Acute Asthma.

[Arctickat]

Geez Dwayne, you've been out in the boonies for too long. When do you rotate back?

[DwayneEMTP]

28/Oct...about 12 years from now it seems...

[J306]

I think it's great that we're able to go into such detail on the pharmacology and chemical structure of the drugs that we're administering. Just learning about the types of receptors in school now and reading about it in practical application really helps things click and fall into place!

As for keeping up with knowledge and re-learning a lot of the things that have been forgotten over the years, I stumbled across a series of medical videos on youtube which are completely free and break down everything into detail step by step, and it didn't feel right to not pass it along to those other than my classmates. Here's the link, his name is Dr. Najeeb and he's been teaching Medical school students for 25 years. http://www.youtube.com/user/DoctorNajeeb?feature=CAQQwRs%3D

[J306]

Sorry, link didn't copy right:

[systemet]

cAMP interacts with receptors on actin/myosin cross bridges and this is what essentially leads to bronchodilation.

Chbare is a really smart guy, and may well have simplified this to help explain a complex phenomenon. I just want to point out quickly that there's no cAMP receptor on the cross-bridges, and that most of the effects of cAMP are mediated via another regulatory molecule called protein kinase A (aka cAMP dependent protein kinase). Depending on whose textbook you read, PKA may inhibit another enzyme called MLCK, ultimately resulting in a decreased number of active cross-bridges available for cycling. Some doubt has been cast on whether this is physiologically relevant, but PKA also affects Ca2+ handling in the smooth muscle cell, which may be more important. To complicate things further, there's a fair amount of cross-talk between cAMP/PKA-mediated pathways and cGMP/PKG mediated pathways. This isn't fully understood yet.

You could in essence say that increased cAMP equals smooth muscle relaxation and bronchodilation.

I think that this is entirely accurate, and likely the most important part of the message for most of us.

Unfortunately, the data that I have seen is not conclusive and some studies contradict each other. I would say the evidence for the use of glucagon in this case is relatively weak, but I do not think it would necessarily be harmful.

While Chbare's knowledge in this area likely outstrips mine, I also agree. For glucagon to be useful, there have to be enough glucagon receptors expressed in the bronchial smooth muscle, with enough cAMP elevation and PKA activation to achieve a measurable incremental benefit beyond beta-agonists, with the doses available prehospitally.

I can't claim an extensive knowledge of the literature, but a quick search revealed one small study that compared 0.03mg/kg (i.e. ~ 1.5-3mg) glucaon IV versus saline in patients with asthma exacerbation (PEFR < 350 L/min), and showed no improvement with glucagon. This study was likely underpowered to find a small difference, and dealt with a fairly homogenous group including a lot of lower acuity patients, but suggests that the bronchodilatory effects of glucagon are pretty weak.

Wilber ST, Wilson JE, Blanda M, Gerson LW, Meerbaum SO, Janas G. The bronchodilator effect of intravenous glucagon in asthma exacerbation: a randomized, controlled trial.Ann Emerg Med. 2000 Nov;36(5):427-31.

[systemet]

I just wanted to address a couple of things here, as well:

So it sounds like steroids would be an option, but more as a prophylaxis - although if they aren't contraindicated and we have time it looks like a good component to consider

I think right general idea, but wrong nomenclature. You're treating a disease state that's already declared itself, versus trying to pre-empt something that might happen. Also, the steroids are unlikely to be contraindicated in any severe asthma exacerbation. It's more a matter or prioritising interventions if you're working with a small crew. In an ideal environment, with lots of hands, steroids should go in at t=0. Most of the time, it just doesn't work out that way.

Would administering adrenaline/epi pre-cardiac arrest - (e.g the phase of respiratory arrest before cardiac) - possibly be of some benefit for resuscitation or defibrillation if needed and therefore act as a sort of therapy and precaution?

Might increase the chance of succesful first-shock defibrillation, although the data supporting that is from the days of monophasic defibrillators. As for benefiting resucitation, there's no evidence that epinephrine does much beyond improving the success of initial defibrillation and raising arterial and thus coronary perfusion pressure during CPR. There's no evidence supporting a benefit of epinephrine on long-term survival / neurological outcome, and there's growing concern that historical use of epinephrine may even have been detrimental.

