Thursday, 23 November 2017

Is Montelukast Too Easy?

How much does the acceptability of a treatment matter when compared to the efficacy of that treatment?  This is a decision that we all make, consciously or unconsciously when prescribing for children.

For example, ten to twenty years ago, it was not uncommon for children to be given salbutamol in a liquid preparation.  The decision to give this preparation (rather than via MDI and spacer) probably went something like this:
  1. A very small person is wheezy
  2. A parent wants a treatment for the wheezy small person
  3. It is difficult to give inhaled bronchodilators to small people
  4. There is a liquid preparation of salbutamol available
At the time, there was probably also an element of inertia which came from the era before the invention of the spacer.  Until spacers came on the market, liquid preparations were the only option for young children.  So despite the change in what was available, it is not surprising that some continued to use what  they had used previously.  Now, I never see children on salbutamol syrup.  Inhaled therapy is the best treatment option and ease of administration is overruled by the superiority of child-friendly spacer devices.

Ease of administration, acceptability of taste and lack of side effects all make a considerable difference to the effectiveness of medicines in children.  One of the most common examples of this is phenoxymethypenicillin, often used for suspected streptococcal throat infections.  It has a vile taste and is often rejected by the child after the first few doses.  It can't work if the child won't take it.  Fortunately it is often not needed, so it doesn't matter when the child votes with their feet.

By contrast, montelukast is one of the great success stories of child-friendly medicines of recent times.  It comes in a chewy tablet or sprinkles.  It's like being Dr Willy Wonka when you prescribe montelukast for children.

Acceptability is not the only factor when it comes to effectiveness.  There has to be a proven clinical efficacy.  Otherwise, montelukast becomes the salbutamol syrup of our generation.  Just because it's a medication for wheezy children doesn't mean it will work in every clinical scenario.  Just because it is easy to administer doesn't mean it should be the first line treatment.

A recent article in the Archives of Disease in Childhood (1) did an excellent job of exploring the evidence for montelukast as a treatment in the various phenotypes of childhood wheeze.  This was no mean feat considering how many there are and that these phenotypes are variously defined and hotly debated.

Here is a summary of what they found:

Bronchiolitis* and montelukast

Unsurprisingly, montelukast can be added to the list of things that don't work when a child under the age of two has wet, inflamed airways (without bronchospasm).  No doubt we will coninue to look for an effective treatment but so far nothing has worked.  The management of bronchiolitis remains the art of doing as much nothing as possible, while knowing exactly when to do something.

* Bronchiolitis is defined slightly differently in the UK  to the USA.  In the UK, it is mainly infants under the age of 12 months with wet lungs of viral aetiology who are given the label bronchiolitis.  In the USA, the definition includes young children with viral induced bronchospasm.  This is why the UK guidelines recommend that bronchodilators are not used, while the guidance in the USA is that they an be tried.

Viral Wheeze (Viral Episodic Wheeze) and montelukast

There is some conflicting evidence for the use of montelukast both as prevention and as rescue treatment for pre-school children who develop bronchospasm only when they get a viral URTI (i.e. no other triggers and no chronic symptoms).  However, a Cochrane review (2) did not find the evidence needed to support the use of montelukast as rescue therapy or as a preventative treatment for viral wheeze.  So it seems that it's not really useful for these children either.

Multi-trigger Wheeze (aka asthma in the under 5 year olds) and montelukast

If you weren't already aware, there is debate about whether children under the age of five should be diagnosed as asthmatic even when they have interval symptoms and wheezy episodes which are not exclusively triggered by viral episodes.  Some are calling this asthma and some call it viral wheeze.  Arguably, it doesn't matter too much what it is called so long as we use evidence based treatment and we avoid mislabelling children who do not fit this phenotype.  For example, it would be a mistake to say that viral episodic wheeze is the same as asthma since the latter benefits from inhaled corticosteroids (ICS) and the former does not.  With multi-trigger wheeze and asthma in the under five year-olds, we essentially have two names for the same clinical scenario.

The article in ADC notes that the BTS/SIGN guidance recommends leukotrine receptor antagonists (LTRAs) as the next step after low dose inhaled corticosteroids or as first line treatment where the ICS is not tolerated.

The authors go on to note that while there is good evidence for benefit in this group of children, the effects of montelukast are moderate and clinically inferior to ICS.  Also, there is no evidence to show that montelukast is effective above and beyond the benefit of ICS therapy.  So, if there is a treatment with good evidence for superiority, how badly does a child have to not tolerate that treatment before you reach for the next option?

