Croup and the speed of dexamethasone

aka Socrates and Sophistry 002

Socrates’ manner of philosophy was one of hypotheses. He is thought to be one of the forefathers of this type of thinking.  He employed a method of negative hypothesis elimination, whereby a series of questions could be asked, and in this way eliminate incorrect suppositions, and those that are contradictory.

In the Socrates and Sophistry series we will continue to look at either widely disseminated misinformation that is carried on through generations of texts and teachers, or ask questions where there is no accepted and agreed upon answer, or simply ask questions where the answer may be quite clear, just out of reach of us mortals with Google. Again we encourage anybody, of any persuasion, qualification, or inclination to contribute. There can be no wrong answers, only crowdsourced ideas.

Question:

Why does dexamethasone work so quickly (as early as 30 minutes) in croup?

Conventional teaching:

Glucocorticoids are required to bind to ligands within the cell and be transported into the nucleus, where they have their effect on DNA transcription.

But…to me, this doesn’t make sense.  Can anybody out there do better?…

Feel free to submit ANY answer to the comments section – we would love to hear your own thoughts, first principle analysis, expert exegesis or revel in revered references.  Remember NO answer can be wrong…otherwise we’d know the right answer already! If you want to discuss ‘Socrates and Sophistry’ topics on Twitter, use the #LITFLSAS hash tag.

If you have your own question, please submit it to… Michelle @ lifeinthefastlane.com

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Comments

  1. says

    The rapid effects of steroids may be mediated by cell surface receptors, such as G protein coupled receptors. This heresy was just gaining a foothold in my last days as budding biochemist before I turned to the medical darkside.

    As far as I know (and I’m no expert!), no GPCR for glucocorticoids have be characterised yet -- but there are pointers that they exist:
    http://www.ncbi.nlm.nih.gov/pubmed/22146309

    Furthermore a GPCR (GPR30) has been found that is thought to be activated by another steroid, estrogen:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847610/

    This is still all pretty heretical, controversial stuff.
    Chris

  2. says

    Another superb response, this time from SIMON CHIVERS -- which came via email.

    Certainly this topic is proving less controversial than the last, but will be followed by many more perplexing problems to come:

    “Glucocorticoids have an effect on immune response and are anti-inflammatory.
    It is the liganded receptor you mentioned that can trigger, within the cytosolic compartment, rapid response effects.

    Glucocorticoid immuno-suppressant effects stem from decreasing the transcription of various cytokine genes in the induction and effector immune-response phases. One of the gene transcriptions that is affected (decreased) is responsible for the proliferation of T-h cells. This immune-suppressant effect (not rapid) is coupled with various anti-inflammatory proteins being synthesised and released…ahh, this is the important bit…
    The anti-inflammatory action of glucocorticoids is due to another cytosolic effect, namely the release of the anti-inflammatory protein annexin-1. This is a potent inhibitor of leukocyte trafficking. This response is receptor mediated.

    So, why does dexamethasone act so quickly? The non-genomic receptor mediated response happens very quickly because they do not require changes in protein synthesis, as in the immune-reponse pathway.

    Simon C.

    Rang, H.P., Dale, M.M., Ritter, J.M., Flower, R.J., & Henderson, G., 2012, Pharmacology, 7th ed., Elsevier, Sydney. “

  3. Mike Jasumback says

    Not up to date on my croup literature, but if Michelle’s reference is the source for the claim that dex works in 60 minutes, i suggest that the assertion itself may be incorrect!

    • says

      Um… Mike, it works. It works quick.
      The curves in Gary’s study (quoted above) start deviating very early on (first 15min), and croup scores are significantly different by 30 minutes when comparing dex with placebo.
      I don’t know why it works so quickly… I’ve heard rumours about vasoconstriction -- decreasing oedema -- and that makes sense to me.
      For an interview with the guru himself, regarding the progress of steroid treatment in croup, check out our podcast on empem.org:
      http://empem.org/2011/01/croup-the-steroid-saga/
      There were non-believers in the past too…
      Cheers
      Colin

  4. says

    Another email response. This time from Tabby Stone, USC
    ? A different demographic in LA -- certainly a very different therapeutic experience from what we see in Australia.

    “I’ve been doing urgent care and until recently hospital pediatrics in the Los Angeles area for years. We see a fair amount of croup at our institution. I haven’t noticed a rapid improvement in croup that I could attribute to dexamethasone alone.

    If the croupy kids are significantly ill, they’re usually also getting inhalations which do work quickly so it would be hard to tell how much contribution the steroid is making in the early response.

    And with croup tending to vary in intensity through the day, I’d think it would depend a lot on time of day. Also, a lot of the kids described as having severe symptoms at home are markedly better by the time they arrive at the clinic following just the change in termperature and humidity on exposure to the cold night air during the trip to the clinic.

    That said, the kids who are not very ill are usually sent home shortly after getting the injection and we don’t see exactly when they get better.

    Tabby Stone, MD”

  5. Evan Cameron says

    Could the older age, 37.1 months versus 27.4, and therefore the larger diameter airway in the steroid group be a confounder? By my rough calculations from ETT sizing, and according to Poiseuille’s Law, airway resistance is 1.3 times less in the older group.

  6. Michael Jasumback says

    Ok, more of a response to Colin, but the way the study is presented there is no way you can legitimately assert that the curves diverge due to the dex alone. There is no data about who received other therapy etc.
    Having said that, Colin’s a smart guy and there is probably other evidence of the speed of dex, I’m just not familiar with it. I’m at work and can’t listen to the steroid saga! If you’ve got other references?????

    Mike Jasumback

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