Acetylcysteine for Acetaminophen Poisoning

The new england journal of medicine

clinical therapeutics

Kennon J. Heard, M.D.

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author’s clinical recommendations.

A 25-year-old man presents to the emergency department with a toothache. During the evaluation, the physician determines that the patient has been taking large doses of over-the-counter acetaminophen along with an acetaminophen–hydrocodone prod- uct for the past 5 days. His daily dose of acetaminophen has been 12 g per day (maxi- mum recommended dose, 4 g per day). He has no other medical problems and typi- cally consumes two beers a day. The patient has no symptoms beyond his toothache, is not icteric, and has no hepatomegaly or right-upper-quadrant tenderness. His serum acetaminophen concentration 8 hours after the most recent dose is undetectable. His serum alanine aminotransferase concentration is 75 IU per liter, his serum biliru- bin concentration is 1.2 mg per deciliter (20.5 μmol per liter), and his international normalized ratio (INR) is 1.1. The emergency department physician contacts the re- gional poison-control center, which recommends treatment with acetylcysteine.

The Clinical Problem

Acetaminophen (known as paracetamol outside the United States) is a commonly From Rocky Mountain Poison and Drug used analgesic and antipyretic agent, and its use is one of the most common causes Center, Denver Health, and the Universi- 1 ty of Colorado Denver School of Medi- of poisoning worldwide. According to poison centers in the United States, acet- cine — both in Denver. Address reprint aminophen poisoning was responsible for more than 70,000 visits to health care requests to Dr. Heard at the Rocky Moun- facilities and approximately 300 deaths in 2005.2 Acetaminophen poisoning can be tain Poison and Drug Center, Denver Health, 777 Bannock St., MS 0180, Denver, due to ingestion of a single overdose (usually as an attempt at self-harm) or inges- CO 80208, or at kennon.heard@rmpdc. tion of excessive repeated doses or too-frequent doses, with therapeutic intent. org. Repeated supratherapeutic ingestion is increasingly recognized as a significant 3,4 N Engl J Med 2008;359:285-92. clinical problem. Copyright © 2008 Massachusetts Medical Society. Regardless of whether it occurs as a result of a single overdose or after repeated supratherapeutic ingestion, the progression of acetaminophen poisoning can be categorized into four stages: preclinical toxic effects (a normal serum alanine aminotransferase concentration), hepatic injury (an elevated alanine amino transferase concentration), hepatic failure (hepatic injury with hepatic encephal- opathy5), and recovery. This categorization is useful because each stage has a different prognosis and is managed differently. Transient liver injury may develop in patients who are treated during the preclinical stage, but they recover fully.3,6 Patients who are not treated until hepatic injury has developed have a variable prognosis,3,4 and patients who present with hepatic failure have a mortality rate of 20 to 40%.4,7

