A 16-year-old female presents to the emergency department at 3 a.m. with vomiting and nausea. The patient’s mother reports that the patient had an argument with her boyfriend last night. The patient woke her mom up early this morning saying that she feels sick. She admits that she took some pills at 11 p.m. (4 hours ago). She has vomited 3-4 times at home. She wanted to kill herself at the time but no longer feels this way. Her mom brought in the bottle of pills. She took acetaminophen 500mg immediate release tablets. Her mother reports it was a new unopened bottle with a quantity of 30 tablets. There are 8 tablets remaining in the bottle (maximum 11 grams of acetaminophen ingested, 220mg/kg).

Exam: VS T 37.2, HR 88, RR 18, BP 110/70, weight 50 kg. She is alert, quiet, shaking her head, with poor eye contact. Her skin is pink with good perfusion. Her oral mucosa is moist. Heart is regular with a normal rhythm and rate. Lungs are clear with good aeration. Her abdomen is soft, with normoactive bowel sounds. She has minimal epigastric tenderness, but no rebound, and no guarding. She is alert, oriented, and walks about the room without difficulty. She denies wanting to hurt herself at this time.

She is started on IV N-acetylcysteine IV 150mg/kg. An acetaminophen level, aspirin level, and urine toxicology screen are simultaneously obtained and sent to the lab. The acetaminophen level drawn at 4.5 hours post-ingestion is 150 mcg/mL. Her aspirin level is undetectable. Her urine pregnancy and urine toxicology screen are negative. She is hospitalized for continued n- acetylcysteine treatment as well as a psychiatric evaluation.

Acetaminophen (N-acetyl-p-aminophenol), also called paracetamol or APAP, is a common antipyretic and analgesic medication. It is a frequent toxic ingestion in young children and adolescents. Because acetaminophen is an ingredient found in many over-the-counter cold medications a patient may not realize that it is one of the components in the combination product taken. Acetaminophen has also been used as a means of intentional overdose (1). In cases of intentional overdose ingestion, acetaminophen levels are potentially toxic. Acetaminophen is one of the top three most common substances reported in suspected suicide attempts in children aged 6 to 19 years of age (2). An acetaminophen overdose, whether accidental or intentional, can cause hepatotoxicity and even death in children. In the US, acetaminophen overdose is the most common identifiable cause of pediatric acute liver failure (3).

Acetaminophen is available as liquid preparations (suspension and elixir), an immediate-release oral administration pill/capsule, immediate-release suppository, sustained-release oral pill/capsule, and an intravenous formulation. After ingestion, acetaminophen is rapidly absorbed from the gastrointestinal tract. The peak plasma level ranges from 30 minutes up to 4 hours. Acetaminophen reduces fever by inhibiting prostaglandins and it is theorized that acetaminophen reduces pain by reversibly inhibiting cyclooxygenase-2. Acetaminophen is metabolized in the liver via glucuronidation, sulfation, and through the cytochrome P-450 pathway. The majority of acetaminophen is metabolized via the sulfation and glucuronidation pathways into nontoxic products which are then excreted via the urine. Only a small percentage (5% to 15%) of the acetaminophen undergoes metabolism via the cytochrome P-450 oxidase system in the liver to produce the toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is potentially toxic and may cause hepatic injury. However, hepatic glutathione conjugates NAPQI to produce APAP-mercapturate and APAP-cysteine which are both nontoxic metabolites. In severe overdoses, the glutathione stores become depleted, and the toxic metabolite NAPQI builds up causing hepatocellular necrosis (3). Damage usually occurs in hepatic zone III as oxidative metabolism is concentrated in this area. In children 1 to 5 years old, severe liver toxicity is rare with a single ingestion of acetaminophen.

