1 Acetylcysteine (N-acetylcysteine) - Adult/Pediatric - Inpatient/Emergency Department Clinical Practice Guideline Note: Active Table of Contents – Click each header below to jump to the section of interest Table of Contents INTRODUCTION ............................................................................................................. 3 SCOPE ........................................................................................................................... 3 DEFINITIONS ................................................................................................................. 3 RECOMMENDATIONS ................................................................................................... 5 TABLE 1. N-ACETYLCYSTEINE DOSING FOR CONFIRMED ACETAMINOPHEN OVERDOSE, NAI-ALF, OR AILFA .................................................................................. 8 METHODOLOGY .......................................................................................................... 10 COLLATERAL TOOLS & RESOURCES ...................................................................... 12 REFERENCES .............................................................................................................. 13 Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 2 Content Expert and Contact for Changes: Philip J. Trapskin, PharmD, BCPS Phone Number: 608-263-1328 Email Address: PTrapskin@uwhealth.org Original Guideline Authors: Timothy Hinkley, PharmD Joshua Vanderloo, PharmD, BCPS Revision Guideline Authors: Cynthia Wong, PharmD Carin Bouchard, PharmD, BCPS Joshua Vanderloo, PharmD, BCPS Reviewers: Joshua Glazer, MD – Emergency Department Nicholas Kuehnel, MD – Emergency Department Michael Lucy, MD – Gastroenterology David Yang, MD – Medical Director, UW Health Clinical Laboratories Carin Bouchard, PharmD, BCPS – Pharmacy Jeff Fish, PharmD, BCCCP – Pharmacy Joe Halfpap, PharmD, BCPS – Pharmacy Committee Approvals: Pharmacy & Therapeutics Committee: July 2019 Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 3 Introduction Acetylcysteine (N-Acetylcysteine or N-Ac) is a derivative of cysteine. It has mucolytic activity that is exerted through physical disruption of chemical bonds in mucous that results in decreased mucous viscosity. N-acetylcysteine also acts as an antidote to acetaminophen toxicity by enhancing glutathione stores, providing a glutathione substitute, and enhancing disposition by nontoxic sulfate conjugation. N-acetylcysteine has also been implicated in free radical scavenging antioxidant activity and subsequent cytoprotection.1 These mechanisms of action have led to FDA-labeled indications for N-Acetylcysteine as an acetaminophen overdose antidote and as a mucolytic agent.1 The diverse mechanisms of action demonstrated by N-acetylcysteine, particularly its antioxidant effects, have resulted in substantive off-label use of this agent for numerous clinical health states. There is evidence to support N-acetylcysteine use for non-acetaminophen-induced acute liver failure (NAI-ALF), alcohol-induced liver failure (AILF), and radiographic contrast agent nephropathy prophylaxis. Additional off-label uses with insufficient evidence to support N-acetylcysteine use includes prophylaxis of acute renal failure in patients with chronic renal insufficiency undergoing cardiac surgery; acute respiratory distress syndrome; administration of anesthesia for procedures; bezoar; blepharitis; cancer; cystinosis; treatment and prophylaxis of cytotoxicity; drug allergies; drug tolerance to nitrates; prophylaxis of hemorrhagic cystitis; hepatic ischemia-reperfusion injury2; hepatorenal syndrome; HIV infection; lamellar ichthyosis; malaria; meconium ileus; prophylaxis of multiple organ failure; mucolysis associated with occlusion of the ureter; otitis media; respiratory tract infection; Sjogren’s syndrome; and Unverricht-Lundborg syndrome. Scope Intended Users: Physicians, advanced practice providers, pharmacists, and nurses. Objective: To guide the use of N-acetylcysteine for appropriate indications and dosing. Target Population: - Adult and pediatric patients with acetaminophen overdose - Adult and pediatric patients