophen levels at 4 hours or more postingestion, lab specimens can't be taken for another hour. As long as you know that antidotal therapy will begin within 8 hours of ingestion, you can wait until the 4-hour acetaminophen level is obtained. Time of ingestion is a key piece of information, and you know that the amount ingested-15 grams-is a toxic dose. (See How much is too much?) When you receive the acetaminophen level, you can plot it on the nomogram to guide ongoing treatment as I'll discuss in detail shortly. First, though, let's look at how acetaminophen is metabolized and what happens in an overdose.
All about acetaminophen
Taken orally in therapeutic doses, acetaminophen is quickly and completely absorbed from the gastrointestional (GI) tract. Peak concentrations occur between 60 and 120 minutes after ingestion of the immediate-release form, and the half-life is about 2 hours.1,2 Acetaminophen metabolism mainly occurs in the liver, with only a small amount excreted unchanged in the urine.1,2
In the liver, most acetaminophen is metabolized through the glucuronidation and sulfation hepatic pathways; the remaining drug in the liver is metabolized by the cytochrome P450 system into a toxic metabolite, N-acetyl-p-benzoquinonimine (NAPQI).1,2 This metabolite couples with hepatic glutathione to produce a nontoxic metabolite.
When a patient overdoses on acetaminophen, the glucuronidation and sulfation pathways become saturated and more acetaminophen in the liver is metabolized by the cytochrome P450 system.1,2 This depletes glutathione stores and lets the toxic metabolite NAPQI accumulate, causing hepatic injury. Peak levels can occur as late as 4 hours after ingestion of a toxic amount of acetaminophen.1,2 This is why the Rumack-Matthew acetaminophen treatment nomogram begins with serum acetaminophen levels drawn 4 or more hours after the reported time of ingestion.1,2
Recognizing the problem
The initial clinical findings in acetaminophen toxicity often are vague and nonspecific, and significant clinical evidence of hepatotoxicity may be delayed. This can result in a dangerous delay in treatment. If the patient doesn't receive antidotal therapy within 8 hours of acetaminophen ingestion, it won't be as effective in restoring glutathione levels and protecting the liver. Because of this, acetaminophen levels should be tested in all patients with suspected drug overdose.
The characteristic clinical course of acute acetaminophen toxicity occurs in four phases.1,2
* Phase 1 (from 30 minutes to 24 hours after ingestion). The patient may experience nausea, vomiting, anorexia, pallor, diaphoresis, and malaise. However, many patients are asymptomatic and appear normal.
* Phase 2 (24 to 72 hours after ingestion). Although the GI effects become less pronounced during this phase, the patient may complain of right upper quadrant pain, indicating the beginning of hepatic injury. Hepatic enzyme levels, bilirubin level, and prothrombin time (PT) will begin to rise. The patient may develop signs and symptoms of renal deterioration, such as decreased level of consciousness and oliguria.
* Phase 3 (72 to 96 hours after ingestion). This phase is characterized by evidence of hepatic necrosis. Patients may experience nausea, vomiting, jaundice, coagulation defects, renal failure, and hepatic encephalopathy. Fulminant hepatic failure usually is fatal.
* Phase 4 (4 days to 2 weeks after ingestion). If the patient survives phase 3, hepatic injury resolves during phase 4 and the liver returns to normal in about 3 months.
Returning to our patient
The ondansetron relieves Ms. Stewart's nausea and vomiting, but she isn't given activated charcoal because it must be given within 2 hours of drug ingestion and Ms. Stewart arrived at the ED 3 hours after the overdose.
When her lab results return, all values are within normal limits except for a potassium level of 3.0 mEq/L (normal range, 3.5 to 5.1 mEq/L) and an acetaminophen level of 240 mcg/mL. The pregnancy test is negative.
After adding supplemental potassium to Ms. Stewart's I.V. fluids, you plot the acetaminophen level on the nomogram to determine toxicity.
Using the nomogram
Determining the time of acetaminophen ingestion as accurately as possible is key to using the nomogram. If you can't accurately determine the time, use the earliest possible time of ingestion.
