2.0 ANCC/AACN CONTACT HOURS acetaminoManaging acute phen

Here’s how to gauge your patient’s risk of potentially fatal liver damage and how to intervene appropriately.

BY DEBORAH H. SMITH, RN, CHCRM, CSPI, BSN, MA

58 Nursing2007, Volume 37, Number 1 www.nursing2007.com o phentoxicity

ACETAMINOPHEN is a safe and 8 hours of an overdose is key to job loss and took 30 500-mg acet- effective antipyretic analgesic reducing hepatic injury and pre- aminophen tablets (15 grams) when used correctly. In excessive venting death.1 But acetamino- about 3 hours ago. Ms. Stewart amounts, however, it can cause phen toxicity can be challenging vomited twice at home and saw a kidney damage, irreversible liver to recognize at first for various few pill fragments in the emesis. damage, and death. reasons, including delayed onset She called 911 after she started to Sold under more than 50 brand of symptoms and an inaccurate vomit. She says she hasn’t taken names and found in more than patient history. any other medication or sub- 200 drug combinations, acet- In this article, I’ll use a case stances, except for her daily aminophen is one of the most study to outline an effective strat- 10 mg of loratadine for seasonal common drugs involved in over- egy for accurately assessing an allergic rhinitis. She has no doses reported to the American adult with acute acetaminophen known drug or food allergies. Association of Poison Control overdose and managing her care. Ms. Stewart’s physical exam is Centers (AAPCC).1-3 In 2004, the unremarkable. Her vital signs are: AAPCC reported 419 deaths that Overdose emergency BP, 122/82; pulse, 112; respira- involved an analgesic.4 Of these, Nadine Stewart, 29, arrives at the tions, 18; and temperature, 67 involved acetaminophen emergency department (ED) by 99.4o F (37.4o C). She weighs alone, 43 were related to acet- ambulance. She’s pale and com- 128 pounds (58 kg). aminophen plus at least one other plains of intermittent episodes of The paramedics established substance, and 108 were associat- nausea after an intentional over- intravenous (I.V.) access in Ms. ed with acetaminophen in a com- dose of acetaminophen at home. Stewart’s left arm, and she’s bination product, usually an opi- Awake and oriented to person, receiving 0.9% sodium chloride oid.4 place, and time, she tells you that solution at 75 mL/hour. The ED Prompt treatment within she was depressed about her recent physician orders 4 mg of I.V.

www.nursing2007.com Nursing2007, January 59 ondansetron to treat Ms. Stewart’s How much is too much? nausea and vomiting and orders The maximum recommended dosage of acetaminophen is 4 grams/day for the following lab work: a chem- short-term use in adults. (Patients with liver problems shouldn’t take acet- istry screen, liver function panel, aminophen or other over-the-counter analgesics without first consulting their pri- urine drug screen, pregnancy test, mary care provider.) and acetaminophen level. Because American Association of Poison Control Centers guidelines indicate that the the treatment nomogram for acute toxic dose of acetaminophen for patients over age 6 is 10 grams or 200 acetaminophen overdose is based mg/kg/day, whichever is lower.8 This is equal to 31 regular-strength or 20 extra- on serum acetaminophen levels at strength tablets over 8 hours or less.1,2 4 hours or more postingestion, The Florida Poison Information Center uses the 10 grams or 200 mg/kg/day lab specimens can’t be taken for for children under age 18, but considers 7.5 grams an acute toxic dose in adults. 1,2 another hour. As long as you This equals 24 regular-strength or 15 extra-strength tablets over 8 hours or less. know that antidotal therapy will begin within 8 hours of ingestion, Rumack-Matthew nomogram you can wait until the 4-hour The lines on the nomogram indicate the risk of hepatic toxicity based on the patient’s acetaminophen level is obtained. serum acetaminophen level between 4 and 24 hours after acute ingestion. Time of ingestion is a key piece of information, and you know that the amount ingested—15 grams— 300- L

is a toxic dose. (See How much is m /

g 200- too much?) When you receive the c

m Probable risk acetaminophen level, you can n i

100- l plot it on the nomogram to guide e Possible risk v e l ongoing treatment as I’ll discuss 50- n in detail shortly. First, though, e

