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Three Part Question

In [patients who need treatment for paracetamol poisoning] is [oral N-acetylcysteine as safe and effective as intravenous N-acetylcysteine] at [preventing liver damage and death].

Clinical Scenario

A 17 year old female has presented to the Emergency Department after taking forty 500mg tablets of paracetamol. Her 4 hour plasma paracetamol levels are above the treatment line. However, she is needle-phobic and refusing intravenous treatment. You want to treat her with an oral antidote and wonder if oral N-acetylcysteine is as effective as intravenous.

Search Strategy

Medline via OVID interface searched to week 2 February 2018
[exp acetaminophen OR acetaminophen.mp OR paracetamol.mp OR paracetamol$.mp] AND [exp poisoning OR poisoning.mp OR poison$.mp OR overdose.mp OR overdose$.mp] AND [exp. Acetylcysteine OR acetylcytseine.mp OR N-acetylcysteine.mp OR parvolex.mp OR antidote.mp] LIMIT human AND english language

Cochrane Database of Systematic Reviews searched to week 2 February 2018
[paracetamol.mp] AND [Overdose.mp] AND [N-acetylcycsteine.mp]

Search Outcome

Medline: 746 papers identified. There were 2 Systematic Reviews and one comparative study published after the most recent review. 3 other studies were included for further relevant information.

Cochrane Database: 3 papers identified, of which 1 was relevant. It was also identified by the Medline search.
One additional Systematic Review did not appear on Medline but was found through the Wikipedia entry for Acetylcysteine.

Data from the studies is shown in Table 1.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Buckley et al. 1999 USA	An observational study: 981 patients who presented with paracetamol overdose, 205 of which required treatment with NAC which was given intravenously. Meta-analysis: systematic search of Medline up to December 1998. No randomised trials were identified. 7 case series were included (4 presented data on patients treated with IV NAC and 3 presented data on patients treated with oral NAC).	Observational study and a meta-analysis	Hepatotoxicity (transaminase >1000 IU/L)/L	279/1462 (19%) of patients treated with oral NAC vs 60/341 (17.5%) of patients treated with IV NAC.	Guidelines on management of paracetamol overdose have since been changed. Variations in the recording times in each study. Exclusion of patients who did not complete IV NAC could cause bias. This study was included in the Cochrane Review by Brok et al.
Heard 2010 USA	503 patients who received treatment for paracetamol overdose across 11 centres. 306 received IV NAC, 145 received oral treatment, 52 had their treatment changed and therefore received both. Chart reviews for the period June 2006-December 2007 with some variation between centres.	Retrospective chart review	One or more non-serious related adverse events	42/306 (13.7%) of IV only patients compared with 37/145 (25.5%) oral only patients.	A safety analysis so did not present efficacy of each route in preventing hepatotoxicity or death. Differences in baseline characteristics of each group. Difference in length of treatment of each group allows longer for adverse reactions to occur in patients receiving oral treatment. Misclassification bias leading to vomiting being more commonly classed as related to treatment in patients receiving oral treatment compared to intravenous.
			Adverse events per treatment administered.	75/200 (37.5%) oral treatment compared with 94/358 (26.3%) for IV treament. Absolute risk difference 11.2% (95% CI 3.3-19.2).
			Nausea and vomiting.	22.8% in oral only group compared to 8.8% in IV only group.
			Anaphylactoid reactions.	2.1% in oral only group compared with 5.9% in the IV only group.
			Serious adverse events.	None in either group.
Perry et al. 1998 USA	25 paediatric patients received IV NAC. 29 controls received oral NAC (these were described by the authors as historical controls but were treated during the same time period as those receiving IV NAC. The IV regime consisted of a 140mg/kg loading dose followed by 12 doses at 70mg/kg every 4 hours. Each IV dose was given over 1 hour.	Observational cohort study	Hepatotoxicity	Severe hepatotoxicity in 8% of patients receiving IV-NAC and 6.9% patients receiving oral NAC (statistically NS). There was no hepatotoxicity in either group for those treated before 10 hours.	Small study conducted when oral NAC was the standard treatment in the USA and with an IV NAC regime very different to that used now. Comparisons were made between treatment completed patients rather than on any intention to treat, so cross-over and incomplete treatment patients were excluded from the final analysis. Hepatotoxicity and severe hepatotoxicity not explicitly defined. Not included in the Cochrane Review by Brok et al.
			Encephalopathy	Present in 1 (3.4%) of the patients given oral treatment compared to none in patients treated intravenously.
			Coagulopathy requiring FFP	None in either group.
			Adverse drug reactions	Occured in 7.1% of patients receiving IV treatment and 6.1% of patients in the oral group.
Martello et al. 2010 USA	70 patients treated with oral NAC between the years 1996-2000 and 191 patients IV NAC between the years 2004-2008.	Retrospective cohort study using historical controls for oral NAC.	Cost	Median cost of treatment higher in patients treated with oral NAC (18,287.63 vs $7,607.82)	The study was primarily about cost analysis rather than clinical outcomes. The study did not account for co-morbitidities of patients which could have affected both cost and duration of stay. Patients were excluded if discharged on oral NAC treatment. This is likely to have affected the results.
			Length of stay in hospital	Length of stay was 7 days for patients in the oral group compared with 4 days in the IV group.
			Liver function	Groups
			Outcomes	Groups
Brok et al. 2006 UK	9 studies informed the comparison of oral vs IV NAC. 1614 patients received oral NAC and 637 received IV NAC.	Systematic review of the management of paracetamol poisoning made up of randomized and quasi-randomized trials and observational studies (not just about oral vs IV NAC).	Mortality	10/1614 (0.6%) of oral patients compared with 6/637 (0.9%) of IV patients	3 observational studies provided data on oral NAC, while 6 studies provided data on IV NAC (5 observational studies and 1 randomized trial of different doses of IV NAC). There were no direct comparisons of oral vs IV NAC. No meta-analysis was possible.
			Hepatotoxicity (serum AST or ALT >1000 IU/L)	306/1614 (19%) of oral patients compared to 80/637 (13%) of IV patients
Green et al. 2013 USA	Literature search for the period 1966-2009: studies evaluating rates of hepatotoxicity after paracetamol overdose for which the treatment was either oral or IV NAC with more than 20 patients. 16 studies included in the meta-analysis (5164 patients). Toxic dose of paracetamol: non-US studies >200 mcg/ml at 4 hours, US studies >150 mcg/ml at 4 hours. A second time-stratified analysis was carried out defining early treatment as treatment started within 10 hours of paracetamol ingestion. 7 studies were included (949 patients treated early, 1293 patients treated late).	Systematic review and meta-analysis	Hepatoxicity (transaminase >1000 IU/L).	12.6% (95% CI 8.2-18.8) for patients treated with oral NAC, 13.2% (95% CI 8.7-19.6) for patients treated with IV NAC.	Not all studies could be included in the time-stratified analysis.
			Hepatotoxicity when treatment started early.	5.9% (95% CI 4.2-8.1) for patients treated with oral NAC, 5.3% (95% CI 3.2-8.5) for patients treated with IV NAC.
			Hepatotoxicity when treatment started late.	26.3% (95% CI 23.6-29) for patients treated with oral NAC, 23.3% (95% CI 11.7-41.1) for patients treated with IV NAC.
Williamson et al. 2013 USA	Patients over 12 years of age referred to a Regional Poison center treated with NAC within 8 hours of their ingestion. 213 received IV NAC over 20 hours. 213 received oral NAC over 36 hours and 369 received oral NAC over 72 hours between January 2002 and December 2007.	Retrospective cohort study from a Regional Poison Center database.	Death	None in any group	Only patients treated within 8 hours of ingestion and who completed their treatment. Selection bias: only patients referred to the Poisons Center (although this may mean that only cases causing concern were referred). No control for co-ingestions.
			Liver transplant	None in any group
			Hepatic encephalopathy	None in any group
			Elevated INR	None in any group

