Croup: Riding the Dex Express

Sooooo….this paper turned up at JC last week (thanks to Nicola P) and whilst I’m not sure that it meets all three of our criteria for a top JC paper it is relevant as a week barely seems to go by without someone questioning the dose/route/brand/colour/size/ethnicity of medicine for croup.
Rule of thumb chaps and chapesses ‘The greater the dogma, the greater the ignorance’. Someone cleverer than I said that, but I’m happy to plagiarise ‘cos it’s true.
Anyway, Croup arrives as a question once again in the journal Emergency Medicine Australia, but this time the question relates to speed of onset in mild to moderate croup.

 STOP! If you are in exam mode at this point you should read the paper. See what you think about it and give it a mark out of 10.

We’ve talked about this paper and it’s a tricky one. The first question is why has this paper been done (which we cannot answer, but can surmise privately). The use of steroids in the management of croup is very well established and is something we led on here in Virchester many years ago. It was even one of the very first BETs back in 2004 (amazing to think that we are still talking about this 8 years later).
I’ve also seen the Cochrane review and even examined some CTRs for FCEM on the subject. So, it pretty much seems to me that the question of whether we give steroids for croup is well made. The research that remains is, I suppose, about refining and polishing what is surely a well established fact.

STEROIDS WORK IN CROUP Click the link and read the Cochrane review.

So, what about the paper this week? Is there anything we can draw from it and learn? Well, the authors have done an RCT (good) on mild/moderate croup patients. Interesting this as for the mild ones would you give steroids or just let nature take its course? (Ed – depends on how mild as croup score 1-3 is mild) I’m not sure so there maybe an element of over-treatment in comparison to other practices. Whatever, the authors tell us that there is an effect of giving steroids that they can define and detect at  30 minutes following administration of steroid and that this counteracts the information given through Cochrane about a delayed effect taking up to 6 hours.

I have major concerns with this paper and I just don’t see how this is going to make a significant difference to our practice in PEM.  I don’t think a paper like this would appear in an exam, but if it did I would be pulling holes in it along the following lines.

1. What is the clinically important question here? It seems that we are looking to see the speed of onset of steroid meds in mild/moderate croup. The clinical importance of this is perhaps unclear except in logistical (admission) terms. What defines a significant difference in this low acuity group? Mild croup is not admitted anyway so what is the issue we are addressing?

2. Sample size. OK. An interest of mine, and if you share that interest (you sad person) then hop over to the podcast to hear more about how to understand and interpret sample size calculations. In this paper they appear to be using tests for continuous data for data which is unlikely to be so. Honestly, it seems as though these are the wrong tests for this data, but there is insufficient information in the paper for us to tell. Where is the clue? Well, the Wesley croup score is a categorical score (at best ordinal). It’s not continuous and is unlikely to be normally distributed, so a t-test is rarely going to be the right test. So hmm, not enough information to know but questions are there to be asked. If you want to know more about stats for Critical Appraisal then click here and here. Apart from anything else, a study of just 70 patients would have to show a massive effect if it is be valid and I don’t see that here. Similarly the graph shows average scores only, and I’m not sure that I’m just interested in the change in average score amongst 35 patients. I want to see the distribution as well. This is a common problem in papers as the mean score reporting removes the depth and character of the data.

3. Right, so we are unsure of the validity of the question and also of the sample size what else? Well,  do applaud the authors for defining the numbers of patients that they ‘could’ have recruited and the difference between that number (828) and the number recruited (70) is huge. This suggests a degree of patient selection which may well affect the results. Now, I don’t want to put a massive downer on this as it is an inevitable problem with EM research, but this ratio really asks questions as to whether this is a representative sample, or whether the results will be heavily skewed because it is a sample of convenience.

So, it sounds as though we were pretty down on this paper from a methodological point of view. We gave it a 3/10 to be honest which is clearly not high, but just wait is there ANYTHING we can take away from this piece of work at all. Well, it’s tricky to be honest. It’s likely (but I’m finding it difficult to tell) that oral dex starts working fairly quickly, but that was never a clinical dilemma for me before I read this paper so I’m not going to change practice. However, it’s a useful to use this as a vehicle to discuss Croup (again), to review the relevant BETs and to talk about how to spot flaws in papers.

 bw

Simon C

PS. If you are still in exam mode try answering the following questions…

1. What is meant by the term ‘double-blinded’ and why is it important in a trial like this?

2. Four patients in the placebo group worsened during the initial phase of the trial and were then given steroids. They were analysed in the placebo group despite getting steroids. What is this type of analysis called and is it the right approach?

Kiddy pills, syrup, compliance and cost.