with non-acetaminophen-induced acute liver failure (NAI- ALF) - Adult patients with alcohol-induced liver failure (AILF) - Adult and pediatric patients at risk for contrast induced nephropathy (CIN) Clinical Questions Considered: 1. What are the indications to support N-acetylcysteine use? 2. What are the dosing regimens of N-acetylcysteine for its indicated disease states? Definitions • AILF: Alcohol-induced liver failure o also referred to as alcoholic hepatitis3 • CIN: contrast induced nephropathy • LFT: liver function test o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) o Alkaline phosphatase o Bilirubin • N-acetylcysteine: N-Ac or acetylcysteine • NAI-ALF: Non-acetaminophen-induced acute liver failure4,5 o includes liver failure etiologies of hepatitis B; other non-acetaminophen, drug-induced hepatotoxicity; and autoimmune hepatitis o excludes alcohol-induced liver failure Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 4 • Rumack-Matthew Nomogram (Figure 1); used for interpretation of acetaminophen concentrations in association with potential acetaminophen overdose6,7 Figure 1. Rumack-Matthew Nomogram Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 5 Recommendations 1. General dosing recommendations 1.1. It is reasonable to use enteral N-acetylcysteine regimens preferentially over intravenous regimens, unless a patient is unable to tolerate an enteral regimen, as the enteral regimen is equally efficacious and less expensive.8-11 (UW Health Conditional Recommendation, Moderate Quality of Evidence) 1.1.1. Enteral N-acetylcysteine provides favorable absorption, delivering antidote directly to the liver1,8 1.1.2. Inability to tolerate enteral therapy may include nausea or vomiting despite antiemetic therapy, receiving gastrointestinal decontamination, suspected or confirmed gastrointestinal bleed, possible obstruction, or surgical conditions that preclude enteral administration. 1.2. For the management of acetaminophen overdose, N-acetylcysteine should be dosed on actual weight up to a maximum of 100 kg for IV administration1 (UW Health Strong Recommendation, High Quality of Evidence) and it is reasonable to dose up to a maximum of 110 kg for enteral administration. (UW Health Conditional Recommendation, Low Quality of Evidence) 1.3. For other indications, it is reasonable to dose on actual weight up to a maximum of 100 kg for IV administration and up to a maximum of 110 kg for enteral administration. (UW Health Conditional Recommendation, Very Low Quality of Evidence) 2. Confirmed acetaminophen ingestion/overdose management1,12 2.1. N-acetylcysteine should be used in the management of acetaminophen overdose for adults and pediatrics. (UW Health Strong Recommendation, High Quality of Evidence) 2.2. In patients with confirmed acetaminophen overdose, no further acetaminophen should be ordered upon admission. (UW Health Strong Recommendation, Moderate Quality of Evidence) 2.3. An acetaminophen concentration should be obtained four hours or greater after acetaminophen overdose ingestion. This acetaminophen concentration should be interpreted according to the Rumack-Matthew nomogram (See Figure 1). If the measured acetaminophen concentration falls on or above the solid line (the FDA 25% safety line), then the concentration is considered toxic and N-acetylcysteine treatment is warranted.7 (UW Health Strong Recommendation, High Quality of Evidence) 2.3.1. Administration should be initiated within 8 hours of ingestion or as soon as possible after ingestion. (UW Health Strong Recommendation, High Quality of Evidence) 2.3.2. If ingestion time is unknown or there have been multiple acetaminophen ingestions, N-acetylcysteine should be administered if there is any evidence to suggest significant acetaminophen overdose and detectable acetaminophen levels or any degree of transaminitis. (UW Health Strong Recommendation, Low Quality of Evidence) 2.3.3. The Rumack-Matthew nomogram should not be applied to patients with evidence of hepatotoxicity, multiple acetaminophen ingestions (i.e. not a single ingestion event), or patients with an uncertain time of acetaminophen ingestion. (UW Health Strong Recommendation, High Quality of Evidence) 2.4. See Table 1 for dosing recommendations. 