Since effect and tolerance are both important factors in the efficacy of a treatment, we need to consider both factors.  Clearly if one factor is the same between two option, then the other is the deciding factor.  In the case of the asthmatic/ MTW three year old, you may be faced with a difficult choice:
  • Inhaled corticosteroids, which their parents are struggling to give
  • Montelukast which is clinically inferior to inhaled corticosteroids but which the child might happily take
If only we had a formula to help us decide...  So, I made one up.  After all, paediatrics is full of things that were invented by clinicians based on what they believed to be true.
So let's try this out.  Say that ICS therapy has a 90% likelihood of improving symptoms and that montelukast has a 20% likelihood.  Then say that parents will manage to give the montelukast every day and that they would manage to give the inhaled corticosteroids half of the time.  This gives us a BS cubed number of 0.11 for the steroid inhalers and 0.2 for the montelukast.

Although the formula is made up, the point is valid.  Efficacy and concordance are the key factors in determining effectiveness.  Since we can't change the efficacy of a treatment, we are only able to influence the concordance.  In the example given above, if we could improve the concordance then this is a complete game changer.  This is where a full team approach comes in.  The prescribing clinician can emphasise the superiority of ICS over other treatments.  The pharmacist can make a huge difference by a good explanation and demonstration.  This can all be reinforced by a practice nurse who reviews technique and encourages the use of the inhaler, giving tips and tricks about how to get the child to take their inhalers.

Persistence counts for a lot with inhaler therapies.  There are few (if any) children who immediately take to the idea of having a mask put on their face and few parents who find it easy to use the inhaler/ spacer combination well with a moving target to begin with.  In time, children come to accept that the inhalers will be given and parents usually find that giving them becomes easier.

If the easy treatment was also the most effective, that would be brilliant wouldn't it?  For some reason, that rarely seems to be the case.  Is montelukast too easy?  If it makes us choose it over trying everything possible to get the inhaled therapy to work, then the answer is yes.

So, choose the treatment with the biggest boom and maximise the sweetness of the delivery.  It that way, the child who will benefit gets the best possible treatment in the most effective way.

Edward Snelson
Order of the Philosophers of Mathematics

Disclaimer - although a made up formula, there is good reason for applying a factor to the concordance.  In very few cases does half the treatment have half the effect.  Small moves away from the centre of the therapeutic window of a drug make a very big difference to the effect that it will have.  I wanted to use a round number for simplicity but I would be willing to bet that the reality for most treatments lies somewhere between squared and cubed.  Wouldn't it be great if the answer was really that the factor was pie?

  1. Haq et al, Should we use montelukast in wheezy children? Archives of Disease in Childhood, October 2017
  2. Brodie M et al, Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children Cochrane Database Syst Rev. 2015 Oct 19

Monday, 6 November 2017

A Paediatric Guide to Anatomy (Things You Should Know about Constipation and Urinary Tract Infection in Children)

Last week, Norfolk and Norwich University Hospitals announced the opening of the UK's first Senior Emergency Department.  A Senior Emergency Department is much like a Paediatric Emergency Department, except that this one will meet the needs of patients over the age of 80, instead of those under the age of 16.  The concept is the same - there is a specific patient group with a different set of needs and who present in different ways to the rest of the adult population.

Children have been able to access paediatric emergency departments for a long time now.  Children benefit from a child-friendly waiting area, an assessment that recognises the way that children are different from adults and treatment by clinicians who are specifically trained in child health.  Perhaps that makes it all sound very exclusive and mysterious.  What are these differences of which you speak?  Well, none of them are a great secret, but as is often the case, having something explained often helps it to be understood better, even if you already knew it.

So, here's something that you probably already knew, but was a fact that you hadn't necessarily known what to do with: Children have a considerable lack of body awareness. 

A child's approach to anatomy and physiology is fairly simple:  I eat, I wee and I poo.  I pick things up if I want them.  If I want to do any of those things in a different location then I move.  If the world isn't the way I want it to be, I make noises.

One of my top tips when teaching paediatric clinical examination is that children don't have a chest before they go to school.  To them, the space between mouth and stomach is presumably some sort of giant food processing area.  Functions like breathing and circulation only truly become a reality when a child is much older.  For that reason I never tell a young child that I am going to listen to their chest.  It only confuses them if you say that.  I tell them I am going to listen to their tummy and tell them what I can hear.  Usually, the answer is sausages.