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Pathophysiology and Effect Figure 1 (facing page). The Metabolism of Acetamino- of Therapy phen and the Synthesis of Glutathione. The primary pathways for acetaminophen metabolism When t aken in therapeutic doses, acet aminophen (Panel A) are glucuronidation and sulfation to nontoxic is safe. Studies in animals have shown that most metabolites. Approximately 5% of a therapeutic dose of a single dose (>90%) is metabolized by glucuroni- is metabolized by cytochrome P450 2E1 to the electro- dation or sulfation to nontoxic metabolites8 (Fig. phile N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is extremely toxic to the liver. Ordinarily, NAPQI is rap- 1A). Approximately 5% of a therapeutic dose is idly detoxified by interaction with glutathione to form metabolized by cytochrome P450 2E1 to the elec- cysteine and mercapturic acid conjugates. If glutathione trophile N-acetyl-p-benzoquinone imine (NAPQI).8 is depleted, NAPQI interacts with various macromole- NAPQI is extremely toxic to the liver, possibly as cules, leading to hepatocyte injury and death. Gluta a result of covalent binding to proteins and nucle- thione is synthesized from the amino acids cysteine, glutamate, and glycine by means of the pathway shown 9 ic acids. However, NAPQI is rapidly detoxified in Panel B. Glutamate and glycine are present in abun- by interaction with glutathione to form cysteine dance in hepatocytes; the availability of cysteine is the and mercapturic acid conjugates.10 As long as rate-limiting factor in glutathione synthesis. However, sufficient glutathione is present, the liver is pro- cysteine itself is not well absorbed after oral adminis- tected from injury. Overdoses of acetaminophen tration. Acetylcysteine, in contrast, is readily absorbed and rapidly enters cells, where it is hydrolyzed to cys (either a single large ingestion or repeated supra teine, thus providing the limiting substrate for glutathi- therapeutic ingestion) can deplete hepatic gluta- one synthesis. thione stores and allow liver injury to occur.11 Acetylcysteine (also known as N-acetylcysteine) prevents hepatic injury primarily by restoring dote for acetaminophen toxicity in 1974.20 Subse- hepatic glutathione (Fig. 1B).10 In addition, in pa- quently, several case series described good out- tients with acetaminophen-induced liver failure, comes for patients with acetaminophen overdose acetylcysteine improves hemodynamics and oxy- who were treated on the basis of the presence of gen use,12 increases clearance of indocyanine a toxic blood concentration with either intrave green (a measure of hepatic clearance),13 and nous21,22 or oral6,23-25 acetylcysteine. The largest decreases cerebral edema.14 The exact mechanism of these was a study involving 2540 patients and of these effects is not clear, but it may involve oral acetylcysteine.6 The study showed that aspar- scavenging of free radicals or changes in hepatic tate aminotransferase or alanine aminotransferase blood flow.12,15 concentrations rose to above 1000 IU per liter in 6.1% of patients who were treated within 10 hours Clinical Evidence after ingestion and in 26.4% of those treated between 10 and 24 hours after ingestion. This In the late 1960s, clinicians recognized that acute was a marked improvement as compared with the acetaminophen overdose caused a dose-related liver findings in historical controls, and this and injury and that without treatment many patients similar studies led to the widespread acceptance die.16 Studies in animals described the metabo- of acetylcysteine for the prevention of hepatic in- lism of acetaminophen to NAPQI and showed jury due to acetaminophen overdose. that as long as hepatic glutathione was present, Two small studies have evaluated the efficacy toxic effects could be prevented.10,17 Soon there of acetylcysteine in patients in whom acetamin- were reports that methionine18 and cysteamine19 ophen-induced hepatic failure had already devel- (two medications known to restore hepatic gluta- oped; both used the intravenous agent. In a retro- thione) could prevent acetaminophen-induced he- spective study involving 98 patients, treatment patic injury. Use of these agents resulted in dra- with acetylcysteine was associated with a 21% matic increases in survival, but the side effects reduction in mortality, as compared with stan- (flushing, vomiting, and “misery”18) associated dard therapy.26 This was followed by a random- with these therapies led researchers to seek alter- ized, placebo-controlled trial involving 50 patients native treatments. that showed a 28% reduction in mortality.14 Acetylcysteine was first suggested as an anti- Larger trials, or trials in other clinical settings,