h Treatment should be initiated p 10- if level above the dotted line let’s look at how acetaminophen o n is metabolized and what happens i m 5- a in an overdose. t Low risk e c A All about acetaminophen 1- Taken orally in therapeutic doses, 4 8 12 16 20 24 acetaminophen is quickly and Hours after ingestion completely absorbed from the gastrointestional (GI) tract. Peak concentrations occur between 60 and 120 minutes after inges- nontoxic metabolite. drawn 4 or more hours after the tion of the immediate-release When a patient overdoses on reported time of ingestion.1,2 form, and the half-life is about 2 acetaminophen, the glucuronida- hours.1,2 Acetaminophen metabo- tion and sulfation pathways Recognizing the problem lism mainly occurs in the liver, become saturated and more acet- The initial clinical findings in with only a small amount excret- aminophen in the liver is metabo- acetaminophen toxicity often are ed unchanged in the urine.1,2 lized by the cytochrome P450 sys- vague and nonspecific, and signif- In the liver, most acetamino- tem.1,2 This depletes glutathione icant clinical evidence of hepato- phen is metabolized through the stores and lets the toxic metabo- toxicity may be delayed. This can glucuronidation and sulfation lite NAPQI accumulate, causing result in a dangerous delay in hepatic pathways; the remaining hepatic injury. Peak levels can treatment. If the patient doesn’t drug in the liver is metabolized by occur as late as 4 hours after in- receive antidotal therapy within the cytochrome P450 system into gestion of a toxic amount of acet- 8 hours of acetaminophen inges- a toxic metabolite, N-acetyl-p- aminophen.1,2 This is why the tion, it won’t be as effective in benzoquinonimine (NAPQI).1,2 Rumack-Matthew acetaminophen restoring glutathione levels and This metabolite couples with treatment nomogram begins with protecting the liver. Because of hepatic glutathione to produce a serum acetaminophen levels this, acetaminophen levels should