Comment(s)

Intravenous N-acetylcysteine (NAC) has been used in the UK since at least 1977 (Prescott et al.) although it was only licensed in the USA in 2004. Until then oral NAC was used, generally as a 72 hour course, although, a shortened course was also sometimes being used and appeared to be equally safe (Betten et al.). To date there have been no randomised controlled trials of oral versus IV NAC. Several systematic reviews have been published over the years and each one has suggested that the two routes of administration are equally effective. The latest study by Williamson et al. confirms the effectiveness of early NAC whether it is given orally or IV (and that a 36 hour oral course is equally effective as a 72 hour course). Oral NAC continues to elicit interest especially for use in children (Dunning et al.) The advantage of the IV course is its shorter duration and fewer gastro-intestinal problems, but there is a greater risk of "anaphylactoid" reactions.

Editor Comment

BF

Clinical Bottom Line

IV treatment is the standard in hospitals in the UK, however, the oral route is a safe alternative in patients in whom IV access may be difficult to obtain.

Level of Evidence

Level 1 - Recent well-done systematic review was considered or a study of high quality is available.

References

1. Buckley NA, Whyte IM, O'Connell DL, et al. Oral or intravenous N-acetylcysteine: which Is the treatment of choice for acetaminophen (paractamol) poisoning? Clinical Toxicology 1999;37(6):759-767.
2. Heard K. A multicentre comparison of the saftey of oral versus intravenous acetylcycsteine for treatment of acetaminophen overdose. Clinical Toxicology 2010;48:424-430.
3. Perry HE and Shannon MW. Efficacy of oral versus intravenous N-acetylcysteine in acetaminophen overdose: Results of an open-label clinical trial. J Pediatr 1998;132:149-152.
4. Martello Jl, Pummer TL, Krenzelok EP. Cost minimization analysis comparing enteral N-acetylcysteine to ntravenous acetylcysteine in the management of acute acetaminophen toxicity Clinical Toxicology 2010;48:79-83
5. Brok J, Buckley, N, Gluud C. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database of Systematic Reviews. 2006;Issue 2: Art. No. CD003328.
6. Green JL, Heard KJ, Reynolds KM et al. Oral and intravenous acetylcysteine for treatment of acetaminophen toxicity: A systematic review and meta-analysis. Western Journal of Emergency Medicine 2013;14(3):218-226.
7. Williamson K, Wahl MS, Mycyk MB. Direct comparison of 20-hour IV, 36-hour oral, and 72-hour oral acetylcysteine for treatment of acute acetaminophen poisoning. American Journal of Therapeutics 2013;20:37-40
8. Dunning JR, Trella J, Osterhoudt KC. A novel formulation of N-acetylcysteine. Pediatric Emergency Care 2016;32(9):652.
9. Prescott LF, Ballantyne A, Proudfoot A, et al. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. The Lancet 1977;310(8035):432-434.
10. Betten DP, Burner EE, Thomas SC, et al. A retrospective evaluation of shortened-duration oral N-acetylcysteine for the treatment of acetaminophen poisoning. J Med Toxicol 2009;5(4):183-190.