For example, suppose the time of ingestion is unknown or uncertain, so a clinically relevant acetaminophen level can't be obtained. If the patient has elevated liver function tests, treat the overdose as potentially toxic, obtain an acetaminophen level when possible, and initiate antidotal therapy.1,2,5 If follow-up liver function tests are normal after 36 to 48 hours of treatment, antidotal therapy can be discontinued.1,2
If the patient's serum acetaminophen level is above the "possible risk" line on the nomogram, initiate antidotal treatment. If the level is below the possible risk line, the patient's risk of hepatic damage is minimal and treatment isn't indicated. If you started treatment before receiving the lab values, you can discontinue it as ordered.
Treating a toxic ingestion
Ms. Stewart's acetaminophen level of 240 mcg/mL is above the dotted line, so antidotal treatment is indicated. The antidote of choice is acetylcysteine, available in an oral form as N-acetylcysteine (NAC, brand name Mucomyst) and in an I.V. form (Acetadote). Administering acetylcysteine helps convert the toxic metabolite NAPQI into a nontoxic form. The I.V. form of acetylcysteine is most effective when given within 10 hours postingestion, but can be used anytime up to 24 hours after an acetaminophen overdose.
The ED physician orders oral NAC for Ms. Stewart, as the antiemetic therapy was effective and the oral regimen is recommended if the patient's GI system is functional. The loading dose is 140 mg/kg; the maintenance dose is 70 mg/kg every 4 hours for an additional 17 doses, or a total of 1,330 mg/kg over 72 hours of treatment.1,2 N-acetylcysteine is available in 10% and 20% solutions. Because NAC has a rotten-egg odor, the 20% solution is typically ordered; patients tolerate the smaller volume better. If your patient vomits a NAC dose within 1 hour of administration, repeat the dose and administer appropriate antiemetic therapy.
To administer oral NAC, dilute it in at least a 1:3 (NAC:diluent) ratio with soda, fruit juice, or water. Most patients tolerate dilution with chilled orange juice the best. If you're administering NAC through a nasogastric tube, use water instead of juice.
Ms. Stewart will drink a loading dose of 8 grams of 20% NAC solution, followed by maintenance doses of 4 grams every 4 hours. While she's receiving NAC therapy, you'll monitor her liver function tests, PT, international normalized ratio (INR), partial thromboplastin time (PTT), serum glucose, blood urea nitrogen, and serum creatinine daily. The prescriber may stop NAC therapy if Ms. Stewart develops no liver function test elevations and no elevation of PT/INR and PTT after 36 to 48 hours of therapy.1,2
Reassessing your patient
Once the NAC preparation arrives from the pharmacy and you've verified the "five rights" (right patient, right drug, right dose, right time and frequency of administration, and right route of administration), reevaluate Ms. Stewart, concentrating on her GI assessment, to ensure that she can tolerate the oral solution. She tells you that she's feeling better and hasn't experienced any further nausea or vomiting. You explain the therapy to her and remain at her bedside to verify that she can tolerate the loading dose. Offer reassurance and answer her questions.
Ms. Stewart tolerates the loading dose of oral NAC without GI distress. She's clinically stable, and you tell her that she'll be admitted to the medical/surgical unit for close observation and continued NAC therapy.
If Ms. Stewart had experienced persistent nausea and vomiting despite aggressive antiemetic therapy, she would have been switched to I.V. acetylcysteine.6,7 Adverse drug reactions (ADRs) to I.V. acetylcysteine are extremely low, and anaphylaxis is rare. But because of the potential for ADRs, my facility recommends that I.V. acetylcysteine be given in a monitored setting.6 Adverse reactions to I.V. acetylcysteine, which appear to be rate-related, include rash, urticaria, bronchospasm, pruritus, and anaphylaxis.2,6,7 Use I.V. acetylcysteine cautiously in patients with a history of asthma or bronchospasm.2,6,7
For I.V. acetylcysteine (Acetadote), the loading dose is 150 mg/kg in 200 mL of D5W, administered over 60 minutes. Immediately follow this with the second dose, 50 mg/kg in 500 mL of D5W given over 4 hours. Then infuse 100 mg/kg in 1,000 mL of D5W over 16 hours. This method is considered a continuous infusion because, in theory, the treatment should be completed in 21 hours.6,7
Some special considerations
Let's briefly look at some special considerations when treating acetaminophen toxicity. Consult your regional poison control or information center (1-800-222-1222) in these situations and in any case when the appropriate protocol for evaluating and treating a patient is unclear.