So, probably not. We can't show that the epinephrine we currently give is much better than walking

into the patients kitchen, finding a jar of peanut butter and smearing them with it.

think magnesium looks like quite an interesting intervention, I remained quite skeptical until now as it is in an natural occurring mineral (or less pharmacuetic than most) and my assumption was that it hasn't been pharmacologically targeted in the same way as most medicines, but then again I suppose adrenaline is quite similar in that respect - It would be interesting to see if magnesium has an analogue by now like salbutamol and adrenaline.

A few thoughts:

* "Analogue" is usually reserved for the description of similar organic compounds, i.e. compounds build on a carbon backbone. It makes some sense to say that dopamine is an analogue of epinephrine, but we don't usually say the same thing when discussing inorganics, e.g. H2S and water.

* Few pharmaceuticals have really been "targeted". Most have been used traditionally, believed to have a beneficial effect, e.g. morphine, ASA, digoxin, or used for years before their pharmacology was really unravelled, e.g. penicillin. Some really aren't understood now, but continue to be used because they work, e.g. lithium in bipolar disorder. Even today, most new pharamaceuticals are designed by taking a structure that's known to have an effect, and developing 10's of thousands of similar looking molecules, and seeing if they have a beneficial effect ("combinatorial design" and "high throughput screening). It's appeaing to see science as this process where the disease is identified, understood at the molecular level, and then some enterprising pharmaceutical chemist designs an agent to target the aberrant process responsible. More often what happens is an agent has been used historically, potentially has a benefit, and is seeing widespread use. Researchers later identify what systems it affects, and then look at whether those systems are involved in the disease pathogenesis. We're starting to see some movement towards targeted design, but the entire multibillion dollar pharmaceutical industry only licences about 2 novel-clinical entities per year. The vast majority of new drugs are modifications on an existing structure that's proposed to have better pharmacokinetics, or less off-target activity.

Is this due to Ketamine's ability to cause respiratory depression?

No. More because ketamine stimulates sympathetic outflow, so it tends to cause tachycardia, hypertension and bronchodilation, at least if the sympathetic nervous system isn't completely exhausted, or the effector tissues unresponsive, e.g. some sepsis patients, a few other conditions. So, if you're going to intubate with something, an agent that might have an added bronchodilator effect is a good idea.

[chbare]

It does not appear that my knowledge outstrips yours brother.

[BushyFromOz]

Most have been used traditionally, believed to have a beneficial effect

My favourite textbook line "the mechanism of action is poorly understood, however is thought to be mainly due to ..........."

You get the idea

Random,. random, random thought.......

More because ketamine stimulates sympathetic outflow, so it tends to cause tachycardia, hypertension and bronchodilation, at least if the sympathetic nervous system isn't completely exhausted, or the effector tissues unresponsive, e.g. some sepsis patients, a few other conditions. So, if you're going to intubate with something, an agent that might have an added bronchodilator effect is a good idea.

Would you be hesitant to use ketamine as an induction agent for a patient with spinal chord lesion / transection who has a history of autonomic dysreflexia?

[systemet]

Would you be hesitant to use ketamine as an induction agent for a patient with spinal chord lesion / transection who has a history of autonomic dysreflexia?

Good question. I'm ashamed to admit I hadn't considered this scenario. It also may be a question that's a little above my paygrade and better asked of someone like ERDoc, or someone with an anesthesia background.

As I understand it, ketamine is a negative inotrope, and also causes smooth muscle relaxation, in isolated cardiac and vessel preparations. Usually we see vasoconstriction, and increases in contractility and heart rate due to increased sympathetic outflow. It seems reasonable that these would be absent in someone with autonomic dysreflexia, but I think we're probably simplifying the situation a little, as both the action of ketamine and the different degrees of spinal cord injury are probably more complex than I'm making them out to be. How significant a drop in blood pressure would occur, and how much bronchodilation would remain without increased sympathetic activation, I honestly don't know.

Sorry for the slow (and waffling) response, I've been travelling a little.

(Edit: Just wanted to add that as we're talking about intubating people with spinal cord injuries, succinylcholine can cause life-threatening hyperkalemia in patients with pre-existing spinal cord injury).

Edited October 12, 2012 by systemet