Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter XIV.10. Acetaminophen Overdose
Lynette L. Young, MD
August 2002

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A 16 year old female presents to the emergency department at 0500 with vomiting and nausea. Her mother reports that she (the patient) had an argument with her boyfriend last night. She woke her mom up early this morning saying that she feels sick. She admits that last night she took some pills at 2100. She has vomited 3-4 times at home. Her mom brought in the bottle of pills. She took acetaminophen 500mg 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).

Exam: VS T 37.2, P 88, R 18, BP 110/70, weight 50kg. She is alert, quiet, shaking her head yes/no to questions, 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, minimal epigastric tenderness, no rebound, and no guarding. She is alert, oriented, and walks about the room without difficulty.

She is given 50 grams of activated charcoal with sorbitol orally. She is also given 10 grams of N-acetylcysteine orally. An acetaminophen level, aspirin level, blood and urine toxicology screen and beta-HCG are drawn. The acetaminophen level drawn at 8.5 hours post-ingestion is 150 mcg/mL. She is hospitalized for further treatment as well as a psychiatric evaluation.


Acetaminophen (N-acetyl-p-aminophenol) 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, it should be considered in intentional overdoses, as the patient may not realize that it is one of the components in the combination product taken.

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 (5-15%) of the acetaminophen undergoes metabolism via the P-450 cytochrome 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, the hepatic glutathione conjugates the 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. In children 1 to 5 years, severe liver toxicity is rare with a single ingestion of acetaminophen, for reasons which are unclear.

There are four stages of acetaminophen overdose. In stage I (first 24 hours), the patient may have symptoms of anorexia, nausea, and vomiting. Sometimes they may have pallor and diaphoresis. In stage II (24-48 hours), the patient may show improvement in their clinical symptoms. The liver enzymes may begin to elevate. Stage III (72-96 hours) is called the hepatic stage. The patient may have vomiting, jaundice, abdominal pain, bleeding, confusion, lethargy, or even be in a coma. The patient may have coagulation defects, such as disseminated intravascular coagulopathy. The patient may progress to death. If the patient survives, the next period is stage IV (4 days to 2 weeks post-ingestion) which is called the recovery phase. Liver function tests return to normal in 1-3 weeks. Symptoms may resolve in 3-5 days.

In the management of acetaminophen ingestions the, basic principals 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 toxicologic screens should be done as well as a pregnancy test if the patient is a menstruating female. If the patient presents with altered level of consciousness, a co-ingestion must be suspected because acetaminophen does not produce any changes in mental status.

Acetaminophen is rapidly absorbed from the gastrointestinal tract. The peak plasma level ranges from 30 minutes up to 4 hours. Syrup of ipecac is not used as a form of gastrointestinal decontamination in the emergency department setting. Gastric lavage in a patient who presents to the emergency department is controversial. There are some toxicologists who feel that gastric lavage has not been proven to be helpful and should be used only if the ingestion is potentially rapidly fatal and the patient presents to the emergency department within 1 hour of the ingestion. In our patient's case, she was already vomiting so gastric lavage was not performed.

Another controversial area in the management of acetaminophen ingestion is activated charcoal administration. With intentional overdoses, there may be other occult co-ingestants that may be inactivated by the charcoal. Those that argue against giving charcoal believe that it may decrease the bioavailability of the antidote N-acetylcysteine (NAC). The proponents of giving activated charcoal recommend increasing the initial loading dose of NAC (140 mg/kg) by 30-40%.

For single acetaminophen ingestions 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 less than 140 mg/kg in children is likely to be nontoxic. There are some who have recommend a higher cutoff for the risk of toxicity in children, but there is no universal consensus on this. An adolescent/adult ingestion of 7.5 grams may be toxic to the liver. The acetaminophen level is best obtained 4 hours post-ingestion. The Rumack-Matthew nomogram is then used to interpret the level obtained. There are some that believe an acetaminophen level may be drawn as early as 2 hours post-ingestion in a child. They proposed that if the level is at or above 225 mg/L at 2 hours than treatment should be started (1,2).