I was wandering through the Paeds journals looking for something relevant to EM recently (there wasn’t much) when I came across two articles in Archives of diease in childhood. The first by Baguley et al tells me that Kids are more likely to take medicines if they taste nice. Not exactly rocket science I agree, but what I did not know is that there is a scale of drugs which are known/not known to be taste nice, and interestingly Flucloxacillin, a drug widely used in emergency medicine is one of the least pleasant tasting. Augmentin on the other hand, for which the penalty for prescribing off protocol is crucifixion (not really but it feels like it) is apparently very tasty indeed. This may seem fairly benign and obvious but it’s really important for us as EPs as clearly there is no point in prescribing if the compliance is going to be poor.

Here’s a list from the paper ranking some of the more commonly prescribed antibiotics in Paeds ED practice from the paper.

• ▶ Antibiotics children will normally swallow

  • ▶ Co-amoxiclav (×3/day) or Augmentin Duo (×2/day)

  • ▶ Cefaclor, cefalexin, Amoxil (branded) (all ×3/day)

  • ▶ Co-trimoxazole

• ▶ Antibiotics children might swallow

  • ▶ Penicillin V (×4/day)

  • ▶ Amoxicillin (generic) (×3/day)

  • ▶ Clarythromycin (×2/day), azithromycin (×1/day)

• ▶ Antibiotics children often spit out or grimace when taking

  • ▶ Erythromycin (×4/day)

  • ▶ Trimethoprim (×2/day)

• ▶ Rarely tolerated with good adherence

  • ▶ Flucloxacillin (×4/day)

  • ▶ Clindamycin (×4/day)

So, is there a way round this rather than just continuing to prescribe and hope for the best? For patients there is some really good generic advice out there on loads of websites and your pharmacy may have advice as well, but what about us as EPs. Is this really a question for us at all or do we just prescribe and say get on with it. There are two suggestions in the journal that I thought were worth a ponder. One we can do right now and one for the future. In the same paper Baguley et al describe the concept of a ‘taste test’ to give the first dose of antibiotics before the child leaves to see if they will tolerate it. This seems perfectly sensible to me. We should probably do this for those drugs down the bottom end of the table, and arguably for all of them. I’m going to suggest and then wait for all the reasons why we can’t, and then I’ll suggest it again, and again…….

The future idea is another paper in Archives which challenges dogma, and I love a bit of dogma baiting! We all know that the only reason we are messing about with antibiotics in syrup form is because kids can’t take tablets. Or can they? Spomer et al have performed a rather nice (admittedly pilot) study looking at whether children aged 0.5-6 years can swallow tablets as compared to syrup….and the result is that they can. Not only that, but they can swallow tablets as well as they can take syrup, and, in children aged 6-12 months they do better with tablets. Ok, it’s a small paper, a pilot and we cannot infer from this that mini-pills are the future, but it does raise some interesting questions that I’d like to see answered over the next few years.

Compliance is a vital component of any successful theraputic intervention but one that we in Paeds EM perhaps do not take account of as much as we should. Better compliance has got to be better for patients, for countering microbiological resistance and ultimately for healthcare costs.

It’s certainly made me think about that next prescription for oral fluclox syrup. I wonder if it will get used in the way that I prescribe it?

Now, at this stage it would be great to tell you the results of my blind tasting of antibiotics in the department. This is of course unethical so I haven’t, but I’d love to hear from anyone who has. It does remind me of my time in Neonates (a long time ago when consultants could make juniors do this sort of thing) when the drug rep came round with all the different types of formula feeds designed from ultraprems right up to full term and beyond. It was possibly the weirdest, most unpleasant and arguably most bizarre taste test I’ve ever undertaken.

Simon C

Through the Looking Glass: Chirocaine vs Bupivicaine

I’ve seen a few paediatric femoral shaft fractures in the last couple of years, and while they always make my spidey-sense tingle for non-accidental injury, most (even the spiral fractures) have been explained away by plausible mechanisms of injury; they are usually late toddling age, have got their feet stuck, twisted and fallen over.

I’ve even seen a few which were pathological – undoubtedly the result of the vitamin d deficiency which stems from the miserable attempt at sunshine we have to put up with here in the North West.

The way I’ve managed these patients has changed with my experience and skill level; as an SHO I looked at them with sympathy while the oramorph, ibuprofen and paracetamol were absorbed slowly from their (no doubt static) GI tracts. As a registrar, they now get a squirt of intranasal diamorphine and an application of ametop over the ipsilateral groin, in anticipation of an ultrasound-guided femoral nerve block when they return from x-ray. I mix up a 50:50 solution of 1% lidocaine with 0.5% bupivacaine and, before ultrasound guidance, used 1mL per year of age. It works out as less than 2mg/kg of lidocaine (usually) and less than 1mg/kg bupivacaine – so relatively small doses. I’ve done it a few times, and it works pretty well, especially in combination with a Thomas splint. The great thing about ultrasound-guidance besides lower failure rates is that you can use even smaller drug volumes – it ends up more like 0.5mL per year of age.