2.4.1. Enteral N-acetylcysteine dosing is 140 mg/kg load, followed by 70 mg/kg every four hours for 17 doses.1,8 (UW Health Strong Recommendation, High Quality of Evidence) 2.4.1.1. If the patient vomits within one hour of administration, consider readministering dose.1 (UW Health Strong Recommendation, Low Quality of Evidence) 2.4.1.2. To improve palatability, may put N-acetylcysteine over ice1 or dilute N- acetylcysteine with water or soft drink.13 (UW Health Strong Recommendation, Very Low Quality of Evidence) Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 6 2.4.2. IV N-acetylcysteine dosing is 150 mg/kg load over one hour, followed by a continuous infusion at 12.5 mg/kg/hr for 20 hours or more.8,14 (UW Health Conditional Recommendation, Low Quality of Evidence) 2.4.2.1. Multiple dosing regimens for IV N-acetylcysteine have been evaluated, but the above recommendation from the Wisconsin Poison Center (WPC) has been adopted as it decreases adverse effects and medication errors,8,15-23 while maintaining clinical efficacy in managing acetaminophen toxicity in comparison to other dosing schemes.14 2.5. The enteral route is as effective as intravenous.9,10 Enteral route provides favorable absorption, higher cumulative dosing leading to higher levels in the liver, and less expense.1,8 Therefore, enteral administration is preferable as it is less invasive and has a lower potential for anaphylaxis than does the intravenous regimen. (UW Health Strong Recommendation, High Quality of Evidence) 2.5.1. Shorter courses of enteral N-acetylcysteine lasting at least 20 hours may be considered in the setting repeat acetaminophen concentrations below 10 mcg/mL and no increase in ALT/AST or INR.24-27 (UW Health Conditional Recommendation, Moderate Quality of Evidence) 2.6. Therapy duration should be guided by patient condition, resolution of transaminase elevation, and completion of acetaminophen metabolism.28 (UW Health Conditional Recommendation, Moderate Quality of Evidence) 2.7. Patients should have serial acetaminophen levels and LFTs measured before completion of N-acetylcysteine.29 (UW Health Conditional Recommendation, Moderate Quality of Evidence) 2.7.1. The first repeat acetaminophen concentration should be drawn four to six hours after the baseline.12 (UW Health Conditional Recommendation, Low Quality of Evidence) 2.8. Periodic acetaminophen concentrations should be drawn while N-acetylcysteine is being continued with a goal of decreasing the acetaminophen concentration below 10 mcg/mL. (UW Health Conditional Recommendation, Very Low Quality of Evidence) 2.9. N-acetylcysteine should be continued if acetaminophen levels remain greater than 10 mcg/mL or if the aminotransferases (AST, ALT) remain elevated.29,30 (UW Health Conditional Recommendation, High Quality of Evidence) 2.9.1. Maintenance treatment courses may be extended beyond 17 doses or 20 hours for enteral or intravenous N-acetylcysteine therapy, respectively, if clinically warranted, especially in patients with liver injury.31 (UW Health Conditional Recommendation, Moderate Quality of Evidence) 2.9.2. Patient status should be reevaluated 12 hours after initiation of continuation of N- acetylcysteine.29 (UW Health Conditional Recommendation, High Quality of Evidence) 2.9.3. With extended courses of N-acetylcysteine, therapeutic endpoints to monitor include INR normalization, encephalopathy resolution, and decreasing AST (to a level at least below 1000 units/L).28 (UW Health Conditional Recommendation, Moderate Quality of Evidence) 2.10. N-acetylcysteine treatment discontinuation may be considered when a single acetaminophen concentration is below 10 mcg/mL and AST has decreased to fewer than 1000 units/L or may be discontinued at the discretion of the provider.12,26 (UW Health Conditional Recommendation, Low Quality of Evidence) 2.10.1. Drawing no further acetaminophen concentrations beyond thirty-six hours may be reasonable.12,26 (UW Health Conditional Recommendation, Moderate Quality of Evidence) 2.10.2. ALT and total bilirubin, if elevated in the setting of acetaminophen overdose, will resolve more slowly in comparison to AST. 