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Three Part Question

In [patients who need an antidote for paracetamol overdose] is [intravenous therapy better than oral therapy] at [preventing liver damage and death]?

Clinical Scenario

A 23 year old woman attends an emergency department having taken sixty 500mg paracetamol tablets. Her four hour paracetamol levels are above the treatment line. She does not want to be treated with intravenous therapy. You wonder whether oral antidote is as effective.

Search Strategy

Medline 1966-12/01 using the OVID interface.
[exp acetaminophen OR acetaminophen.mp OR exp paracetamol OR paracetamol$.mp OR co-codamol.mp OR co-dydramol.mp OR co-proxamol.mp] AND [exp acetylcysteine OR acetylcysteine.mp OR n-acetylcysteine.mp OR exp methionine OR methionine.mp OR exp antidote OR antidote.mp] AND [exp poisons OR poison$.mp OR exp overdose OR overdos$.mp OR acute intoxic$.mp OR acute toxic$.mp] LIMIT to human AND English language

Search Outcome

330 papers were identified, of which two were directly relevant to the three part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Perry HE et al, 1998, USA	25 patients (<16 years) attending an emergency department less than 24 hours after a single, potentially toxic overdose of paracetamol, given IV N-acetylcysteine (NAC). 29 patients previously given oral NAC were used as historical controls.	Prospective, observational study with historical controls	Hepatotoxicity (transaminases >1000u/1)	No significant difference was discovered between IV and oral NAC. Hepatotoxicity 8% IV; 6.9% oral; 0% either group when treated <10 hours after ingestion	non-randomised study (patients were treated at the clinicians' discretion) patients were not enrolled sequentially small study
			Encephalopathy	0% IV; 3.4% oral
			Coagulopathy requiring FFP	None noted
Buckley NA et al, 1999, Australia	981 patients attending an ED following paracetamol overdose; 205 patietnts were given IV NAC	1. Prospective, observational study. 2. Meta-analysis of studies of IV or oral NAC (including authors' study)	Hepatotoxicity (transaminases >1000 u/l)	Observational - Hepatotoxicity was associated with larger ingestions and delayed presentations. Meta-analysis - there was no significant difference in the hepatotoxicity rates between IV and oral NAC, irrespective of time from ingestion to treatment. <10 hours: 3% IV, 6% oral. 10-24 hours: 30% IV, 26% oral. Total: 16% IV, 19% oral.	Observational: The criteria for giving NAC changed after 3 years from <15 hours post-ingestion to <24 hours. Meta-analysis: IV data was pooled from 4 studies (total of 341 patients) but oral data was taken from only one (1462 patients) of the 3 eligible studies (248 patients excluded) Coagulopathy was not studied, this may have more prognostic value than transaminase levels nomograms used to assess risk are not validated >12 hours post-ingestion the duration of the IV regimes varied with 3 studies using 20 hours and one using 48 hours

Comment(s)

Perry's study used historical controls although the demographic characteristcs of the two groups were remarkably similar. It was not included in Buckley's meta-analysis because the patients were not recruited sequentially and it was unclear whether the patients were treated solely at the study centre (possible variations in other treatment modalities could act as confounding factors). A number of other papers compared methionine, either IV or oral, with symptomatic treatment only, although with two exceptions it is difficult to directly compare the results. The studies undertaken by Prescott et al and Vale et al in the 1970's seem to involve similar groups of patients, and there were no significant differences between oral and IV methionine (7% and 2% hepatotoxicity respectively). There were slight differences in overdose co-ingestants and other treatment variables were not mentioned, so the results should be interpreted with caution. In conclusion, although there have been no RCTs, a meta-analysis of observational studies has failed to show a difference in efficacy between the oral and intravenous routes for antidote therapy following paracetamol overdose. However, these studies do not address the other factors that may influence the choice of route, which include: activated charcoal absorbs antidote and therefore precludes its use; the IV route is safer with patients with altered levels of consciousness (eg due to co-ingestants) who may subsequently lose their airway protective reflexes

Clinical Bottom Line

The IV route is the treatment of choice for paracetamol poisoning, but the oral route has a similar efficacy and is a suitable alternative if IV access is difficult (for example IV drug abusers) or refused by the patient.

References

1. Perry HE, Shannon MW. Efficacy of oral versus intravenous N-acetylcysteine in acetaminophen overdose: results of an open-label, clinical trial. J Pediatr 1998;132:149-52.
2. Buckley NA, Whyte IM, O'Connell DL et al. Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning? J Toxicol Clin Toxicol 1999;37:759-67.
3. Prescott LF, Illingworth RN, Critchley JAJH, Stewart MJ, Adam RD and Proudfoot AT. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J. 1979;2(6198):1097-1100.
4. Prescott LF. Treatment of severe acetaminophen poisoning with intravenous acetylcysteine. Arch Intern Med 1981;141(3 spec no):386-389.
5. Vale JA, Meredith TJ, Crome P, Helliwell M, Volans GN, Widdop B and Goulding R. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J. 1979;2(6198):1435-1436.
6. Vale JA, Meredith TJ and Goulding R. Treatment of severe acetaminophen poisoning: the use of oral methionine. Arch Intern Med 1981;141(3 spec no):394-396.