There are four stages of acetaminophen overdose (4). In stage I (first 24 hours), the patient may have symptoms of anorexia, nausea, vomiting, pallor, and diaphoresis. In stage II (24 to 72 hours), the patient may show improvement in their clinical symptoms. The liver enzymes may begin to elevate. Stage III (72 to 96 hours) is called the hepatic stage. The patient may have vomiting, jaundice, abdominal pain, bleeding, confusion, lethargy, hepatic failure, or even be in a coma. The patient may have coagulation defects due to hepatic failure and/or disseminated intravascular coagulopathy. During this stage, death may occur. If the patient survives, the next period is stage IV (4 days to 2 weeks) (4). This stage is also called the recovery phase. Symptoms may resolve in 3 to 5 days. Liver function tests return to normal in 1 to 3 weeks.

If acetaminophen overdose is suspected, treatment should begin with evaluation and stabilization of the patient’s airway, breathing, and circulation. Next, the basic principles of toxicology are followed. If it was an intentional ingestion, acetaminophen and aspirin levels should be obtained. Patients may present stating that they took "aspirin" when in fact they took acetaminophen. Blood and urine toxicology screens should be done as well as a pregnancy test if the patient is a menstruating female. If the patient presents with an altered level of consciousness, a co-ingestion (e.g., with medications such as diphenhydramine or dextromethorphan) must be suspected since acetaminophen does not typically produce early changes in mental status prior to the development of hepatic failure. If the initial serum acetaminophen concentration or history indicates possible hepatic toxicity, additional tests including ALT, AST, electrolytes, blood gas, lactic acid, PT/PTT(INR), bilirubin, creatinine, and BUN should be obtained.

In the setting of acute intoxication, gastrointestinal decontamination in the emergency department may be used. Gastric lavage in a patient who presents to the emergency department should be used only if the ingestion is potentially fatal and the patient presents to the emergency department within 1 hour of the ingestion. Gastric lavage requires a large tube to recover pill fragments and most patients have great difficulty tolerating this. Performing a gastric lavage can delay the administration of N-acetylcysteine (NAC). In our patient's case, she was already vomiting therefore gastric lavage was not performed.

There are differing opinions on the use of activated charcoal in the management of acetaminophen ingestion. With intentional overdoses, there may be other occult co-ingestants that may be adsorbed by the charcoal, reducing their toxic potential. Charcoal should only be administered to patients who present within 4 hours of ingestion. Patients should ideally be awake and able to protect their airway. A theorized consequence of activated charcoal is that it may decrease the bioavailability of the oral antidote NAC, although the research on this topic has been inconclusive (5).

For single acute acetaminophen ingestions occurring within 24 hours of patient presentation, a Rumack-Matthew nomogram is used to estimate the severity of the poisoning. The serum acetaminophen concentration is plotted against the time (hours) post-ingestion. The "toxic" level is a function of time after ingestion. If the APAP level is above the toxic level for that time after ingestion (i.e., the level is above the toxic line), there is possible risk for hepatotoxicity and NAC treatment is warranted. An acute single ingestion of acetaminophen of at least 150 mg/kg in children may be toxic, and management is indicated. For adolescent or adult patients, an ingestion of 7.5 grams may be toxic to the liver. The acetaminophen level is best obtained 4 hours post-ingestion, assuming the acetaminophen formulation is immediate-release and not sustained release. The Rumack-Matthew nomogram is then used to interpret the level obtained. If the patient ingested a sustained-release formulation, the peak acetaminophen level may be delayed beyond 4 hours, although the total dose absorbed will not be affected (6, 7, 8). This makes the interpretation of the Rumack-Matthew nomogram uncertain because the nomogram is based on rapid release products. If an ingestion of delayed/sustained release acetaminophen cannot be rule out, it might be safest to continue NAC treatment since the toxicity cutoff values are less certain and are likely to be lower in the first few hours after ingestion. In other words, significant toxicity could still occur even if the 4-hour level is significantly below the critical value of 150 mcg/mL.