60 Nursing2007, Volume 37, Number 1 www.nursing2007.com be tested in all patients with sus- except for a potassium level of an I.V. form (Acetadote). pected drug overdose. 3.0 mEq/L (normal range, Administering acetylcysteine The characteristic clinical 3.5 to 5.1 mEq/L) and an acet- helps convert the toxic metabo- course of acute acetaminophen aminophen level of 240 mcg/mL. lite NAPQI into a nontoxic form. toxicity occurs in four phases.1,2 The pregnancy test is negative. The I.V. form of acetylcysteine is • Phase 1 (from 30 minutes to After adding supplemental most effective when given within 24 hours after ingestion). The pa- potassium to Ms. Stewart’s I.V. 10 hours postingestion, but can tient may experience nausea, fluids, you plot the acetamino- be used anytime up to 24 hours vomiting, anorexia, pallor, dia- phen level on the nomogram to after an acetaminophen overdose. phoresis, and malaise. However, determine toxicity. The ED physician orders oral many patients are asymptomatic NAC for Ms. Stewart, as the and appear normal. Using the nomogram antiemetic therapy was effective • Phase 2 (24 to 72 hours after Determining the time of acet- and the oral regimen is recom- ingestion). Although the GI aminophen ingestion as accurate- mended if the patient’s GI system effects become less pronounced ly as possible is key to using the is functional. The loading dose is during this phase, the patient nomogram. If you can’t accurately 140 mg/kg; the maintenance dose may complain of right upper determine the time, use the earli- is 70 mg/kg every 4 hours for an quadrant pain, indicating the est possible time of ingestion. additional 17 doses, or a total of beginning of hepatic injury. For example, suppose the time 1,330 mg/kg over 72 hours of Hepatic enzyme levels, bilirubin of ingestion is unknown or treatment.1,2 N-acetylcysteine is level, and prothrombin time (PT) uncertain, so a clinically relevant available in 10% and 20% solu- will begin to rise. The patient acetaminophen level can’t be ob- tions. Because NAC has a rotten- may develop signs and symptoms tained. If the patient has elevated egg odor, the 20% solution is of renal deterioration, such as liver function tests, treat the over- typically ordered; patients toler- decreased level of consciousness dose as potentially toxic, obtain ate the smaller volume better. If and oliguria. an acetaminophen level when your patient vomits a NAC dose • Phase 3 (72 to 96 hours after possible, and initiate antidotal within 1 hour of administration, ingestion). This phase is charac- therapy.1,2,5 If follow-up liver repeat the dose and administer terized by evidence of hepatic function tests are normal after appropriate antiemetic therapy. necrosis. Patients may experience 36 to 48 hours of treatment, anti- To administer oral NAC, dilute nausea, vomiting, jaundice, coag- dotal therapy can be discontin- it in at least a 1:3 (NAC:diluent) ulation defects, renal failure, and ued.1,2 ratio with soda, fruit juice, or hepatic encephalopathy. Ful- If the patient’s serum acet- water. Most patients tolerate minant hepatic failure usually is aminophen level is above the dilution with chilled orange juice fatal. “possible risk” line on the nomo- the best. If you’re administering • Phase 4 (4 days to 2 weeks gram, initiate antidotal treatment. NAC through a nasogastric tube, after ingestion). If the patient sur- If the level is below the possible use water instead of juice. vives phase 3, hepatic injury risk line, the patient’s risk of Ms. Stewart will drink a load- resolves during phase 4 and the hepatic damage is minimal and ing dose of 8 grams of 20% NAC liver returns to normal in about treatment isn’t indicated. If you solution, followed by mainte- 3 months. started treatment before receiving nance doses of 4 grams every the lab values, you can discontin- 4 hours. While she’s receiving Returning to our patient ue it as ordered. NAC therapy, you’ll monitor her The ondansetron relieves Ms. liver function tests, PT, interna- Stewart’s nausea and vomiting, Treating a toxic ingestion tional normalized ratio (INR), but she isn’t given activated char- Ms. Stewart’s acetaminophen level partial thromboplastin time coal because it must be given of 240 mcg/mL is above the dotted (PTT), serum glucose, blood urea within 2 hours of drug ingestion line, so antidotal treatment is indi- nitrogen, and serum creatinine and Ms. Stewart arrived at the ED cated. The antidote of choice is daily. The prescriber may stop 3 hours after the overdose. acetylcysteine, available in an oral NAC therapy if Ms. Stewart When her lab results return, all form as N-acetylcysteine (NAC, develops no liver function test values are within normal limits brand name Mucomyst) and in elevations and no elevation of www.nursing2007.com Nursing2007, January 61 PT/INR and PTT after 36 to 48 Immediately follow this with the 6 grams (150 mg/kg or which- hours of therapy.1,2 second dose, 50 mg/kg in 500 mL ever is less) per 24-hour period of D5W given over 4 hours. Then for the preceding 48 hours or Reassessing your patient infuse 100 mg/kg in 1,000 mL of longer. Once the NAC preparation arrives D5W over 16 hours. This method • Acetylcysteine therapy also from the pharmacy and you’ve is considered a continuous infu- should be started for patients verified the “five rights” (right sion because, in theory, the treat- who report to the ED more than patient, right drug, right dose, ment should be completed in 21 24 hours after ingestion and right time and frequency of hours.6,7 who have elevated liver en- administration, and right route of zymes.8 You may not see a rise administration), reevaluate Ms. Some special considerations in liver function tests for up to Stewart, concentrating on her GI Let’s briefly look at some special 36 hours, so continue therapy assessment, to ensure that she can considerations when treating for at least that long. For these tolerate the oral solution. She tells acetaminophen toxicity. Consult patients, therapy appears to offer you that she’s feeling better and your regional poison control or some hepatic protective benefits hasn’t experienced any further information center (1-800-222- and improves survival rates.1,2 nausea or vomiting. You explain 1222) in these situations and in • Pregnancy isn’t a contraindica- the therapy to her and remain at any case when the appropriate tion for antidotal therapy for her bedside to verify that she can protocol for evaluating and acetaminophen toxicity. Acet- tolerate the loading dose. Offer treating a patient is unclear. aminophen crosses the placenta reassurance and answer her ques- • The treatment protocol must and can cause fetal liver tions. be modified if the patient has toxicity.1,2 If your patient is Ms. Stewart tolerates the load- overdosed on extended-release pregnant, use the adult guide- ing dose of oral NAC without GI acetaminophen because this for- lines and don’t delay antidotal distress. She’s clinically stable, mulation has slightly different therapy. and you tell her that she’ll be pharmacokinetics than the • Alcohol abuse, when combined admitted to the medical/surgical immediate-release formulation. with chronic acetaminophen unit for close observation and Absorption may be delayed, so therapy, can lead to liver failure. continued NAC therapy. the patient’s 4-hour post- Some studies indicate that If Ms. Stewart had experienced ingestion acetaminophen level chronic alcohol abuse combined persistent nausea and vomiting may not plot in the toxic range with acetaminophen overdose despite aggressive antiemetic of the treatment nomogram. If increases the risk of liver dam- therapy, she would have been your patient has taken extended- age, but the significance of the switched to I.V. acetylcysteine.6,7 release acetaminophen, obtain risk is unclear.1,3 Antidotal Adverse drug reactions (ADRs) to levels at 4, 6, and 8 hours treatment for a patient with I.V. acetylcysteine are extremely postingestion and treat him acetaminophen toxicity who low, and anaphylaxis is rare. But accordingly. abuses alcohol is the same as for because of the potential for ADRs, • Someone who takes therapeu- other adults. my facility recommends that I.V. tic levels of acetaminophen reg- • Because children aren’t as like- acetylcysteine be given in a moni- ularly and develops signs and ly as adults to ingest toxic tored setting.6 Adverse reactions symptoms of acetaminophen dosages of acetaminophen, they to I.V. acetylcysteine, which toxicity presents a clinical chal- rarely suffer serious acet- appear to be rate-related, include lenge because researchers aren’t aminophen toxicity and death. rash, urticaria, bronchospasm, sure how to determine acet- Possibly due to different metab- pruritus, and anaphylaxis.2,6,7 aminophen toxicity due to olism, children under age 12 Use I.V. acetylcysteine cautiously chronic use. The AAPCC guide- experience less hepatotoxicity in patients with a history of asth- lines recommend acetylcysteine than adults, suggesting they may ma or bronchospasm.2,6,7 therapy for all patients age 6 and also be less susceptible to acet- For I.V. acetylcysteine (Aceta- older who report an ingestion of aminophen toxicity.1,8 However, dote), the loading dose is 10 grams or 200 mg/kg children over age 6 should be 150 mg/kg in 200 mL of D5W, (whichever is less) over a single treated with the same guidelines administered over 60 minutes. 24-hour period, or as those for adults. Children