2.10.3. INR may be considered to evaluate liver injury. (UW Health Conditional Recommendation, Very Low Quality of Evidence) Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 7 3. Non-acetaminophen-induced acute liver failure (NAI-ALF) management 3.1. N-acetylcysteine use is reasonable for use in adults for NAI-ALF management.5,32-34 (UW Health Conditional Recommendation, Moderate Quality of Evidence) 3.2. N-acetylcysteine use may be considered in pediatric patients for NAI-ALF management.33,35,36 (UW Health Conditional Recommendation, Low Quality of Evidence) 3.3. See Table 1 for dosing recommendations.5,37 3.3.1. Enteral N-acetylcysteine dosing is 140 mg/kg load, followed by 70 mg/kg every four hours for 17 doses. (UW Health Conditional Recommendation, Moderate Quality of Evidence) 3.3.2. IV N-acetylcysteine dosing is 150 mg/kg load over one hour, followed by 12.5 mg/kg/hr for four hours, then 6.25 mg/kg/hr for 67 hours. (UW Health Conditional Recommendation, Moderate Quality of Evidence) 3.4. N-acetylcysteine treatment discontinuation may be considered if AST has fallen below the threshold of five times the upper limit of normal or may be discontinued at the discretion of the provider. (UW Health Conditional Recommendation, Very Low Quality of Evidence) 4. Alcohol-induced liver failure (AILF) management38-40 4.1. N-acetylcysteine may be reasonable for alcohol-induced liver failure management. (intravenous: UW Health Conditional Recommendation, Moderate Quality of Evidence; enteral: UW Health Conditional Recommendation, Very Low Quality of Evidence) 4.1.1. Data supporting the use of IV N-acetylcysteine for AILF is not robust, but may provide some benefit when combined with corticosteroids.38 4.1.2. N-acetylcysteine in addition to adequate enteral nutritional support40 or antioxidant demonstrated no survival benefit.41 4.1.3. Increased risk of infection may be associated with N-acetylcysteine use alone; however, the combination of N-acetylcysteine and corticosteroids may be associated with decreased risk of infection.39 4.2. See Table 1 for dosing recommendations. 4.2.1. Enteral N-acetylcysteine dosing is 140 mg/kg load, followed by 70 mg/kg every four hours for 17 doses. (UW Health Conditional Recommendation, Very Low Quality of Evidence) 4.2.2. IV N-acetylcysteine dosing is 150 mg/kg load over one hour, followed by 12.5 mg/kg/hr for four hours, then 6.25 mg/kg/hr for 16 hours on day 1. On days 2-5, IV dosing is 4.17 mg/kg/hr. (UW Health Conditional Recommendation, Moderate Quality of Evidence) 4.3. N-acetylcysteine discontinuation may be considered at the discretion of the provider or if there is no improvement of total bilirubin at day seven of treatment. (UW Health Conditional Recommendation, Very Low Quality of Evidence) 5. Therapeutic use as a mucolytic1 5.1. N-acetylcysteine is recommended as a mucolytic agent. (UW Health Strong Recommendation, High Quality of Evidence) 5.2. Nebulize via face mask, mouth piece or into a tracheostomy. 5.3. Use 1 to 10 mL of 20% N-acetylcysteine solution every two to six hours. Frequency and volume of medication administration will vary within this range depending on health condition or surgical procedure necessitating mucolytic therapy. Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 8 Table 1. N-acetylcysteine dosing for confirmed acetaminophen overdose, NAI-ALF, or AILFA Adult Pediatric Confirmed acetaminophen ingestion or overdose Enteral Loading DoseB 140 mg/kg 140 mg/kg Enteral Maintenance DoseB Following loading dose, 70 mg/kg every 4 hours for 17 doses Following loading dose, 70 mg/kg every 4 hours for 17 doses Intravenous Loading DoseC 150 mg/kg over 60 minutes 150 mg/kg over 60 minutes Intravenous Maintenance DoseC 12.5 mg/kg/hr for 20 hours or more 12.5 mg/kg/hr for 20 hours or more Adult NAI-ALF Enteral Loading DoseB 140 mg/kg Enteral Maintenance DoseB Following loading dose, 70 mg/kg every 4 hours for 17 doses Intravenous Loading DoseC 150 mg/kg over 60 minutes Intravenous Maintenance DoseC 12.5 mg/kg/hr for 4 hours, then 6.25 mg/kg/hr for 67 hours Adult AILF Enteral Loading DoseB 140 mg/kg Enteral Maintenance DoseB Following loading dose, 70 mg/kg every 4 hours for 17 doses