Interpretation of the Rumack-Matthew nomogram is potentially error prone because different units of concentration are used (e.g., micromoles per liter versus micrograms per mL). Confirm that the units on the laboratory drug level are the same as that on the nomogram being used to assess toxicity.

Although acetaminophen toxicity is more likely to be recognized in the acute setting, repeated supratherapeutic doses may become dangerous when the doses reach greater than 200 mg/kg per day over 1 day or 150 mg/kg per day over 2 days (9).

The antidote N-acetylcysteine (NAC) is available in the United States as an oral form (liquid and effervescent tablet) and an intravenous form (4,9). The intravenous form should be used for patients with uncontrollable vomiting, fulminant hepatic failure, or pregnant patients. A more practical consideration is that the taste of oral NAC is unpleasant, thus the initial dose is often given IV due to other clinical factors such as more rapid NAC administration, nausea, vomiting, anorexia, and concurrent activated charcoal administration. Adverse effects of IV NAC include anaphylaxis, especially in patients with a history of asthma. Adverse effects of oral NAC include nausea and vomiting. Since the oral form has an unpleasant odor and taste, some providers suggest mixing it with soda or juice or administration via a naso-gastric or naso-duodenal tube. Oral administration is often slow for these reasons, delaying its effect. Antiemetics such as metoclopramide (Reglan) or ondansetron (Zofran) can be effective for excessive vomiting in patients. NAC is very effective in preventing hepatotoxicity, especially if it is given within 8 hours of the ingestion. If the ingestion has occurred close to this 8 hour time window, NAC should be given prior to receiving the acetaminophen level back from the laboratory, since waiting for the level will unnecessarily delay treatment. NAC is theorized to act as a glutathione substitute. In this process, increased sulfation would lead to less APAP entering the P-450 pathway, potentially reducing toxic metabolites. Another theory is that NAC may bind directly to the toxic intermediates formed, acting as a free-radical scavenger (10). Finally, it is theorized that NAC is able to help replenish and restore glutathione in the liver and scavenge reactive oxygen species to detoxify APAP metabolites (11,12).

The loading dose for oral NAC is 140 mg/kg. The dose is repeated if vomiting occurs within 1 hour. The maintenance dose is 70 mg/kg every 4 hours for 17 doses (total of 18 doses requiring 72 hours of treatment). There are some who advocate a shortened course of NAC treatment for those who are at low risk for hepatotoxicity (13,14). IV NAC can be given as 150mg/kg over 1 hour, followed by 50mg/kg over 4 hours, followed by 100mg/kg over 16 hours (21 hours total) (14).

Patients with acetaminophen toxicity have a generally good prognosis. Young children rarely progress to hepatotoxicity, even without treatment. Some studies have indicated that since a child’s liver and kidney are relatively larger than an adult, they are better able to clear the medication (15,16).

The most effective prevention for pediatric acetaminophen overdose is caregiver education on proper medication administration. Caregivers should be informed on using age-appropriate concentrations, weight-based dosing, and keeping all acetaminophen products (including over the counter cough/cold products that often contain acetaminophen) out of reach from children (9).

Questions
1. The toxic intermediate N-acetyl-p-benzoquinoneimine is formed via which pathway?
   a. Sulfation
   b. Glucuronidation
   c. Cytochrome P-450
   d. Glutathionylation

2. True/False: An adolescent presents with an acute ingestion of acetaminophen 5 hours prior. She is lethargic and is not responding appropriately. This clinical presentation is due to the acetaminophen toxicity.

3. True/False: Hepatotoxicity is rare in children with a single dose acetaminophen ingestion.

4. N-acetylcysteine is most effective if given within how many hours of the acetaminophen ingestion?

5. Which clinical stage is death most likely to occur in?
   a. Stage I
   b. Stage II
   c. Stage III
   d. Stage IV

6. A patient arrives at the emergency department 7 hours after intentionally ingesting an unknown amount of acetaminophen. What should be done?
   a. Directly admit the patient to the floor and await a psychiatric consult.
   b. Draw a stat acetaminophen level and await the result before further treatment.
   c. Give the patient syrup of ipecac if she has not vomited and then administer activated charcoal.
   d. Simultaneously draw a stat acetaminophen level and administer NAC empirically.