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have not been performed. For example, there are supratherapeutic ingestion cannot be risk-strati- no systematic studies evaluating the usefulness fied with the Rumack–Matthew nomogram. My of acetylcysteine for patients who have hepatic colleagues and I at the Rocky Mountain Poison injury but not hepatic failure. Nonetheless, the and Drug Center recommend treating such pa- efficacy and apparent safety of this agent, as dem- tients with acetylcysteine if they have a supra onstrated in the two small studies,14,26 have led therapeutic serum acetaminophen concentration to widespread use of acetylcysteine therapy in (>20 μg per milliliter), even if their alanine amino almost all cases of acetaminophen-induced liver transferase concentration is normal. We also injury. A 2006 Cochrane review of the available recommend treatment for any patient with an data concluded that acetylcysteine “should be elevated alanine aminotransferase concentration given to patients with overdose” but acknowledged and a history of ingesting more than 4 g of acet- that the quality of the evidence is limited.27 aminophen per day. Such approaches are not standard in all centers. In addition, on the basis of data Clinical Use from two small clinical studies, acetylcysteine is generally recommended in patients with estab- The first studies of acetylcysteine therapy in- lished hepatic failure.11,14 volved patients who presented to a health care The choice of oral or intravenous administra- facility within 24 hours after a single acute ingestion depends on the clinical scenario; to my tion of acetaminophen and had a plasma concen- knowledge, no clinical trials comparing the two tration above the “study line” (also known as the routes in adults have been performed. Oral ad- “possible toxicity” line) on the Rumack–Matthew ministration is convenient for patients with pre- nomogram (Fig. 2).6,22,23,28 Patients who have a clinical toxic effects or hepatic injury, but in many timed serum acetaminophen concentration (i.e., as patients, vomiting or altered mental status may measured between 4 hours and 24 hours after preclude oral therapy. Patients who are treated for ingestion) that falls above the study line on this hepatic failure should receive intravenous therapy. nomogram are considered to be at risk for toxic The optimal route of administration for preg- effects, even if no clinical or laboratory evidence nant patients has been debated.29 In pregnancy, of hepatic injury is present. Most poison centers high hepatic extraction of the oral dose may mean in the United States would recommend treatment that very low concentrations of acetylcysteine for such patients. Several centers in the United are available to the fetus. Nevertheless, there is States and in many other countries recommend experience with the use of oral acetylcysteine treatment only for patients who have a serum con- after maternal acetaminophen overdose.30 Fur- centration that falls above the “probable toxicity” thermore, acetylcysteine concentrations in the line, which starts at 200 μg per milliliter 4 hours fetus are similar to maternal systemic concen- after ingestion. trations during oral treatment, suggesting that Patients for whom the time of ingestion is un- the fetus will have therapeutic levels.31 There are known cannot be risk-stratified with the use of no compelling clinical or pharmacokinetic data the Rumack–Matthew nomogram. For example, a to suggest that intravenous administration is bet- “therapeutic” serum concentration of 20 μg per ter than oral administration for pregnant patients. milliliter would fall above the threshold for treat- Acetylcysteine is in Food and Drug Administra- ment if the ingestion occurred more than 16 hours tion (FDA) pregnancy category B (meaning that before the concentration was measured. In such there are no data from adequate and well-con- cases, I believe that it is prudent to administer trolled studies of safety in this population, but acetylcysteine to any patient who may have taken studies in animals have not suggested any effect an overdose and who has a measurable acetamino- on the fetus). phen concentration until risk stratification can According to current FDA-approved protocols be performed (i.e., until the time of ingestion is for the treatment of acute acetaminophen inges- determined), until the patient meets the criteria tion, oral acetylcysteine is given as a loading for stopping, or until the course is completed. dose of 140 mg per kilogram of body weight, This approach, however, is not standard practice with maintenance doses of 70 mg per kilogram for all poison-control centers. that are repeated every 4 hours for a total of 17 Similarly, patients with a history of repeated doses.6 The intravenous loading dose is 150 mg

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Downloaded from www.nejm.org at UNIVERSITY OF KANSAS MEDICAL CENTER on July 21, 2008 . Copyright © 2008 Massachusetts Medical Society. All rights reserved. Clinical Therapeutics per kilogram over a period of 15 to 60 minutes, followed by an infusion of 12.5 mg per kilogram µmol/ µg/ liter ml per hour over a 4-hour period, and finally an in- 4000 500 fusion of 6.25 mg per kilogram per hour over a 3000 400 16-hour period.21 The dose does not require ad- 2000 300 justment for renal or hepatic impairment or for dialysis. 1300 200 Although these standard protocols are based 1000 150 on a prespecified duration of therapy, many toxi- 100 cologists believe that the defined oral course (72 500 hours) is often too long and that the defined in- 50 travenous course (20 hours) may be too short for patients in whom hepatic injury develops or for those who have ingested massive amounts of acetaminophen. Therefore, our poison center rec- 100 ommends that practitioners base the treatment Lower limit for