Intravenous Loading DoseC 150 mg/kg over 60 minutes Intravenous Maintenance DoseC 1) Day 1: 12.5 mg/kg/hr for 4 hours, then 6.25 mg/kg/hr for 16 hours 2) Days 2-5: 4.17 mg/kg/hr for 4 days A See text for specific recommendations regarding enteral and parenteral administration; enteral is acceptable for any patient who may tolerate it B Use actual body weight up to a maximum of 110 kg C Use actual body weight up to a maximum of 100 kg Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 9 Disclaimer Clinical practice guidelines assist clinicians by providing a framework for the evaluation and treatment of patients. This guideline outlines the preferred approach for most patients. It is not intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely establish the only appropriate approach to a problem. Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 10 Methodology Development Process Each guideline is reviewed and updated a minimum of every 3 years. All guidelines are developed using the guiding principles, standard processes, and styling outlined in the UW Health Clinical Practice Guideline Resource Guide. This includes expectations for workgroup composition and recruitment strategies, disclosure and management of conflict of interest for participating workgroup members, literature review techniques, evidence grading resources, required approval bodies, and suggestions for communication and implementation. Methods Used to Collect the Evidence/Select the Evidence: The following criteria were used by the guideline authors and workgroup members to conduct electronic database searches in the collection of evidence for review. Literature Sources: • Electronic database search (e.g., PubMed) • Databases of systematic reviews (e.g., Cochrane Library) • Hand-searching journals, external guidelines, and conference publications Time Period: 2015 to 2018 Search Terms: • N-acetylcysteine • Acetaminophen overdose • Non-acetaminophen acute liver failure • Alcohol induced liver failure • Monitoring For the first version of this guideline and subsequent 2018 revision, an extensive evidence review was performed through August 2018. Searches were extended to studies, reviews, and other evidence that were conducted in human subjects, published in English, and accessible via PubMed, EMBASE, Cochrane, Agency for Healthcare Research and Quality Reports, and other selected databases relevant to this guideline. Search terms included n-acetylcysteine and treatment, acetaminophen overdose, non- acetaminophen acute liver failure, alcohol-induced liver failure, monitoring, administration, and dosing. References from the articles were also searched. The 2018 revision evaluated new clinical evidence published between 2015 and 2018. Methods Used to Formulate the Recommendations: The workgroup members created recommendations internally via a consensus process using discussion of the literature and expert experience/opinion. If issues or controversies arose where consensus could not be reached, the topic was escalated appropriately per the guiding principles outlined in the UW Health Clinical Practice Guideline Resource Guide. Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations: Internally developed recommendations, or those adopted from external sources without an assigned evidence grade, were evaluated by the guideline workgroup using an algorithm adapted from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (see Figure 2). Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 11 Figure 2. GRADE Methodology adapted by UW Health Rating Scheme for the Strength of the Evidence/Recommendations: GRADE Ranking of Evidence High We are confident that the effect in the study reflects the actual effect. Moderate We are quite confident that the effect in the study is close to the true effect, but it is also possible it is substantially different. Low The true effect may differ significantly from the estimate. Very Low The true effect is likely to be substantially different from the estimated effect. GRADE Ratings for Recommendations For or Against Practice Strong The net benefit of the treatment is clear, patient values and circumstances are unlikely to affect the decision. Conditional Recommendation may be conditional upon patient values and preferences, the resources available, or the setting in which the intervention will be implemented. Recognition of Potential Health Care Disparities: No health care disparities identified. Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 12 Collateral Tools & Resources The following collateral tools and resources support staff execution and performance of the evidence- based guideline recommendations in everyday clinical practice. Metrics Successful management of patients treated with n-acetylcysteine include achievement of undetectable acetaminophen levels, normalization of liver function tests, and incidence of acute liver failure and subsequent transplant. Order Sets & Smart Sets ED/IP – Acetylcysteine Administration – Adult – Supplemental Order Set [3528] Clinical Practice Guidelines UW Health Prevention of Contrast Induced Nephropathy – Adult – Inpatient/Ambulatory – Clinical Practice Guideline Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 13 References 1. Acetylcysteine. In: Lexicomp Online. Hudson, OH: Lexicomp, Inc.; [Updated June 26, 2018; Accessed September 4, 2018]. https://online.lexi.com/lco/action/doc/retrieve/docid/uofwisconsin_f/3680102. 2. Jegatheeswaran S, Siriwardena AK. Experimental and clinical evidence for modification of hepatic ischaemia-reperfusion injury by N-acetylcysteine during major liver surgery. HPB (Oxford). Feb 2011;13(2):71-78. 3. Bass S, Zook N. Intravenous acetylcysteine for indications other than acetaminophen overdose. Am J Health Syst Pharm. Sep 1 2013;70(17):1496-1501. 4. Riordan SM WR. Management of non-acetaminophen-induced ALF. Nat Rev Gastroentero. 2010;7:75-77. 5. Lee WM HL, Rassaro L, et al. Intravenous N-Acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009;137:856-864. 6. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. Jun 1975;55(6):871-876. 7. Wolf SJ, Heard K, Sloan EP, Jagoda AS. Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose. Annals of emergency medicine. Sep 2007;50(3):292-313. 8. Stanton M, Kostic M, Theobald J, Zosel A, Gummin D. Wisconsin Poison Center Intravenous N- acetylcysteine Dosing Recommendations in Acetaminophen Toxicity. Journal of the Pharmacy Society of Wisconsin. 2018(May/June):47-49. 9. Buckley NA, Whyte IM, O'Connell DL, Dawson AH. Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning? Journal of toxicology. Clinical toxicology. 1999;37(6):759-767. 10. Prescott L. Oral or intravenous N-acetylcysteine for acetaminophen poisoning? Annals of emergency medicine. Apr 2005;45(4):409-413. 11. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). The New England journal of medicine. Dec 15 1988;319(24):1557-1562. 12. Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Critical care clinics. Oct 2012;28(4):499- 516. 13. Crouch BI, Caravati EM, Dandoy C. Effect of dilution with beverages on the smell and taste of oral acetylcysteine. Am J Health Syst Pharm. Sep 15 2007;64(18):1965-1968. 14. Chiew AL, Isbister GK, Kirby KA, Page CB, Chan BSH, Buckley NA. Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clinical toxicology (Philadelphia, Pa.). Dec 2017;55(10):1055-1065. 15. Bateman DN, Dear JW, Thomas SH. New regimens for intravenous acetylcysteine, where are we now? Clinical toxicology (Philadelphia, Pa.). 2016;54(2):75-78. 16. Waring WS. Novel acetylcysteine regimens for treatment of paracetamol overdose. Ther Adv Drug Saf. Dec 2012;3(6):305-315. 17. McNulty R, Lim JME, Chandru P, Gunja N. Fewer adverse effects with a modified two-bag acetylcysteine protocol in paracetamol overdose. Clinical toxicology (Philadelphia, Pa.). Jul 2018;56(7):618-621. 18. Isbister GK, Downes MA, McNamara K, Berling I, Whyte IM, Page CB. A prospective observational study of a novel 2-phase infusion protocol for the administration of acetylcysteine in paracetamol poisoning. Clinical toxicology (Philadelphia, Pa.). 2016;54(2):120-126. 19. Wong A, Graudins A. Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions. Clinical toxicology (Philadelphia, Pa.). 2016;54(2):115-119. 20. Oakley E, Robinson J, Deasy C. Using 0.45% saline solution and a modified dosing regimen for infusing N- acetylcysteine in children with paracetamol poisoning. Emerg Med Australas. Feb 2011;23(1):63-67. 