Make it SNAPpy! Paracetamol overdoses in teenagers

This is the ninth in a series of blog posts on new research in emergency toxicology. The last post was about hydrofluoric acid burns and can be found here. We deal with all sorts of poisons here in Virchester, so be prepared for anything.

Paracetamol poisoning is an uncommon, but not rare event in children. The ingestion is accidental most of the time, and the risk of liver toxicity is low. If treatment is required, however, N-acetylcysteine (NAC) is the antidote of choice, just as it is with adults. It is given intravenously.

Most emergency clinicians will be familiar with NAC, although many (myself included!) struggle to get their head around the mechanism. The key target is N-acetyl-p-benzoquinone imine (NAPQI), which is a destructive metabolite formed from paracetamol by hepatic enzymes. NAC, once administered, forms a precursor (cysteine) for the natural “counter” to NAPQI, glutathione. As long as glutathione levels remain high, NAPQI can be conjugated, inactivated, and eliminated from the body without causing harm. Glutathione also has a beneficial role as a scavenger of free radicals and other reactive oxygen species, which are generated by NAPQI and similar toxic compounds, such as ethanol.

Unfortunately, like all antidotes, NAC has side-effects. It is associated with anaphylactoid symptoms (largely due to histamine release) which can be problematic for children with reactive airways or sensitive skin. Unusually, the mast cell response in NAC is dependent on the rate of loading. This is why a high rate of adverse reactions have been reported with the “traditional” NAC regimen, which consists of three infusions (150mg/kg, 50mg/kg, 100mg/kg) spread out over 21 hours. Fewer reactions are seen when NAC is administered more quickly, as in the Scottish and Newcastle Anti-emetic Protocol (SNAP), where two infusions (100mg/kg, 200mg/kg) are given over 12 hours.

Here at St Emlyn’s, we have fully switched to the SNAP regimen for adult paracetamol toxicity, but are still using a 21-hour protocol for children. I gather this is the case at many centres in the UK, despite a statement from the Royal College of Emergency Medicine in 2023 emphasising that ‘there is no compelling data to suggest the SNAP regimen is associated with less efficacy than the 21-hour regimen or associated with more adverse events’ and supporting ‘the routine use of the SNAP regimen in […] paediatric patients.’

The problem here is the double-negative. What we are clearly lacking is research evidence demonstrating benefit (or at least non-inferiority) of the SNAP regimen compared to current practice. I had a search through the literature earlier this year, and all I could find was two conference abstracts (here and here) in the Archives of Diseases in Childhood describing retrospective studies with small numbers of children. For what it’s worth, their data seems to support the SNAP regimen, and I will keep an eye out for the published papers.

In the meantime: a large, prospective study was published on this topic a few months ago in the EMJ. The aim was to see if the SNAP regimen reduces anaphylactoid reactions in children without compromising treatment efficacy.

Abstract

Background & Objectives: Ondansetron improves outcomes when administered in emergency departments to children with acute gastroenteritis–associated vomiting. It is commonly prescribed at discharge to reduce symptoms, but evidence to support this practice is limited.Treatment with the 12-hour Scottish and Newcastle Antiemetic Protocol (SNAP) acetylcysteine regimen is associated with decreased length of stay and fewer anaphylactoid reactions in adult patients, and the protocol is now recommended by several UK organisations and used widely. One potential barrier to adoption is concern regarding the potential for variation in protocol performance with patient age. Anecdotally, this has led to slower adoption in paediatric settings.
Methods: Secondary analysis of data from 2212 patients at the Royal Infirmary of Edinburgh, UK, treated with acetylcysteine for paracetamol overdose between 28 September 2013 and 27 September 2017. Patients were grouped into 10-year age ranges to allow comparison of treatment regimen performance across ages. Groups were compared for their rates of anaphylactoid reactions, duration of admission attributable to acetylcysteine infusion and severity of liver injury assessed by biochemical markers.
Results: Patients in all age groups treated with SNAP experienced statistically significant reductions in anaphylactoid reactions. There were no significant differences in the severity of acute liver injury as assessed by biochemical results.
Conclusions: This secondary analysis provides data to support the use of SNAP regardless of patient age and reassure clinicians that there is no evidence of previously unrecognised variation in protocol performance.
Humphries C, […], Dear J. SNAP 12-hour acetylcysteine regimen for paracetamol overdose reduces anaphylactoid reactions without compromising hepatic protection in all age groups
EMJ. 2025 Aug.

