Acetaminophen Poisoning

Above the recommended dosage, this over-the-counter medication causes illness and even death.

hristine Smithson, 18, is brought to the ED by her parents after she tells them she took a bunch of 500-mg acetaminophen (Extra Strength Tylenol) about four hours ago (this case is a composite based on my experience). In tears, Ms. Smithson says she didnt really want to hurt herself; she had a fight with her boyfriend and took the pills to make him sorry. After vomiting once, Ms. Smithson became frightened and told her mother what shed done. Her mother brought the bottle to the ED. She tells the hospital staff it was new, originally containing 225 caplets; 175 caplets remain. She says her daughter is a good girl and has never done anything like this before. Ms. Smithson is in good health and has no past medical history. Upon questioning, she says there were only a few pill fragments visible in her emesis. Her vital signs are temperature, 98.8F; blood pressure, 112/60 mmHg; sinus rhythm, 95 per minute; and respiratory rate, 24 breaths per minute. She is 55 and 170 lbs. A general assessment shows her to be awake and alert but slightly pale and diaphoretic. She reports nausea but hasnt had additional episodes of vomiting. After an IV line of normal saline is started, her blood is drawn to ascertain the serum concentration of acetaminophen. This will help to determine the severity of the overdose, which will guide any further testing and treatment. ACETAMINOPHEN: AN OVERVIEW Acetaminophen is an analgesic and antipyretic. Its safe when taken as directed but can cause extreme harm and even death in amounts above the recommended dosage. Indeed, in the American Association of Poison Control Centers most recent annual report, acetaminophen appears twice in the top 10 list of substances associated with the most fatalities. In 2007, at number four, acetaminophen in combination was the cause of 208 deaths and at number eight, acetaminophen alone was the cause of 140 fatalities.1 Peak concentrations normally occur between 60 and 120 minutes after ingestion, although in the

case of an overdose they can occur as late as four hours after intake; acetaminophen has a half life of approximately two hours.2 Maximum daily dosages are 4 g for short-term use in adults (no more than eight extra strength tablets per day) and 75 mg/kg in children under 12.3 The recommended daily dosage is 325 to 1,000 mg every four to six hours in adults and 10 to 15 mg/kg every four to six hours in children under 12. In prescribed doses, acetaminophen is quickly absorbed from the stomach and small intestine; 90% is metabolized in the liver into nontoxic compounds.4 Of the remaining 10%, half is excreted unchanged in the urine and the other half is metabolized to N-acetyl-p-benzoquinone imine (NAPQI), an electrophile thats extremely toxic to the liver. Normally, with therapeutic levels of acetaminophen, hepatic glutathione rapidly detoxifies NAPQI, so that it presents no danger to the liver. However, in the case of an acetaminophen overdose, the body doesnt have enough glutathione to metabolize such high levels of NAPQI, and liver injury ensues.
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By Diana Platt Lopez, BSN, CCRN, CEN