Plasma Acetaminophen Concentration high-risk group course on clinical end points. Many toxicologists 10 50 Lower limit for would recommend repeating the measurements probable-risk group of alanine aminotransferase and acetaminophen 30 5 Study nomogram line concentrations as the patient approaches the end 0 0 of the 16-hour infusion period and continuing 0 0 4 8 12 16 20 24 treatment if the alanine aminotransferase con- Hours after Acetaminophen Ingestion centration is elevated or if the acetaminophen concentration is measurable. Rechecking the Figure 2. The Rumack–Matthew Nomogram. The Rumack–Matthew nomogram, first published in RETAKE 1st alanine aminotransferase and serum acetamino- ICM AUTHOR: Heard 1975, was developed to estimate the likelihood of he2nd- phen concentrations is particularly important if REG F FIGURE: 2 of 2 patic injury due to acetaminophen toxicity for patients3rd the patient presents more than 8 hours after in- withCASE a single ingestion at a known time. To useRevised the no- EMail Line 4-C SIZE gestion, has an elevated alanine aminotransferase mogram, theARTIST: patient’sts plasma acetaminophen concen- H/T H/T 16p6 concentration at the time treatment is started, or trationEnon and the time interval Combosince ingestion are plotted. If the resulting point is above and to the right of the has a very high acetaminophen concentration AUTHOR, PLEASE NOTE: sloping Figureline, hepatichas been injury redrawn is andlikely type to hasresult been and reset. the (>300 μg per milliliter). use of acetylcysteinePlease is indicated. check carefully. If the point is below In general, patients are hospitalized in an and to the left of the line, hepatic injury is unlikely. Pa- acute care facility for acetylcysteine therapy. tientsJOB: 35703with repeated supratherapeutic ingestion,ISSUE: 07-17-08 or with However, outpatient therapy may be considered an unknown time of ingestion, cannot be evaluated for patients with a confirmed accidental, repeated with the use of the Rumack–Matthew nomogram. supratherapeutic ingestion, a supratherapeutic serum acetaminophen concentration (I use a thresh- meet criteria for outpatient treatment and can be old of <70 μg per milliliter), and no more than given their maintenance doses every 4 hours. low-grade elevation of the alanine aminotrans- Patients treated with oral acetylcysteine should ferase concentration (<3 times the upper limit of be monitored for vomiting, and the dose should the reference range for the laboratory). If the pa- be repeated if the patient vomits within 60 min- tient has no adverse effects associated with the utes after any dose.6 oral loading dose, he or she can be discharged Patients receiving intravenous acetylcysteine with three maintenance doses to be taken every for liver failure should be hospitalized in a criti- 4 hours. The patient should be reevaluated 12 cal care unit. Monitoring should include frequent hours after the loading dose, and treatment can blood-pressure measurements, measurement of be discontinued if the patient meets the criteria oxygen saturation by pulse oximetry, and close for stopping therapy (i.e., the alanine aminotrans- nursing observation for hypoglycemia and signs ferase concentration is decreasing, and the serum of infection. Liver and renal function should also acetaminophen concentration is undetectable). be monitored, but there is little use in obtaining Patients may be treated with oral acetylcysteine blood samples for testing more often than every on a psychiatric (i.e., nonmedical) ward if they 12 hours. Treatment is continued until the hepatic

