SNAP for reduced side effects in paracetamol OD?

I hope winter is treating you all well and that a new rotation of junior docs has brought some renewed enthusiasm for EM and teaching within your departments!

This journal club article is a little old (2014) but was inspired by one of our awesome HST trainees (Nikki) and her QIP project for the FRCEM. The SNAP protocol for N-acetylcysteine (NAC) in paracetamol overdose patients.

So what do you currently do for paracetamol OD? Most places I’ve worked in the UK follow the Toxbase guidance and the RCEM guidance based on the toxbase info can be found here – its worth a refresher . Essentially you give a weight based series of 3 bags of NAC diluted in differing volumes of 5% Dextrose, over 1, 4 and 16 hours. The first bag (150mg/kg) has been subject to a change in 2013 with the rate of delivery decreased from 15 minutes to an hour. This was done due to concerns about side effect frequency.

So what’s SNAP? Its a modified and shorter regime that delivers the same total quantity of NAC but over a 12 hours period. The first bag being 100mg/kg over 2 hours, followed by 200mg/kg over 10 hours. I think most of us working in ED have seen patients ‘react’ to the first bag even at the 1hour rate, with vomiting and or histamine mediated symptoms being the most common. This paper quotes side effect rates of up to 60%!

Title of Paper:  Reduction of side effects from intravenous acetylcysteine treatment for paracetamol poisoning:  a randomised controlled trial.

Clinical question: Does a simplified regime of acetylcysteine, with a first bag given over 2 hours at 100mg/kg, reduce side effects of vomiting?

Population:  Adult patients with paracetamol overdose requiring N-acetylcysteine.

Intervention: Modified acetylcysteine regime with or without ondansetron pre-medication.

Comparitor: Standard regime with or without ondansetron.

Outcome: Vomiting, retching or need for rescue anti-emetic.

So whats all this ondansetron all about? This is one of the interesting things with this paper. They’ve run a factorial trial to look at two interventions at the same time and their effect on the primary outcome measure of choice. I’ll be honest, this was a new one on me, although we were reassured by one of in-house Profs (thanks Steve Goodacre!) reassuring us that it is a legitimate and good way to undertake this sort of trial. You can measure the effect of treatments that would otherwise need two separate RCTs with a smaller sample size. The only concerns would be if there was a possible interaction or compound effect between the treatments being tested. Patients can be randomised to both groups and in a 2×2 design as here you get an even split across the treatment arms (in this case there are 4).

Randomisation was undertaken using offsite computer based schedule which is the gold standard for the process so we were pleased to see this, and an intention to treat analysis was performed. Blinding of the ondansetron vs placebo was undertaken but the decision was taken that the dosing and allocation of the NAC regimes wa to be unblinded due to the complexity of setting the infusions and potential ethical concerns. We wondered about this – given that this was a side effects study, not a non inferiority study, what ere those ethical concerns? We also wonder if they could have made some weight based bag regimes so they were blinded. If the clinicians and then the investigators were unblinded to the NAC grouping would it affect the way they asked questions about retching, or the need for rescue meds?

This brings us nicely on to the primary outcome measure – it’s certainly patient orientated which is great but is it really just one or is it three? Vomiting – is a very definite outcome but ‘retching’ – who and how do you define this, and is it significant? Need for rescue anti-emetic as demonstrated by clinical record or patient self reporting – again this could be open to bias based on the clinicians known or unknown bias. ‘Feel sick sir? I have just the thing, lets get you an anti-emetic’. That sort of thing……..

So what were their results?

Firstly they recruited around 50 patients in each arm of the trial which was enough to meet their sample size calculation to detect a relative risk of 0.6 for the proportion of patients vomiting within 2 hours.

They screened 3000 plus patients, excluded 1100 plus as not needing treatment, followed by a significant number who were staggered overdose patients. We weren’t clear why they excluded staggered OD patients as the treatment regimes are the same irrespective of the mechanism of OD, we could hypothesis that a patient with staggered OD may be more likely to vomit as they have had longer to develop hepatotoxicity. We didn’t know so Nikki has emailed the authors to ask – we’ll let you know as soon as we do!

Interesting to see that they found a benefit from the shortened NAC regime with 39/108 compared to 71/109 in the standard arm reporting vomiting based symptoms within the first 2 hours. when you calculate that out it works out as a relative risk of 55%, an ARR of 29% and an NNT of 3.5 – double check them for yourself (these are my calculations and I haven’t worked out the 95% CI!!). Ondansetron seemed to confer some benefit too, and in combination at 2 hours a modified regime with or without ondansetron pre-med seemed to confer benefit.

In their secondary outcome analysis they noted a correlation with ondanstron pre-medication and a raise of 50% in transaminase levels – but this may be solely down to chance given that this study wasn’t powered to detect that difference and the confidence limits crossed 1 – the odds ratio quoted at 3.47 (97.5% CI 0.95-12.66).

Where does this all leave us? Well we talked a lot about the idea of wanting to know whether the modified regime would have any harm effect in terms of treatment outcome – i.e. no liver failure or death, but it is hypothesised that the effect size difference one would be looking is so small that the sample size needed would be huge (we’re talking CRASH-2 levels here) so its unlikely we’ll ever see that trial. We know that Edinburgh and Newcastle are already using this regime (and due to publish soon some before and after data) and a umber of other units are looking to implement this too, so we look forward to hearing from them!

In terms of side effects this trial seems to show a favourable benefit of the modified regime without ondansetron, the patients largely represent our own patients and other than some slight concerns around the excluded staggered ODs and a small proportion of patient who were ‘too intoxicated’ to be included, we thought this was the best evidence we had on this regime.

Let us know your thoughts on the SNAP protocol and what you thought of this paper – we’d love to hear from you!

Keep fighting the good fight!

Chris

Refs:

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62062-0/fulltext

https://www.rcem.ac.uk/RCEM/Quality-Policy/Clinical_Standards_Guidance/RCEM_Guidance.aspx?WebsiteKey=b3d6bb2a-abba-44ed-b758-467776a958cd&hkey=862bd964-0363-4f7f-bdab-89e4a68c9de4&RCEM_Guidance=6

https://www.bmj.com/content/349/bmj.g5455

https://study.com/academy/lesson/what-is-factorial-design-definition-example.html

https://www.rcem.ac.uk/RCEM/Quality-Policy/Clinical_Standards_Guidance/RCEM_Guidance.aspx?WebsiteKey=b3d6bb2a-abba-44ed-b758-467776a958cd&hkey=862bd964-0363-4f7f-bdab-89e4a68c9de4&RCEM_Guidance=6h

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