STAGES OF ACETAMINOPHEN POISONING Acetaminophen overdose occurs in four stages.3 Stage 1 (0.5 hours to 24 hours after ingestion): patients may be asymptomatic or present with nausea, vomiting, diaphoresis, pallor, lethargy, and malaise. (Central nervous system depression, if demonstrated, is related to elevated anion gap metabolic acidosis and is rare.) Laboratory studies are usually normal. Stage 2 (24 to 72 hours after ingestion): laboratory tests show evidence of hepatotoxicity and, occasionally, nephrotoxicity. Patients may appear to improve, but as hepatotoxicity progresses they develop right upper quadrant pain and liver enlargement and tenderness. They may demonstrate elevations in prothrombin time (PT) and total bilirubin and may also show signs of renal impairment such as elevations in serum creatinine and blood urea nitrogen, along with proteinuria, hematuria, and granular casts on urinalysis. Stage 3 (72 to 96 hours after ingestion): liver function abnormalities peak during this time. Nausea and vomiting may return along with other stage 1 signs and symptoms. In addition, jaundice and confusion related to hepatic encephalopathy may appear. Laboratory test results may show markedly elevated hepatic enzymes, a high concentration of ammonia, and bleeding problems such as prolonged PT or elevated international normalized ratio (INR). Acute renal failure will occur in approximately a quarter to half of patients. Stage 4 (four days to two weeks after ingestion): patients who survive stage 3 enter a recovery phase. Clinical signs and symptoms resolve, although laboratory values may not return to normal for several weeks. If the patient recovers, healing is complete; there is no residual chronic hepatic disease. DIAGNOSIS Diagnosis of an acetaminophen overdose involves recognition that an overdose has occurred, identification of the agents taken, determination of the severity of the overdose, and a prediction of the degree of toxicity. Serum acetaminophen levels should be determined in the ED, checked again four hours after the patient is admitted, and again 24 hours later. Additional laboratory tests may include serum electrolytes, serum glucose, blood urea nitrogen, PT with INR, serum creatinine, amylase, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), bilirubin, aspartate

not admit this. Urinalysis and, in women, a urine pregnancy test may be performed, and when drugs are involved the behavioral health department is often consulted. TREATMENT Treatment goals are to prevent or decrease acetaminophen absorption. For a single ingestion, the RumackMatthew nomogram is used to determine the probability of toxicity.4 (See The Rumack Matthew Nomogram.) For patients admitted within two hours of ingestion, oral administration of activated charcoal, which will bind to the acetaminophen, can prevent or reduce the absorption of the drug. Acetylcysteine is the approved treatment in patients in danger of hepatotoxicity. Its available in two forms: oral (Mucomyst and others) and IV (Acetadote and others). Published dosing recommendations vary slightly. The New England Journal of Medicine recently published the following protocol4: Oral acetylcysteine Loading dose: 140 mg/kg Maintenance dose: 70 mg/kg every four hours for a total of 17 doses Intravenous acetylcysteine Loading dose: 150 mg/kg over 15 to 60 minutes Next 4 hours: 12.5 mg/kg per hour Final 16 hours: 6.25 mg/kg per hour Cumberland Pharmaceuticals, a manufacturer of IV acetylcysteine, provides an online dosage calculator on the medications Web site (www.acetadote.net). Oral acetylcysteine works as well as the IV form, but it smells like rotten eggs, and some patients cant tolerate it even when its mixed with cola or fruit juice. If a patient has trouble retaining or refuses to take the oral medication, either it must be administered via nasogastric tube or IV acetylcysteine must be used. Intravenous acetylcysteine should also be considered in patients with altered mental status or gastrointestinal bleeding or obstruction, as well as in those whove coingested other drugs or alcohol and require whole bowel irrigation. Moreover, pregnant women should receive the IV drug (because it achieves higher placental concentrations),5 as should patients in whom liver failure may already be present. Reactions to acetylcysteine are generally dose and rate dependent. Flushing, nausea, urticaria, and anaphylactoid reactions have been reported.6-8 True anaphylactic reactions are rare. In one study, patients treated for anaphylactoid reactions to acetylcysteine with steroids, antihistamines, and bronchodilators were able to resume acetylcysteine infusions an hour after treatment, although at a slower rate than before.9
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aminotransferase (AST), and alanine transaminase (ALT). A toxicology screening and alcohol levels are
also required because patients often coingest alcohol and other drugs at the time of the overdose and may
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The RumackMatthew Nomogram

he RumackMatthew nomogram used to estimate likeinjury as a result Tinlihood of hepatic single ingestion isatofa acetaminophenthetoxicity patients with a known time. To use the nomogram, plot the patients serum acetaminophen concentration and the time interval since ingestion. If the resulting point is above and to the right of the sloping line, hepatic injury is likely to result and the use of acetylcysteine is indicated. If the point is below and to the left of the line, hepatic injury is unlikely. The nomogram cant be used in patients who have overdosed because of chronic acetaminophen ingestion or in those in whom the time of ingestion is unknown.4 The RumackMatthew nomogram can be generated online by plugging in the patients acetaminophen level and time since ingestion on the Ars Informatica Web site at http://bit.ly/19b0Dy.