62 Nursing2007, Volume 37, Number 1 www.nursing2007.com under age 6 should be taken to provider because certain medica- 1. Bizovi KE, Smilkstein MJ. Analgesics and non- prescription medications: Acetaminophen. In the ED if they’ve ingested 10 tions (such as phenobarbital, Goldfrank LR, et al., Goldfrank’s Toxicologic grams or 200 mg/kg/day of phenytoin, carbamazepine, and Emergencies, 7th edition. New York, N.Y., Apple- ton & Lange, 2002. acetaminophen (whichever isoniazid) can interfere with acet- 2. Acetaminophen (management/treatment pro- is lower) or an unknown aminophen metabolism, potential- tocol). In Klasco RK (ed), POISINDEX System. 8 Greenwood Village, Colo., Thomson Micro- amount. ly causing toxicity. medex. (Edition expires March 2007.) Teach her about the risks associ- 3. O’Malley P. Too much of a good thing: Para- Preventing future problems ated with acetaminophen use and cetamol (acetaminophen) toxicity: Update for the clinical nurse specialist. Clinical Nurse You can help Ms. Stewart by offer- explain that acetaminophen toxi- Specialist. 19(1):18-19, January-February 2005. ing education and emotional sup- city is a common cause of liver 4. Watson A, et al. 2004 annual report of the port. She should have a psychiatric transplantation in the United American Association of Poison Control Centers Toxic Exposure Surveillance System. American consult to determine if she needs States. Warn her never to exceed Journal of Emergency Medicine. 23(5):597-598, psychiatric treatment. Explain why the daily recommended dose for September 2005. adhering to treatment is important acetaminophen (4 grams/day for 5. Gyamlani GG, et al. Acetaminophen toxicity: Suicidal vs. accidental. Critical Care. 6(2):155- and reassure her that acetylcysteine most healthy adults) and to care- 159, April 2002. therapy is almost 100% effective in fully read drug labels to identify 6. Acetadote package insert. Nashville, Tenn., preventing liver damage if given combination products containing Cumberland Pharmaceuticals, February 2006. 7. Westendorf K, et al. Intravenous N-acetylcys- within 8 hours of acetaminophen acetaminophen. teine: Antidote for acetaminophen toxicity. US ingestion. By understanding how to recog- Pharmacist. http://www.uspharmacist.com. Ac- To help Ms. Stewart avoid inad- nize and treat acetaminophen toxi- cessed July 18, 2005. 8. Dart RC, et al. Acetaminophen poisoning: An vertent acetaminophen overdose in city, you’re better prepared to evidence-based consensus guideline for out-of- the future, teach her to tell her implement and manage your pa- hospital management. American Association of Poison Control Centers. Clinical Toxicology. health care providers about all tient’s therapy. With support, 44(1):1-18, 2006. medications she uses, including education, and treatment, she can Deborah H. Smith is education coordinator for the over-the-counter medications and recover from this life-threatening Florida Poison Information Center in Jacksonville.