What was the study design?

This was a secondary analysis of prospective data collected at the Royal Infirmary of Edinburgh (RIE) between 2013 and 2017.

The significance of this time period is that in 2015, the SNAP regimen was introduced as standard for paracetamol poisoning at RIE. Before this, all patients received the 21-hour NAC protocol. Effectively, then, this is a “before-and-after” design.

Can you tell me about the patients?

The study included 2212 paracetamol overdoses in total, of which 180 occurred in patients aged 13-16. Younger children were not included in this study.

Within this 13-16 subgroup, the majority (~92%) were female. The dose of paracetamol ingested was high (median 208 mg/kg) and most patients (~63%) received NAC within 8 hours of poisoning.

A small number (~2%) of teenagers in this study over-used paracetamol accidentally (‘therapeutic excess’) but the implication is that the rest took an intentional overdose.

What was given in each group?

84 teenagers received the 21-hour NAC protocol (2013-2015) and 96 received the SNAP regimen (2015-2017).

Treatment was initiated at varying time points: ~63% within 8 hours of overdose, ~16% at 8-24 hours, and ~2% over 24 hours. A staggered overdose was taken by ~17% of patients, and NAC was given as quickly as possible in these cases.

What outcome measures were used?

The primary safety outcome for this study was the proportion of patients experiencing anaphylactoid reactions to NAC. To estimate this, the researchers looked for antihistamine prescriptions co-occurring with NAC infusion.

Other outcomes included the incidence of liver injury (defined by peak ALT and INR levels) and treatment extension beyond the standard course. Acute liver failure and death were also reported.

What were the main results?

Antihistamines were prescribed for 8% of teenagers on the 21-hour protocol. None were prescribed for children on the SNAP protocol. Precise confidence intervals were not reported, but did not appear to cross zero in the wider 13-19 age group.

There was no statistically significant difference between groups on peak ALT or INR.

Slightly more children in the SNAP group required an extension of their treatment: 25% compared to 13% in the comparator group. No deaths occurred in either group. Thankfully, this is a very rare outcome in children who overdose on paracetamol – as is acute liver failure, which also did not occur in this study.

What did the authors conclude from these results?

‘This subanalysis provides data to support the widespread adoption of SNAP and reassure clinicians that the protocol is suitable for use in all patient groups. [T]he benefits of SNAP […] have the potential to benefit all patients, regardless of age.’

What should we take away from this study?

This was a (relatively) large, prospective cohort study. The researchers evaluated a NAC regimen that is widely — albeit inconsistently – used in paediatric emergency medicine. Most of their sample had taken an intentional overdose of paracetamol, which is helpful, as these are generally the patients we worry about the most.

With that said: there are clear limitations to this data. A “before and after” design is not a randomised controlled trial, and with such minimal clinical information provided about the patients, it is hard to know whether the groups were “balanced” to the extent that would be achieved by randomisation.

https://www.edinburghclinicaltoxicology.org/aboutSimilarly, this was an open-label study with an outcome (anti-histamine prescription) that is [non-patient-oriented] and heavily dependent on clinician discretion. It may be that the doctors, working on a specialist toxicology unit, were well-educated on the theoretical benefits of the SNAP regimen, and felt that anaphylactoid reactions would be less likely when it was used. This may have triggered an observer-expectancy effect in their interactions with participants, or at least some degree of confirmation bias in their physical examination – with the overall result of fewer anti-histamines given.

I was also disappointed to see that younger children were not included in this study. I was already fairly convinced that the SNAP protocol is suitable for teenagers, as they are not too far off adult physiology. I wanted to see some data supporting its use in the patients least generalisable to our existing evidence base.

Should this study change our practice?

Yes. Emergency clinicians should use the SNAP protocol in teenagers to ease suffering in the department and reduce nursing burden. We recommended this in a previous blog post on paediatric toxicology.

On a related note: while preparing this blog post I re-listened to the EMCRIT episode on ‘massive’ paracetamol toxicity, which is a completely different beast to the poisonings we typically see. I would really recommend learning more about this if you work in paediatric settings, as some of the teenagers we care for take huge amounts of paracetamol when they overdose.

Greg Yates