Nausea and vomiting. Ondansetron (Zofran), a selective 5-HT3 receptor antagonist used as an antiemetic, can be given for nausea and vomiting. The recommended IV dose is 4 mg administered over two to five minutes.10 Ondansetron is well tolerated; the most common adverse effects are headache and dizziness. OTHER CONSIDERATIONS Extended-release acetaminophen. Acetylcysteine therapy should be modified in patients whove ingested extended-release acetaminophen.7 In these patients, the IV acetylcysteine package insert says that acetaminophen measured less than eight hours after ingestion may be misleading and that a second measurement should be performed four to six hours after the initial one. If either falls above the toxicity line [on the RumackMatthew nomogram], acetylcysteine treatment should be initiated. Chronic acetaminophen use. Its not clear how to determine toxicity caused by chronic use of acetaminophen. In a study of patients who presented with chronic acetaminophen toxicity, Daly and colleagues found that all those with aspartate aminotransferase levels above 50 units per liter developed hepatotoxicity. However, they also reiterated that no tool exists to guide risk assessment and treatment of the patient with a history of repeated ingestion.11 Regional poison control centers ([800] 222-1222) may offer treatment guidance. Patients who chronically use acetaminophen may ultimately have a worse prognosis than patients whove taken an overdose because treatment of the chronic user is more likely to be delayed.
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PATIENT EDUCATION Given the number of over-the-counter and prescription medications that include acetaminophen, its important to review all the medications patients are taking and teach them to check for hidden acetaminophen in the drugs labels. In 2006 the Food and Drug Administration (FDA) issued proposed labeling changes to over-the-counter pain relievers because of the risk of liver toxicity and stomach bleeding in patients who unknowingly take more than one acetaminophen-containing product, who take acetaminophen with moderate amounts of alcohol, or who take it in high doses.12 In April the FDA announced that these labeling changes had to be completed by April 29, 2010 (see Drug Watch, August).13 In late June an FDA advisory committee recommended the elimination of combination drugs containing acetaminophen and the lowering of its maximum daily dosage, among other changes. The FDA is waiting until the end of September to receive comments from the public before acting on the recommendations.14 Accidental overdose in infants or children is, unfortunately, a common occurrence. This happens because parents dont realize that the infant formulation of acetaminophen is approximately three times more potent than the childrens formulation.15 Incorrect dosing can also be a problem, when, for example, parents or caregivers miscalculate what a dropperful should be or use household spoons instead of measuring spoons or the measuring cups that come with the medicine. MS. SMITHSON, REVISITED Ms. Smithson took approximately 25 g of acetaminophen in a short period of time. Laboratory results show that her serum acetaminophen concentration on arrival in the ED was 300 micrograms per milliliter. When plotted on the RumackMatthew nonogram, this concentration of acetaminophen in her blood at about four hours after ingestion can be expected to cause significant hepatic injury or death unless shes treated quickly. Because Ms. Smithson was brought to the ED right away, her stage 1 acetaminophen poisoning is not expected to progress. Because of her reports of nausea and previous vomiting, shes given initial doses of IV acetylcysteine 57.83 mL and IV ondansetron 4 mg. Shes admitted to the ICU for close observation and is assigned one-to-one observation to prevent her from harming herself. She has no adverse effects from the medication, nor any further episodes of vomiting. During her recovery, she meets with both a behavioral health evaluator and a nurse who educate her and her family on the
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risks associated with acetaminophen use. Although her course of treatment in the hospital is uneventful, because she attempted suicide, Ms. Smithson is transferred to the psychiatric unit, where she can expect to stay at least a week for evaluation. M
Diana Platt Lopez is a clinical educator at Carondelet St. Marys Hospital Emergency Center in Tucson, AZ. Contact author: dplopez@carondelet.org.

