Can a simplified 2-bag acetylcysteine approach improve tolerability in acetaminophen overdoses?
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Update: Can a simplified 2-bag acetylcysteine approach improve tolerability in acetaminophen overdoses?
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Introduction
N-acetylcysteine (NAC) is an important antidote for acetaminophen overdoses and when administered early it can prevent acetaminophen-induced hepatotoxicity.1 N-acetylcysteine is indicated in patients at risk for hepatotoxicity which is determined by use of the Rumack-Matthew nomogram. For acute overdoses, NAC is initiated if the initial acetaminophen serum concentration is above the treatment line of the nomogram. While NAC has been utilized since the 1970s and many different dosing and administration regimens have been studied, the current Food and Drug Administration-approved regimen for intravenous NAC involves a 3-bag regimen (150 mg/kg over 1 hour, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours).1,2
Rationale for simplified regimen
The current intravenous NAC regimen is complex and has been associated with a high rate of medical errors.1 A 2008 retrospective evaluation of intravenous NAC cases in a regional poison center revealed that medical errors occurred in 33% of patients.3 Furthermore, a prospective analysis of NAC infusion bags prepared for acetaminophen overdoses revealed a large variation between the anticipated dose and the actual dose given.4 The authors reported a systematic calculation error in 5% of cases and inadequate preparation of the NAC infusion bag in 12% of cases.
Additionally, NAC is associated with adverse reactions including nausea, vomiting, and systemic hypersensitivity reactions.5 Hypersensitivity reactions are mediated through a non-immunoglobulin-E pathway leading to an anaphylactic reaction characterized by rash, flushing, tachycardia, bronchospasm, hypotension, and angioedema. The majority of adverse reactions occurs within the first hour of NAC administration and appears to correspond to peak NAC concentrations. Therefore, many investigators have hypothesized that a lower dose or a slower initial infusion rate could reduce adverse reactions associated with NAC.
Evidence
Three recent studies have evaluated whether adverse reactions associated with NAC administration can be reduced with a simplified, 2-bag dosing approach.6-8 All 3 studies evaluated the incidence of NAC-related adverse reactions in patients who were admitted to the emergency department with an acetaminophen overdose and received an abbreviated NAC dosing regimen. Each of the regimens utilizes a slower initial infusion rate. The Table summarizes the study design characteristics and NAC regimens used in these studies.
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| Table. Design characteristics of studies evaluating an abbreviated NAC dosing regimen.6-8 | |||
|---|---|---|---|
| Study | Population | Abbreviated NAC protocol | Control group |
| Isbister 20166 | All patients presenting to 2 EDs who ingested >4 g of APAP initiated prior to receiving APAP serum concentration levels | First infusion: 200 mg/kg in 500 mL D5W over a variable durationa Second infusion: 100 mg/kg in 1000 mL D5W over 16 h | None |
| Wong 20167 | All patients presenting to 3 EDs with an APAP overdose requiring treatment with NAC as determined by the treating physician | First infusion: 200 mg/kg in 500 mL NS over 4 h Second infusion: 100 mg/kg in 1000 mL NS over 16 h | Historical control: First infusion: 150 mg/kg in 200 mL NS over 1 h Second infusion: 50 mg/kg in 500 mL NS over 4 h Third infusion: 100 mg/kg in 1000 mL NS over 16 h |
| Bateman 20148 | All patients presenting to 2 EDs with an APAP overdose requiring NAC on the basis of their APAP serum concentration | First infusion: 100 mg/kg in 200 mL D5W over 2 h Second infusion: 200 mg/kg in 1000 mL D5W over 10 h Third infusionb: 500 mL of D5W continued until 20-25 h after initiation of the protocol | Prospective, parallel control: First infusion: 150 mg/kg in 200 mL D5W over 15 min Second infusion: 50 mg/kg in 500 mL D5W over 4 h Third infusion: 100 mg/kg in 1000 mL D5W over 16 h |
| aDuration of the first infusion was determined based on time of overdose: 11 hours minus time since ingestion (eg, a patient presenting at 3 h post-ingestion would receive a 8 h infusion). Exceptions included: all patients presenting within 2 hours of ingestion received a 9 hour infusion; all patients presenting after 7 hours of ingestion, those who had poisoning associated with staggered, repeated supratherapeutic ingestions, or those who had an unknown ingestion time received a 4 hour infusion. bThird infusion was utilized to protect the blind in the experiment, but is not considered part of the abbreviated protocol. Abbreviations: APAP=acetaminophen; D5W=5% dextrose in water; ED=emergency department; NAC=N-acetylcysteine; NS=normal saline. |
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Isbister and colleagues conducted a prospective, observational study to measure the proportion of patients who developed gastrointestinal symptoms or systemic hypersensitivity reactions with the introduction of their abbreviated protocol.6 The protocol for this study differed substantially from current clinical practice as NAC was initiated immediately on presentation and terminated if it was later determined that the patient had a low-risk acetaminophen serum concentration (1000 Unit/L) was observed in 16 patients; all of those patients presented ≥11 hours after ingestion. Based on the time course and rates of adverse reactions, the authors concluded that an initial dose of 200 mg/kg over 4 hours followed by 100 mg/kg over 16 hours in patients with established toxic acetaminophen concentrations would be a preferred regimen over the variable duration approach utilized in the trial.