References
1. Shekunov J, Lewis CP, Vande Voort JL, et al. Clinical Characteristics, Outcomes, Disposition, and Acute Care of Children and Adolescents Treated for Acetaminophen Toxicity. Psychiatr Serv. 2021;72(7):758-765. doi:10.1176/appi.ps.202000081
2. Ross JA, Woodfin MH, Rege SV, Holstege CP. Pediatric suicides reported to U.S. poison centers. Clin Toxicol (Phila). 2022;60(7):869-871. doi:10.1080/15563650.2022.2042013
3. Ramachandran A, Jaeschke H. Acetaminophen Toxicity: Novel Insights Into Mechanisms and Future Perspectives. Gene Expr. 2018;18(1):19-30. doi:10.3727/105221617X15084371374138
4. Fisher ES, Curry SC. Evaluation and treatment of acetaminophen toxicity. Adv Pharmacol. 2019;85:263-272. doi:10.1016/bs.apha.2018.12.004
5. Villeneuve E, Gosselin S. Chapter 27. Antidote. In: Brent J, Burkhart K, Dargan P, et al (eds). Critical Care Toxicology. Springer; Berlin/Heidelberg: 2017. pp:2879-2888.
6. Cetaruk EW, Dart RC, Hurlbut KM, et al. Tylenol Extended Relief overdose. Ann Emerg Med. 1997;30(1):104-108. doi:10.1016/s0196-0644(97)70120-3 [This reference is really old, 26 years old. Is there something newer? If not, OK to leave it in.]
7. Graudins A, Chiew A, Chan B. Overdose with modified-release paracetamol results in delayed and prolonged absorption of paracetamol. Intern Med J. 2010;40(1):72-76. doi: 10.1111/j.1445-5994.2009.02096.x
8. Michienzi A, Tobarran N, Hieger MA. Extended Release Acetaminophen Overdose With Delayed Peak Concentrations. Am J Ther. 2022;29(6):e655-e656. doi: 10.1097/MJT.0000000000001329
9. Nadler A, Fein DM. Acetaminophen Poisoning. Pediatr Rev. 2018;39(6):316-318. doi:10.1542/pir.2017-0093
10. Pedre B, Barayeu U, Ezeri?a D, Dick TP. The mechanism of action of N-acetylcysteine (NAC): The emerging role of H2S and sulfane sulfur species. Pharmacol Ther. 2021;228:107916. doi:10.1016/j.pharmthera.2021.107916
11. Mazaleuskaya LL, Sangkuhl K, Thorn CF, et al. PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015;25(8):416-426. doi:10.1097/FPC.0000000000000150
12. Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008;359(3):285-292. doi:10.1056/NEJMct0708278)
13. Wong A, McNulty R, Taylor D, et al. The NACSTOP Trial: A Multicenter, Cluster-Controlled Trial of Early Cessation of Acetylcysteine in Acetaminophen Overdose. Hepatology. 2019;69(2):774-784. doi:10.1002/hep.30224
14. Acetaminophen-Acute (Toxicology). In: Merative Micromedex. Ann Arbor, MI, USA. Accessed September, 2023.
15. Tenenbein M. Why young children are resistant to acetaminophen poisoning. J Pediatr. 2000;136(6):891-892. doi:10.1067/mpd.2000.105195
16. Yoon E, Babar A, Choudhary M, et al. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. J Clin Transl Hepatol. 2016;4(2):131-142. doi:10.14218/JCTH.2015.00052

Answers to questions
1. C
2. False. Acute ingestion of acetaminophen does not cause early altered mental status unless the overdose is exceptionally large or associated with other drug ingestions.
3. True
4. 8 Hours
5. C
6. D