REFERENCES
1. Bronstein AC, et al. 2007 Annual Report of the American Association of Poison Control Centers National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila) 2008;46(10):927-1057. 2. Bizovi KE, Smilkstein MJ. Acetaminophen. In: Goldfrank LR, et al., editors. Goldfranks toxicologic emergencies. 7th ed. New York City: McGraw-Hill; 2002. p. 480-506. 3. Burns MJ, et al. Acetaminophen (paracetamol) poisoning in adults: pathophysiology, presentation, and diagnosis. UpToDate. 2008. http://www.uptodate.com/patients/content/ topic.do?topicKey=~.w7Ylf1gLPmR. 4. Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008;359(3):285-92. 5. Crowell C, et al. Caring for the mother, concentrating on the fetus: intravenous N-acetylcysteine in pregnancy. Am J Emerg Med 2008;26(6):735. e1-e2.

6. Rowden AK, et al. Updates on acetaminophen toxicity. Med Clin North Am 2005;89(6):1145-59. 7. Cumberland Pharmaceuticals. Acetadote (acetylcysteine) injection: new safety data [prescribing information]. Nashville, TN; 2008 Dec. http://www.acetadote.net/AcetadotePI_rDec08.pdf. 8. Mant TG, et al. Adverse reactions to acetylcysteine and effects of overdose. Br Med J (Clin Res Ed) 1984;289(6439): 217-9. 9. Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med 1998;31(6):710-5. 10. GlaxoSmithKline. Zofran (ondansetron hydrochloride) injection [prescribing information]. Research Triangle Park, NC; 2006. http://us.gsk.com/products/assets/us_zofran.pdf. 11. Daly FF, et al. Prospective evaluation of repeated supratherapeutic acetaminophen (paracetamol) ingestion. Ann Emerg Med 2004;44(4):393-8. 12. FDA proposes labeling changes to over-the-counter pain relievers [press release]. FDA news and events 2006 Dec 19. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/2006/ucm108811.htm. 13. FDA requires additional labeling for over-the-counter pain relievers and fever reducers to help consumers use products safely [press release]. FDA news and events 2009 Apr 28. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm149573.htm. 14. U.S. Food and Drug Administration. Acetaminophen information. 2009. http://www.fda.gov/Drugs/DrugSafety/ informationbydrugclass/ucm165107.htm. 15. Cohen H. Helping patients and families avoid inadvertent acetaminophen overdose. J Emerg Nurs 2007;33(3):249-51.

On the Cover
rom to 1966 painter specialist Charles Kaiman studF nurse1960Students League ofand clinical ied at the Art New York. The technique he learned there has informed his work ever since. It forces me to clear my mind of all extraneous thoughts, he says. Ive found it immensely helpful in avoiding burnout. I treat a lot of veterans who have survived horrific trauma and have posttraumatic stress disorder. Practicing this technique daily allows me to clean house emotionally and be fully present for my patients. Theyve often asked me how I continue to cope with hearing about trauma all day long. Ive never told them about this painting technique. Perhaps I should. Maybe they can use it themselves. Kaiman explains, The first step is to clear your mind of any preconceptions about what things look like. For example, most people would describe the color of a McIntosh apple as red. Ignore that preconception and carefully examine a small spot on the apple. The goal is to match the color at that spot precisely, as if your life

depended on it, and then go on to match the color of the adjacent spot, and so on until the image is complete. The most difficult images can be rendered this way. The real difficulty lies in totally clearing the mind of the preconception. Its a form of visual meditation. For more of Kaimans work, see this months Art of Nursing and visit www.charleskaimanpainter.com. M
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