21. Pauley KA, Sandritter TL, Lowry JA, Algren DA. Evaluation of an Alternative Intravenous N-Acetylcysteine Regimen in Pediatric Patients. J Pediatr Pharmacol Ther. May-Jun 2015;20(3):178-185. 22. Johnson MT, McCammon CA, Mullins ME, Halcomb SE. Evaluation of a simplified N-acetylcysteine dosing regimen for the treatment of acetaminophen toxicity. Ann Pharmacother. Jun 2011;45(6):713-720. 23. Chiew AL, Gluud C, Brok J, Buckley NA. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. Feb 23 2018;2:CD003328. 24. Betten DP, Cantrell FL, Thomas SC, Williams SR, Clark RF. A prospective evaluation of shortened course oral N-acetylcysteine for the treatment of acute acetaminophen poisoning. Annals of emergency medicine. Sep 2007;50(3):272-279. 25. Betten DP, Burner EE, Thomas SC, Tomaszewski C, Clark RF. A retrospective evaluation of shortened- duration oral N-acetylcysteine for the treatment of acetaminophen poisoning. Journal of medical toxicology : official journal of the American College of Medical Toxicology. Dec 2009;5(4):183-190. 26. Woo OF, Mueller PD, Olson KR, Anderson IB, Kim SY. Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose. Annals of emergency medicine. Apr 2000;35(4):363-368. Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. 14 27. Yip L, Dart RC. A 20-hour treatment for acute acetaminophen overdose. The New England journal of medicine. Jun 12 2003;348(24):2471-2472. 28. Mottram A, Kumar A. "Focus On: Acetaminophen Toxicity and Treatment". American College of Emergency Physicians. May 2007. https://www.acep.org/Clinical---Practice-Management/Focus-On--Acetaminophen- Toxicity-and-Treatment/. Accessed 10/18/16. 29. Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. J Clin Transl Hepatol. Jun 28 2016;4(2):131-142. 30. Janssen J, Singh-Saluja S. How much did you take? Reviewing acetaminophen toxicity. Can Fam Physician. Apr 2015;61(4):347-349. 31. Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ (Clinical research ed.). Oct 26 1991;303(6809):1026-1029. 32. Mumtaz K, Azam Z, Hamid S, et al. Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center without the facility of liver transplantation. Hepatol Int. Dec 2009;3(4):563-570. 33. Hu J, Zhang Q, Ren X, Sun Z, Quan Q. Efficacy and safety of acetylcysteine in "non-acetaminophen" acute liver failure: A meta-analysis of prospective clinical trials. Clin Res Hepatol Gastroenterol. Oct 2015;39(5):594-599. 34. Darweesh SK, Ibrahim MF, El-Tahawy MA. Effect of N-Acetylcysteine on Mortality and Liver Transplantation Rate in Non-Acetaminophen-Induced Acute Liver Failure: A Multicenter Study. Clin Drug Investig. May 2017;37(5):473-482. 35. Squires RH, Dhawan A, Alonso E, et al. Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial. Hepatology (Baltimore, Md.). Apr 2013;57(4):1542-1549. 36. Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-Vergani G, Dhawan A. Safety and efficacy of N- acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Jan 2008;14(1):25-30. 37. Nabi T, Nabi S, Rafiq N, Shah A. Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: A prospective study. Saudi J Gastroenterol. May-Jun 2017;23(3):169-175. 38. Nguyen-Khac E TT, Piquet MA, et al. Treatment of severe acute alcoholic hepatitis (AAH) with corticoids plus n-acetylcysteine (C+NAC) versus corticoids alone (C): a multicentre, randomized, controlled trial. Hepatology (Baltimore, Md.). 2009;50(4 Suppl):346-347. 39. Singh S, Murad MH, Chandar AK, et al. Comparative Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis. Gastroenterology. Oct 2015;149(4):958-970 e912. 40. Moreno C, Langlet P, Hittelet A, et al. Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial. J Hepatol. Dec 2010;53(6):1117- 1122. 41. Stewart S, Prince M, Bassendine M, et al. A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. J Hepatol. Aug 2007;47(2):277-283. Copyright © 2019 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2019CCKM@uwhealth.org Effective date 7/29/2019. Contact CCKM@uwhealth.org for previous versions. Introduction Scope Definitions Recommendations Methodology Collateral Tools & Resources References