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encephalopathy resolves and the alanine amino toms do not recur.37 Alternatively, patients with transferase and creatinine concentrations and severe symptoms who do not have liver failure INR have substantially improved or until the pa- can be treated with oral acetylcysteine. tient receives a liver transplant. The most severe adverse effects occur with Oral acetylcysteine is inexpensive; a full 18- erroneous dosing of intravenous acetylcysteine dose course will cost the pharmacy less than $50 in children. These effects include cerebral ede- (in 2005 U.S. dollars).32 However, this does not ma38,39 and hyponatremia (due to administration include the nursing required to ensure adminis- in 5% dextrose).40 There are rare reports of deaths tration or the costs of the antiemetic agents that due to anaphylactoid reactions.41,42 are often required. Intravenous acetylcysteine is also relatively inexpensive (approximately $470 for Areas of Uncertainty a full course32), but there are additional costs for preparation of the medications and intravenous The initial studies of intravenous administration administration. of acetylcysteine demonstrated the efficacy of a 20-hour regimen, whereas studies of oral admin- Adverse Effects istration evaluated a 72-hour regimen. This dis- crepancy has led to the question, “How long is Acetylcysteine has an unpleasant smell and taste, long enough?” Several reports have described trun- and vomiting is common with oral administra- cation of oral acetylcysteine therapy in some pa- tion. However, in a large study at a poison center, tients. One study reported good outcomes among only 5% of patients ultimately required intrave- patients who were treated with a 20-hour course nous therapy because they could not tolerate the that was started within 8 hours after ingestion oral agent.33 In adults, even very high doses of of acetaminophen.43 In three other studies (two oral acetylcysteine are not associated with severe retrospective and one prospective), patients were toxic effects.34 treated until the acetaminophen concentration was The most commonly reported adverse effects undetectable and the serum alanine aminotrans- of intravenous acetylcysteine are anaphylactoid ferase activity was normal. In these studies, most reactions, including rash, pruritus, angioedema, patients received at least 20 hours of therapy.44-46 bronchospasm, tachycardia, and hypotension. Kerr These studies suggest that patients who receive et al. reported that approximately 15% of pa- early treatment may be candidates for a shorter tients who were treated with intravenous ace course of therapy; however, the most appropriate tylcysteine had an anaphylactoid reaction within duration of therapy is not clear. 2 hours after the initial infusion and that increas- The clinical studies of acetylcysteine therapy ing the infusion time from 15 to 60 minutes did have evaluated either treatment of preclinical toxic not alter the rate of adverse events.35 Other com- effects (based on the Rumack–Matthew nomo- mon adverse effects included vomiting and flush- gram) or therapy in patients with established he- ing. However, administration of the drug was patic failure. As a result, explicit data for the discontinued in only 2% of patients because of an earlier stage of hepatic injury without hepatic adverse reaction. Retrospective studies identified failure are not available. We believe that patients adverse effects in approximately 5% of cases.33,36 who present with hepatic injury and detectable Recommendations for the treatment of adverse acetaminophen concentrations should be treated effects during acetylcysteine therapy have been at least until the acetaminophen has been elimi- proposed.37 According to these recommendations, nated. The role of treatment is less clear for pa- no treatment is necessary for flushing alone. Pa- tients who have no measurable acetaminophen tients with urticaria should be treated with diphen concentration but have hepatic injury without hydramine. Those with angioedema, hypoten- hepatic failure. Our poison center recommends sion, or respiratory symptoms (e.g., bronchospasm) treatment based on the evidence that acetylcys should be treated with diphenhydramine, cortico teine is effective early, for the prevention of he- steroids, and bronchodilators for bronchospasm. patic injury, as well as late, for treatment of The acetylcysteine infusion should be stopped, hepatic failure. Therefore, it seems logical that but it can be restarted at a slower rate 1 hour after patients with a presentation between these two the administration of diphenhydramine if symp- extremes would also benefit.