So as I examined the two year old, who was refusing to weight bear, with little deformity to his leg but clear femoral tenderness, I reached for the trusty bupivacaine/lidocaine combination to make splint application less of an auditory assault. But shock! Horror! No bupivacaine!

Instead, there was chirocaine – which completely confused me, as I had no idea what it was (and there was apparently no bupivacaine to be had anywhere). I asked around – and no-one seemed to be entirely sure how the two drugs related to one another. So, after some research, I thought I’d share.

Chirocaine (levobupivacaine), as you may know (I didn’t), is “the pure S-enantiomer” of bupivacaine. The story is that some drugs exist in a 50:50 (racaemic) mixture of two stereo-isomers; molecules which are mirror images of one another. Where the mirror images cannot be superimposed, the molecules are said to be chiral, and the most common cause for this is an asymmetrical carbon atom. There is a right (dex-, or d-) and left (levo-, or l-) version of the molecules which cannot be made symmetrical no matter the orientation in the same way as your left foot just doesn’t fit in your right shoe [NB: an important differential in the non-weight bearing child]. Where drugs bind to receptors, one isomer may be able to bind, while the other cannot – or may generate alternative effects.

You probably knew this already, right? Every time you prescribe levothyroxine, esomeprazole, escitalopram or levofloxacin, you think proudly about how you are selecting out the correct isomer for your patient, yes? And how you are therefore giving half the dose, as they aren’t getting the 50% of isomers which don’t give a clinical effect? Well, it doesn’t quite work as predictably as that. In fact, in some cases the dose is significantly lower for the same clinical effect (notably escitalopram, 30 times more potent than citalopram) and in others confers no therapeutic advantage at equivalent doses (see esomeprazole) or may even be harmful (see thalidomide).

So what’s so special about chirocaine? It’s twice the price of standard bupivacaine per 10mL ampule, so it’s twice as good, isn’t it?

Well, no – it seems to be equivalent at providing analgesia in a variety of blocks (caudal, ilioinguinial, rectus sheath… The list goes on…), but every study is focussed on the reduction in adverse (cardiac) effects with levobupivacaine. It seems the rationale for selecting out this isomer is reducing cardiac toxicity. Where does this come from?

Most data comes from animal studies (in case you didn’t know, children are no more little adults than they are little rats, pigs, rabbits…).

You have to dig quite deep for original studies. All roads seem to lead back to this one paper. 14 healthy, adult, male subjects were injected with bupivacaine or levobupivacaine infusion and asked “do you have any symptoms?”. OK, let’s be fair, they’ve powered the study to detect a 10% difference in their primary outcome (stroke volume), but their bottom line conclusion is “that levobupivacaine may be a safer drug than rac-bupivacaine for procedures requiring high doses of local anaesthetic.” So not really our fractured femur toddlers, then.

Which brings us back to the beginning. Studies in children have suggested that levobupivacaine produces equivalent anaesthetic efficacy, but what they haven’t done is convince me that we should ditch bupivacaine when we are using such tiny doses. It’s cheaper, and with ultrasound guidance we can use a miniscule amount to achieve local anaesthesia long enough to reduce the fracture in a Thomas splint.

So the bottom line is this; use what you’ve got unless there’s specific cardiac risk for your paed patient, and using 50:50 with 0.5% chirocaine provides the same analgesia as bupivacaine (in our hospital the maximum dosing for ilioinguinal block is apparently 1.25mg/kg/side). Whatever you use, do the block; your patients will probably thank you (but we might have to wait to find out).

Natalie May

Ref

• A comparison of the cardiovascular effects of levobupivicane and rac-bupivicane following intravenous administration to healthy volunteers. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873676/pdf/bcp0046-0245.pdf
• EPG data sheet on Chirocaine http://www.epgonline.org/drugs/chirocaine/
• Regional anaesthesia for kids with femoral fractures at BestBets http://www.bestbets.org/bets/bet.php?id=130

The Ondansetron question

In your standard ED practice – do you give anti-emetics (specifically ondansetron) to children with gastroenteritis, hoping to improve the tolerance of oral rehydration?

This has always been a debated topic, but has recently been given extra fuel by the issue of a drug safety warning by the FDA – Ondansetron: risk of abnormal heart rhythms…..

In the resource-rich world use of anti-emetics in gastroenteritis is questioned because we have resources available for NG and IV rehydration strategies and we also rarely see death in this cohort of patients. Still the burden of the attendance to ED’s huge, gastroenteritis in the UK accounts for more than 500,000 consultations and 7% of hospital admissions in children under 5years.

