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In Paracetamol Overdose is Oral NAC as effective as IV NAC

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 Week 4 June 2017
[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 Week 2 August 2017
[paracetamol.mp] AND [Overdose.mp] AND [N-acetylcycsteine.mp]

Search Outcome

Medline: 713 papers identified, of which 4 were relevant.

Cochrane Database: 3 papers identified, of which 1 was relevant.

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Buckley et al.
1999
USA
Observational study: 981 patients who present with paracetamol overdose, 205 of which required treatment with NAC which was given intravenously Meta-analysis: systematic search of Medline u to December 1998, no randomized trials identified, case series were included if they met a certain criteria.1.Observational Study 2. Meta-analysisHepatotoxicity (transaminase >1000u/L1. 14 patients developed hepatotoxicity, these patients were more liiely to have ingested larger doses and present later. 2.No clear difference in hepatotoxicity between the results of patients treated with oral or IV NAC.1.Guidelines on management of paracetamol overdose have since been changed. 2. 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.Retrospective Chart ReviewPatients suffering from any of 14 predefined adverse events.No serious adverse reactions were identified as being related to either route of treatment.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. Does not measure efficacy of each route in preventing hepatotoxicity and death.
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 studyHepatotoxicitySevere 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.
EncephalopathyPresent in 1 (3.4%) of the patients that received oral treatment compared to no patients treated intravenously.
Coagulopathy requiring FFPNone in either group.
Adverse drug reactionsOccured 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.CostMedian 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 NAC treatment, this is likely to have affected the results.
Length of stay in hospitalLength of stay was 7 days for patients in the oral group compared with 4 days in the IV group.
Liver functionGroups "well matched", but results not specified.
OutcomesGroups "well matched", but results not specified.
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).Mortality10/1614 (0.6%) of oral patients compared with 6/637 (0.9%) of IV patients3 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

Clinical Bottom Line

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

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.