Wong and colleagues conducted a quasi-experimental study which evaluated the rate of non-allergic anaphylactic reactions (systemic hypersensitivity reactions) and gastrointestinal symptoms with an abbreviated, 2-bag NAC protocol compared to an historical cohort receiving a traditional 3-bag regimen (Table).7 Adverse reactions for both groups were collected retrospectively through a chart review. During the 2-bag regimen treatment period, 470 patients presented with an acetaminophen overdose and 44.7% received the NAC regimen. This was similar to the historical control period where there were 920 presentations and 42.3% received NAC. There were no significant differences observed between the 2 groups for gastrointestinal symptoms (41% for 2-bag vs 39% for 3-bag; odds ratio [OR], 1.17; 95% confidence interval [CI], 0.83 to 1.65; p=0.38). However, the 2-bag regimen was associated with fewer non-allergic anaphylactic reactions compared to the 3-bag regimen (4.3% vs 10%; OR, 2.5; 95% CI, 1.1 to 5.8; p=0.02). The study also reported no significant differences in the rate of hepatotoxicity (ALT >1000 Unit/L) between groups (5.2% for 2-bag vs 4.3% for 3-bag; OR, 1.2; 95% CI, 0.55 to 2.63; p=0.68).
Bateman and colleagues conducted a double-blind, randomized, factorial trial assessing the effect of shortening the NAC regimen and antiemetic pretreatment on the rate of nausea and vomiting.8 Patients presenting with toxic acetaminophen serum concentrations were randomized to 4 treatment groups: shortened NAC regimen with ondansetron pretreatment (ondansetron-modified), shortened NAC regimen with placebo (placebo-modified), standard NAC with ondansetron pretreatment (ondansetron-standard), or standard NAC with placebo (placebo-standard) (Table). A total of 222 patients were randomized in the trial in a 1:1:1:1 ratio. The incidence of nausea or vomiting within 2 hours of initiation was significantly less with the modified NAC regimens compared to the standard NAC regimen (adjusted OR, 0.26; 97.5% CI, 0.13 to 0.52; p1000 Unit/L (2 ondansetron-modified, 1 ondansetron-standard, and 2 placebo-standard). Further, a post-hoc analysis demonstrated that patients receiving ondansetron had a higher risk of ALT doubling than those receiving placebo. Therefore, the authors concluded that an abbreviated NAC regimen can reduce vomiting and serious anaphylactoid reactions, but the addition of ondansetron pretreatment is not clinically warranted due to its effect on ALT.
Limitations
A key limitation to all of these trials includes their inability to establish non-inferiority between traditional NAC regimens and new, abbreviated regimens from a hepatotoxicity perspective. Since each of these trials was designed to assess rate of adverse reactions, they cannot inform a full clinical decision on whether these simplified approaches can replace traditional dosing schemes. Furthermore it is difficult to compare the adverse reaction rates reported in each trial due to differences in the data collected. The Isbister and Bateman trials collected data prospectively while the Wong trial identified adverse reactions retrospectively through documentation in the medical record. Rates of adverse reactions may be underrepresented in retrospective data collection as very mild reactions may not be recorded. Lastly, the Bateman trial compared their abbreviated protocol to a traditional protocol that administered the first infusion over 15 minutes. The majority of organizations recommend a 60 minute initial infusion duration based on a previous study which investigated whether a 60 minute regimen can reduce the rate of adverse reactions compared to the original 15 minute regimen.1,9 Therefore, the control group may represent an overinflation in the expected rate of adverse reactions with traditional regimens commonly used in current clinical practice.
Conclusion
A simplified, 2-bag NAC regimen has promise as a future treatment option based on evidence supporting its ability to reduce adverse reactions associated with NAC including both nausea and vomiting and systemic hypersensitivity reactions. Further investigation is needed, however, before these regimens can be fully accepted into clinical practice as their efficacy in preventing hepatotoxicity has not yet been adequately studied.
References
1. Howland MA, Hendrickson RG. Antidotes in depth: N-acetylcysteine. In: Nelson LS, Lewin NA, Howland M, Hoffman RS, Goldfrank LR, eds. Goldfrank’s Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill; 2011. http://accesspharmacy.mhmedical.com/Content.aspx?bookid=454&Sectionid=40199409. Accessed June 27, 2016.
2. Acetadote [package insert]. Nashville, TN: Cumberland Pharmaceuticals Inc; 2013.
3. Hayes BD, Klein-Schwartz W, Doyon S. Frequency of medication errors with intravenous acetylcysteine for acetaminophen overdose. Ann Pharmacother. 2008;42(6):766-770.
4. Ferner RE, Langford NJ, Anton C, Hutchings A, Bateman DN, Routledge PA. Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example. Br J Clin Pharmacol. 2001;52(5):573-577.
5. Chiew AL, Isbister GK, Duffull SB, Buckley NA. Evidence for the changing regimens of acetylcysteine. Br J Clin Pharmacol. 2016;81(3):471-481.
6. 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. Clin Toxicol (Phila). 2016;54(2):120-126.
7. 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. Clin Toxicol (Phila). 2016;54(2):115-119.
8. Bateman DN, Dear JW, Thanacoody HK, et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet. 2014;383(9918):697-704.
9. Kerr F, Dawson A, Whyte IM, et al. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. Ann Emerg Med. 2005;45(4):402-408.
August 2016
The information presented is current as July 18, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.