The antidote NAC is available in the United States as an oral form which has an unpleasant odor and taste. An intravenous form is available in Canada and Europe but is not yet FDA approved in the USA. The patient may experience nausea and vomiting with the NAC treatment. Some suggestions include mixing it with soda or juice or administration via a naso-gastric or naso-duodenal tube. Antiemetics such as metoclopramide (Reglan) or ondansetron (Zofran) have been suggested. NAC given orally is very effective in preventing hepatotoxicity 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. N-acetylcysteine is believed to act as a glutathione substitute. The sulfation is increased and less APAP is thought to enter the P-450 pathway so there is less toxic metabolite formed. Another theory is that NAC may bind directly to the toxic intermediates formed. The loading dose for NAC is 140 mg/kg. This should be increased by 30-40% if charcoal has been given. 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). There are some who advocate a shortened course of NAC treatment for those who are at low risk for hepatotoxicity (3,4). The alternative is to discontinue NAC if at 36 hours the liver transaminase level are normal and the APAP level is less than 10 mcg/mL.

The prognosis for patients of acetaminophen overdoses is generally good. Young children rarely progress to hepatotoxicity. Some believe that APAP is metabolized more via sulfation so there are less toxic intermediates formed. There are others that believe, since a child's liver and kidney are relatively larger than an adult, they are better able to clear the medication (5). Also children may vomit sooner after the ingestion, therefore eliminating the toxic substance. Children with accidental APAP overdoses are usually brought in earlier for medical care, as compared to adults with intentional APAP overdoses who typically present for medical care many hours or days after the overdose. Of the patients who progress past clinical stage III, 99% have clinical resolution.


Questions

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

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. If charcoal has been given, the dose of N-acetylcysteine should be increased by:
. . . . . a. Not increased.
. . . . . b. 5-10%
. . . . . c. 10- 20%
. . . . . d. 30-40%
. . . . . e. 50-60%

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

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

6. Which is the first clinical stage that liver function tests may be abnormal?
. . . . . a. Stage I
. . . . . b. Stage II
. . . . . c. Stage III
. . . . . d. Stage IV

7. A patient arrives to 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. Draw a stat acetaminophen level and administer NAC.


References

1. Anderson BJ, Holford NHG, Armishaw JC, Aicken R. Predicting concentrations in children presenting with acetaminophen overdose. J Pediatr 1999;135:290-295.

2. Rumack BH. Acetaminophen overdoes? A quick answer. J Pediatr 1999;135:269-270.

3. James LP, Well E, Beard RH, Farrar HC. Predictors of outcome after acetaminophen poisoning in children and adolescents. J Pediatr 2002;140:522-526.

4. Woo OF, Mueller PD, Olson KR, Anderson IB, Kim SY. Shorter duration of oral N-Acetylcysteine therapy for acute acetaminophen overdose. Ann Emerg Med 2000;35:363-368.

5. Tenenbein M. Why young children are resistant to acetaminophen poisoning. J Pediatr 2000;891-892.

6. Osterhoudt KC, Shannon M, Henretig FM. Chapter 88 - Toxicologic Emergencies. In: Fleisher GR, Ludwig S (eds). Textbook of Pediatric Emergency Medicine, fourth edition. 2000, Baltimore: Lippincott Williams & Wilkins, pp. 887-901.

7. Mydler TT, Wasserman GS. Chapter 43 Specific Toxins. In: Barkin RM (ed). Pediatric Emergency Medicine Concepts and Clinical Practice, second edition. 1997, St. Louis: Mosby Year Book, pp. 536-539.

8. Bizovi KE, Parker SJ, Smilkstein MJ. Chapter 142 - Acetaminophen. In: Marx JA (ed). Rosen's Emergency Medicine Concepts and Clinical Practice, fifth edition. 2002, St. Louis: Mosby Year Book, pp. 2069-2075.

9. Dart RC (ed). The 5 Minute Toxicology Consult. 2000, Baltimore: Lippincott Williams & Wilkins, pp. 164-167.

10. Olson KR. Acetaminophen. In: Olsen KR (ed). Poisoning & Drug Overdose, third edition. 1999, Stamford: Appleton & Lange, pp. 62-65.

11. Smilkstein MJ. Chapter 31 Acetaminophen. In Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA, Hoffman RS (eds). Goldfrank's Toxicologic Emergencies, sixth edition. 1998, Stamford: Appleton & Lange; pp. 541-564.


Answers to questions

1. c

2. False. Acute ingestion of acetaminophen does not cause altered mental status.

3. d

4. True.

5. 8 hours

6. b

7. d


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