herbal preparations. She should complication and avoid acetamino- The author has disclosed that she has no significant relationship with or financial interest in any commer- regularly review all her medica- phen toxicity in the future.‹› cial companies that pertain to this educational activity. tions with her primary care REFERENCES

Earn CE credit online: Go to http://www.nursingcenter.com/CE/nursing and receive a certificate within minutes.

INSTRUCTIONS Managing acute acetaminophen toxicity TEST INSTRUCTIONS Lippincott Williams & Wilkins together and deduct $0.95 from the • To take the test online, go to our secure Web site at price of each test. http://www.nursingcenter.com/ce/nursing. • We also offer CE accounts for hospitals and other health care • On the print form, record your answers in the test answer section facilities on nursingcenter.com. Call 1-800-787-8985 for details. of the CE enrollment form on page 64. Each question has only one correct answer. You may make copies of these forms. PROVIDER ACCREDITATION • Complete the registration information and course evaluation. Lippincott Williams & Wilkins, publisher of Nursing2007, will Mail the completed form and registration fee of $19.95 to: award 2.0 contact hours for this continuing nursing education Lippincott Williams & Wilkins, CE Group, 2710 Yorktowne activity. Blvd., Brick, NJ 08723. We will mail your certificate in 4 to 6 Lippincott Williams & Wilkins is accredited as a provider of contin- weeks. For faster service, include a fax number and we will fax uing nursing education by the American Nurses Credentialing your certificate within 2 business days of receiving your enroll- Center’s Commission on Accreditation. ment form. • You will receive your CE certificate of earned contact hours and an Lippincott Williams & Wilkins is also an approved provider of con- tinuing nursing education by the American Association of Critical- answer key to review your results. There is no minimum passing grade. Care Nurses #00012278 (CERP category A), California CEP 11749, • Registration deadline is January 31, 2009. District of Columbia, Florida #FBN2454, and Iowa #75. Lippincott Williams & Wilkins home study activities are classified for Texas DISCOUNTS and CUSTOMER SERVICE nursing continuing education requirements as Type 1. Your certifi- • Send two or more tests in any nursing journal published by cate is valid in all states.

www.nursing2007.com Nursing2007, January 63 2.0 ANCC/AACN CONTACT HOURS

Managing acute acetaminophen toxicity GENERAL PURPOSE To provide nurses with an overview of acetaminophen toxicity. LEARNING OBJECTIVES After reading the preceding article and taking this test, you should be able to: 1. Discuss assessment findings in the patient with acetaminophen toxicity. 2. Discuss the pathophysiology of acet- aminophen toxicity. 3. Describe treatment strategies for acetaminophen toxicity.