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Guidelines concentration and without liver injury. These patients will do well as long as they receive timely There are several guidelines describing the use of acetylcysteine therapy. Patients who present with acetylcysteine for acute acetaminophen poisoning. liver failure have a less favorable prognosis, but it The United Kingdom National Health Service is clear that acetylcysteine treatment improves guideline recommends treating patients who their chance of surviving. The best treatment for have acute acetaminophen overdose and a serum the patient who cannot be risk-stratified with the acetaminophen concentration above the probable- use of the Rumack–Matthew nomogram, or who toxicity line (the line that begins at 200 μg per has hepatic injury without hepatic failure, is less milliliter at 4 hours after ingestion) and high-risk well defined. (alcoholic or malnourished) patients who have a On the basis of the established benefit of serum concentration above a high-risk line that acetylcysteine therapy in other specific settings, begins at 100 μg per milliliter at 4 hours.47 The I favor treatment of the patient described in the American Academy of Pediatrics recommends vignette. I would choose oral therapy and ad- acetylcysteine therapy for acetaminophen poison- minister the loading dose of 140 mg per kilo- ing, but it does not suggest indications or support gram in the emergency department. Since the any treatment protocol.48 The American College patient does not appear to have intended to harm of Emergency Physicians recommends acetylcys himself and is clinically well, I would discharge teine therapy for any patient with acute acetamino- him from the emergency department with addi- phen ingestion and a timed serum concentration tional doses of 70 mg per kilogram to be taken above the line that begins at 150 μg per milliliter every 4 hours. I would recommend that he be seen at 4 hours, as well as for any patient with liver in the outpatient clinic 12 hours after discharge injury or liver failure.49 in order to obtain a repeat measurement of alanine aminotransferase activity; if it is clearly Recommendations decreasing, his therapy can be terminated before he completes a course of 17 doses. Although in many cases acute acetaminophen Dr. Heard reports receiving grant support from McNeil Con- poisoning is a straightforward problem, the vi- sumer Products, Cumberland Pharmaceuticals, and the National gnette illustrates a common situation for which Institute on Drug Abuse (training grant DA020573). No other there are no clear answers. Published protocols potential conflict of interest relevant to this article was reported. I thank the Medical Toxicology Fellows of the Rocky Mountain have focused on patients with acetaminophen poi- Poison and Drug Center and Dr. Richard Dart for their thought- soning who present with a toxic acetaminophen ful review and suggestions.

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Prescott LF, Illingworth RN, Critchley The Australasian Clinical Toxicology In- National Poisons Information Service JA, Stewart MJ, Adam RD, Proudfoot AT. vestigators Collaboration randomized 1998 (supplied to accident and emergency Intravenous N-acetylcystine: the treatment trial of different loading infusion rates of centres in the United Kingdom by the Par- of choice for paracetamol poisoning. BMJ N-acetylcysteine. Ann Emerg Med 2005; acetamol Information Centre in collabo- 1979;2:1097-100. 45:402-8. ration with the British Association for 23. Rumack BH, Peterson RC, Koch GG, 36. Kao LW, Kirk MA, Furbee RB, Mehta Accident and Emergency Medicine). Lon- Amara IA. Acetaminophen overdose: 662 NH, Skinner JR, Brizendine EJ. What is don: National Poisons Information Ser- cases with evaluation of oral acetylcysteine the rate of adverse events after oral N- vice, 1998. treatment. Arch Intern Med 1981;141:380-5. acetylcysteine administered by the intra- 48. American Academy of Pediatrics 24. Rumack BH. Acetaminophen over- venous route to patients with suspected Committee on Drugs. Acetaminophen dose in young children: treatment and ef- acetaminophen poisoning? Ann Emerg toxicity in children. Pediatrics 2001;108: fects of alcohol and other additional in- Med 2003;42:741-50. 1020-4. gestants in 417 cases. Am J Dis Child 37. Bailey B, McGuigan MA. Management 49. Wolf SJ, Heard K, Sloan EP, Jagoda AS. 1984;138:428-33. of anaphylactoid reactions to intravenous Clinical policy: critical issues in the man- 25. Rumack BH, Peterson RG. Acetamin- N-acetylcysteine. Ann Emerg Med 1998; agement of patients presenting to the ophen overdose: incidence, diagnosis, 31:710-5. emergency department with acetamino- and management in 416 patients. Pediat- 38. Bailey B, Blais R, Letarte A. Status epi- phen overdose. Ann Emerg Med 2007; rics 1978;62:898-903. lepticus after a massive intravenous N-ace- 50:292-313. 26. Harrison PM, Keays R, Bray GP, Alex- tylcysteine overdose leading to intracranial Copyright © 2008 Massachusetts Medical Society. ander GJ, Williams R. Improved outcome hypertension and death. Ann Emerg Med of paracetamol-induced fulminant hepat- 2004;44:401-6.

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