Besides helping me to know what to say to children, my knowledge of their lack of body awareness is crucial when it comes to understanding visceral presentations in children.  The important thing to understand is that children seem mostly unable to recognise the significance of visceral symptoms.  In other words, the feelings in their bowel and bladder either make no sense to them, or they are unable to articulate these feelings.  For whatever reason, young children have a tendency to leave bowel and bladder symptoms unreported, and so the presentation of problems such as urinary tract infection (UTI) and constipation are always delayed.

Take this case history example:
A two year old child presents with a 12 hour history of dysuria and frequency of urine.  They have no fever or abdominal pain.

Well, that's all very well, but that's just not how it goes.  Let's try something more realistic:
A two year old presents with a three day history of fever.  The child first presented two days ago and was diagnosed as having viral gastroenteritis.  The child is vomiting intermittently.  There is no blood or bile in the vomit.  The child does not have diarrhoea.
Today the parents have noticed that their child is more unsettled and they think that the child has abdominal pain, although the child has not specifically said that their tummy hurts.

Why is it important to recognise this peculiarity of children?

The first reason is that we need to be aware that UTI is a diagnosis that we have to actively  seek in children.  UTI in younger children does not have specific (urinary) symptoms.  Instead, all of the features are those also found in the more common viral infections such as gastroenteritis or URTI.

This does not mean that all unwell children should have a urine tested.  Routine testing would be great if it were painless for the family and the clinician.  Neither of these things are true.  Getting an uncontaminated sample (a 'clean catch') is hard work much of the time.  Interpreting the results and making sense of conflicting information is a challenge once a sample is obtained.  For that reason I would not routinely ask for a urine sample in a child who has an obvious otitis media for example.

The things that make UTI more likely in children include:

  • previous UTI
  • abdominal pain/ tenderness
  • vomiting without diarrhoea
  • a report of odd smelling urine
  • absence of signs or symptoms of URTI
  • new urinary symptoms (enuresis, dysuria)

The second reason is that we need to be aware that both UTI and constipation are likely to be well established by the time they are diagnosed.   This means that in children, we have to take each of these diagnoses a little more seriously.

Although most children with UTI are well at presentation, they probably have an infection that is a little more than what would be considered cystitis.  They may not have a proper pyelonephritis yet, but they are likely to have a more established infection than a young adult would have.  It is for this reason that we need to make sure that we do pick up a diagnosis of UTI as early as possible.  Every day left untreated increases the risk of renal scarring.

With constipation, the significance of the way it presents is more to do with the length of treatment needed to resolve the problem than the urgency to start treatment (as with UTI in children).  By the time that the child and parent are aware of the problem, constipation is usually very well established.  The child's bowel has been full of stool for weeks or months.  The bowel is stretched, weak and insensitive.  Prune juice and porridge are simply not going to do the job of resolving the constipation by the time that a child gets as far as their first medical assessment.

At this point, a short course of treatment for constipation simply will not suffice to truly resolve the problem.  Macrogol laxatives (the treatment recommended by the UK's NICE guideline) will do a great job, in almost every case, of clearing out the bowel.  This is not the same as treating the underlying condition.  We need to continue treatment until the bowel has a chance to do its thing again.

The effective treatment of idiopathic constipation in children requires two things.  Firstly, it requires adequate doses the right laxative (I avoid lactulose) for as long as it takes to allow the return of strength, shape and sensation to the bowel.  The consensus on this is that this will take about six months of maintenance therapy to achieve.

The second thing needed is some sort of modification to lifestyle that will help to avoid the return to constipation once treatment is stopped.  Changing diet, fluid intake and toileting habits may make all the difference, once the treatment has given the child their normal bowel back.

So I would suggest that we never think in terms of 'just a UTI' or 'a little bit of constipation' in children.  The delay in presentation, coupled with the extra time it may take us to actually get to the diagnosis means that neither of these terms apply.

I suspect that this could all be applied to the elderly with a little modification, but I'm not about to start  I'll just leave that thought with my innovative colleagues at the Norfolk and Norwich University Hospitals.

Edward Snelson
Part-time Vicerologist

Disclaimer - While I know deep down that it would be a terrible idea, part of me wants to combine a Paediatric Emergency Department with a Senior Emergency Department.  I can imagine how the two patient groups would be quite good for each other.  And that folks, is why I should never be allowed to have ideas.