1. The key to reducing hepatic injury and 6. Which phase of acetaminophen toxicity 10. Acetadote is most effective when preventing death from acetaminophen is characterized by evidence of hepatic given within what time frame postinges- toxicity is prompt treatment of an necrosis? tion? overdose within a. phase 1 c. phase 3 a. 10 hours c. 14 hours a. 8 hours. c. 16 hours. b. phase 2 d. phase 4 b. 12 hours d. 24 hours b. 12 hours. d. 24 hours. 7. If you don’t know the time of 11. Which of the following is best tolerat- 2. The treatment nomogram for acetaminophen ingestion, initiate anti- ed by most patients as the diluent for acetaminophen overdose is based on dotal therapy if the patient has elevated oral NAC? postingestion serum acetaminophen serum a. soda c. warm water levels at a. liver function tests. c. PT. b. water d. chilled orange juice a. 30 minutes. c. 2 hours. b. creatinine. d. albumin. b. 1 hour. d. 4 hours or more. 12. The maximum recommended daily 8. The antidote of choice to treat dose of acetaminophen for healthy adults 3. Acetaminophen is metabolized mostly acetaminophen toxicity is is in the a. NAPQI. c. acetylcysteine. a. 1 gram. c. 4 grams. a. liver. c. stomach. b. glutathione. d. protamine sulfate. b. 2 grams. d. 8 grams. b. kidneys. d. duodenum. 9. Which statement is correct about 13. According to the AAPCC, how many 4. Right upper quadrant pain may first acetaminophen toxicity? acetaminophen tablets would an adult appear in which phase of acetaminophen a. Pregnancy is a contraindication to antidotal have to take within 8 hours to reach a toxicity? therapy. toxic dose? a. phase 1 c. phase 3 b. Acetaminophen crosses the placenta. a. 20 regular-strength c. 15 extra-strength b. phase 2 d. phase 4 c. Use the child guidelines for acetylcysteine if b. 30 regular-strength d. 20 extra-strength your patient is pregnant. 5. Phase 3 of acetaminophen toxicity d. Acetaminophen doesn’t cause liver toxicity in a 14. The loading dose for oral NAC in occurs pregnant woman’s fetus. acetaminophen toxicity is a. 4 to 12 hours after ingestion. a. 7 mg/kg. c. 70 mg/kg. b. 24 to 36 hours after ingestion. b. 14 mg/kg. d. 140 mg/kg. c. 72 to 96 hours after ingestion. d. 5 days to 2 weeks after ingestion.

£ £ ENROLLMENT FORM Nursing2007, January, Managing acute acetaminophen toxicity

A. Registration Information: K LPN K RN K CNS K NP K CRNA K CNM K other ______Last name ______First name ______MI _____ Job title ______Specialty ______Type of facility ______Are you cer tified? K Yes K No Address ______Certified by ______City ______State ______ZI P ______State of license (1) ______License # ______State of license (2) ______License # ______Telephone ______Fax ______E-mail ______K Please fax my certificate to me. Registration Deadline: January 31, 2009 K From time to time, we make our mailing list available to outside organizations to announce special offers. Contact hours: 2.0 Pharmacology hours: 0.0 Fee: $19.95 Please check here if you do not wish us to release your name and address.

B. Test Answers: Darken one circle for your answer to each question. a b cd a b cd a b cd a b cd 1. HHHH 5. HHHH 9. HHHH 13. HHHH 2. HHHH 6. HHHH 10. HHHH 14. HHHH 3. H H H H 7. H H H H 11. H H H H 4. H H H H 8. H H H H 12. H H H H

C. Course Evaluation* D. Two Easy Ways to Pay: 1. Did this CE activity's learning objectives relate to its general purpose? K Yes K No K Check or money order enclosed (Payable to Lippincott Williams & Wilkins) 2. Was the journal home study format an effective way to present the material? K Yes K No K Charge my K Mastercard K Visa K American Express 3. Was the content relevant to your nursing practice? K Yes K No Card # ______Exp. date ______4. How long did it take you to complete this CE activity?___ hours___minutes 5. Suggestion for future topics ______Signature ______

*In accordance with the Iowa Board of Nursing administrative rules governing grievances, a copy of your evaluation of the CE offering may be submitted directly to the Iowa Board of Nursing. N0207