In developing countries, the situation is starkly about mortality: diarrhoeal disease was the third leading cause of death in resource-poor (and middle-income) countries, causing 6.9% of deaths overall. In children under five years old, diarrhoeal disease is the second leading cause of death – 1.5 million deaths (figures from WHO).

Oral rehydration is still the mainstay of treatment of children with gastroenteritis throughout the world. Recently studies have showed that the addition of oral ondansetron can reduce vomiting episodes and facilitate oral rehydration (see Bestbet No.1442 for a succinct overview of the evidence). In the UK, NICE have produced guidance on childhood gastroenteritis (CG84), devoting a large section to a discussion on the evidence for and against ondansetron. In which they fall short of advocating its use (this was produced prior to the drug safety warning).

At the ICEM2012 recently, Hezi Waisman from Israel spoke of the efficacy and advantages of using ondansetron in children with gastroenteritis and was supportive of routine use. However debate was started when Baljit Cheema – a Paediatric Emergency Physician in South Africa – said that ondansetron had been withheld from formularies in ED’s in South Africa since the drug safety warning.

So what is the drug safety warning? Well, the information has come from the FDA who give this advice:

“The anti-nausea drug ondansetron (marketed as Zofran and in generic forms) should not be used in patients with congenital long QT syndrome, as they are at particular risk for developing torsade de pointes while taking the drug. Also at increased risk are patients with congestive heart failure or bradyarrhythmias, those predisposed to low potassium and magnesium levels, and those taking other drugs that can lead to QT prolongation. Accordingly, ECG monitoring is now recommended for such patients using ondansetron.”

The evidence cited by the FDA comes from 3 papers that have been published in anaesthetic journals. These papers have suggested that ondansetron can prolong the cardiac QT interval in some patients and extrapolated that this could be proarrythmic (patients with QTc >500ms are at risk of developing ventricular tachyarrythmia).

Looking closely at the cited evidence:

The first paper (Charbit et al) took a group of 85 patients under going anaesthetic (note that all inhalational anaesthetics and suxamethonium and patient temperature and known to prolong QT interval) then recorded ECG’s after the administration of ondansetron and droperidol (another anti-emetic known to prolong QT intervals). Patients were not randomized and there were no placebo groups. They found that in the ondansetron group showed a significant difference in (prolonged) QT interval after drug administration, however only 13% of these patients showed a QT >500ms and there were no other ECG abnormalities or adverse events during the study. Apart from the metholodical flaws in selection, it is unclear how this study relates to practice outside of the anaesthetic department as the sample had a baseline of 20% prevalence of prolonged QT prior to drug administration compared to the general population prevalence of 0.1% (thought to be due to anaesthetic drugs)….

The second paper (by the same team Charbit et al) is a well-designed, prospective cross-over trial in a healthy population, powered to detect a difference in QT length. This time they found again that ondansetron significantly (statistically) prolonged the QT interval. But no patient reached a QT of >500ms or indeed experience any arrhythmia or adverse event.

The final paper (by Nathan et al) is a retrospective chart based cohort study looking at all adverse events in children with known prolonged QT syndrome undergoing anaesthesia. There were 76 patients with 114 anaesthetic encounters. Only 2 adverse events (i.e. cardiac dysrrythmia requiring treatment) occurred but these were thought to be in close temporal proximity to administration of either reversal agent or ondansetron. Despite the fact that the adverse event rate was only 2.6% in a population known to already have prolonged QT and the fact that the events might or might not have been related to anti-emetic or reversal of anaesthetic or sympathetic drive during emergence from anaesthesia the authors conclude that ondansetron should be avoided…..

This is the evidence that has supported the FDA decision and, whilst I agree patient safety is paramount and all potential drug adverse effects should be flagged, I’m not sure that these 3 papers should induce clinical panic…

Now I want to write an impartial piece to generate discussion around the issue of ondansetron use in the ED, but as I write I am becoming a little distracted and bias – so I will sum up….

Gastroenteritis is a worldwide problem and leading cause of death amongst children under the age of 5years. The mainstay of treatment is oral rehydration, and ondansetron is clinically effective to aid this approach – increasing oral intake and reducing the use of IV therapy. In many countries the use of ondansetron is still debated (and specific to the UK not endorsed by NICE). Based on the evidence presented above the FDA has produced a drug warning that has resulted in some countries – notably a middle income country with a significant disease burden – withholding ondansetron use in children with gastroenteritis.

The question about ondansetron is actually opens a number of clinical, ethical and understanding of risk debates? What conclusions do you draw?

I’d be interested in your opinions.

Tom Bartram