* The treatment protocol must be modified if the patient has overdosed on extended-release acetaminophen because this formulation has slightly different pharmacokinetics than the immediate-release formulation. Absorption may be delayed, so the patient's 4-hour postingestion acetaminophen level may not plot in the toxic range of the treatment nomogram. If your patient has taken extended-release acetaminophen, obtain levels at 4, 6, and 8 hours postingestion and treat him accordingly.
* Someone who takes therapeutic levels of acetaminophen regularly and develops signs and symptoms of acetaminophen toxicity presents a clinical challenge because researchers aren't sure how to determine acetaminophen toxicity due to chronic use. The AAPCC guidelines recommend acetylcysteine therapy for all patients age 6 and older who report an ingestion of 10 grams or 200 mg/kg (whichever is less) over a single 24-hour period, or 6 grams (150 mg/kg or whichever is less) per 24-hour period for the preceding 48 hours or longer.
* Acetylcysteine therapy also should be started for patients who report to the ED more than 24 hours after ingestion and who have elevated liver enzymes.8 You may not see a rise in liver function tests for up to 36 hours, so continue therapy for at least that long. For these patients, therapy appears to offer some hepatic protective benefits and improves survival rates.1,2
* Pregnancy isn't a contraindication for antidotal therapy for acetaminophen toxicity. Acetaminophen crosses the placenta and can cause fetal liver toxicity.1,2 If your patient is pregnant, use the adult guidelines and don't delay antidotal therapy.
* Alcohol abuse, when combined with chronic acetaminophen therapy, can lead to liver failure. Some studies indicate that chronic alcohol abuse combined with acetaminophen overdose increases the risk of liver damage, but the significance of the risk is unclear.1,3 Antidotal treatment for a patient with acetaminophen toxicity who abuses alcohol is the same as for other adults.
* Because children aren't as likely as adults to ingest toxic dosages of acetaminophen, they rarely suffer serious acetaminophen toxicity and death. Possibly due to different metabolism, children under age 12 experience less hepatotoxicity than adults, suggesting they may also be less susceptible to acetaminophen toxicity.1,8 However, children over age 6 should be treated with the same guidelines as those for adults. Children under age 6 should be taken to the ED if they've ingested 10 grams or 200 mg/kg/day of acetaminophen (whichever is lower) or an unknown amount.8
Preventing future problems
You can help Ms. Stewart by offering education and emotional support. She should have a psychiatric consult to determine if she needs psychiatric treatment. Explain why adhering to treatment is important and reassure her that acetylcysteine therapy is almost 100% effective in preventing liver damage if given within 8 hours of acetaminophen ingestion.
To help Ms. Stewart avoid inadvertent acetaminophen overdose in the future, teach her to tell her health care providers about all medications she uses, including over-the-counter medications and herbal preparations. She should regularly review all her medications with her primary care provider because certain medications (such as phenobarbital, phenytoin, carbamazepine, and isoniazid) can interfere with acetaminophen metabolism, potentially causing toxicity.
Teach her about the risks associated with acetaminophen use and explain that acetaminophen toxicity is a common cause of liver transplantation in the United States. Warn her never to exceed the daily recommended dose for acetaminophen (4 grams/day for most healthy adults) and to carefully read drug labels to identify combination products containing acetaminophen.
By understanding how to recognize and treat acetaminophen toxicity, you're better prepared to implement and manage your patient's therapy. With support, education, and treatment, she can recover from this life-threatening complication and avoid acetaminophen toxicity in the future.
How much is too much?
The maximum recommended dosage of acetaminophen is 4 grams/day for short-term use in adults. (Patients with liver problems shouldn't take acetaminophen or other over-the-counter analgesics without first consulting their primary care provider.)
American Association of Poison Control Centers guidelines indicate that the acute toxic dose of acetaminophen for patients over age 6 is 10 grams or 200 mg/kg/day, whichever is lower.8 This is equal to 31 regular-strength or 20 extra-strength tablets over 8 hours or less.1,2
The Florida Poison Information Center uses the 10 grams or 200 mg/kg/day for children under age 18, but considers 7.5 grams an acute toxic dose in adults. This equals 24 regular-strength or 15 extra-strength tablets over 8 hours or less.1,2
The lines on the nomogram indicate the risk of hepatic toxicity based on the patient's serum acetaminophen level between 4 and 24 hours after acute ingestion.