INTRODUCTION

 

In this podcast, I’m going to be giving an overview of the drug adrenaline.  I’m going to talk a bit about the history of adrenaline and then I’m going to go through the mechanism of action of adrenaline, which means I’ll be describing what it does in the body, down to the receptor level, so you can really understand what adrenaline is all about. 

 

Adrenaline is probably the best paramedic drug to talk about first because if you could only carry one drug as a paramedic, it would probably be adrenaline.  I’d say it’s the most fundamental drug that we use as paramedics, and if you ever meet a paramedic who doesn’t understand how adrenaline works, you would be safe to assume that that is not a very well-educated paramedic.

 

In the process of teaching you about adrenaline I’m going to be using terms like receptors, agonists, and antagonists.  So, if you’re not comfortable with those terms – stop, go review those ideas – and come back to this podcast when you’re comfortable with them.

 

PRE-DISCOVERY

 

Probably the first, real-life experience to bring awareness of adrenaline to humans happened early in our 200,000 year history when our distant ancestors came face-to-face with some sort of frightening danger and experienced the nausea and shiver inducing rush-of-energy we now call an ‘adrenaline rush’.

 

In the late 1800’s scientists had determined that the source of this ‘rush’ came from the medulla – the middle – of the adrenal glands.  We learned this due to fearless scientific adventurers like George Oliver, who in 1893, had his son swallow the adrenal gland of a sheep and noted how it caused his son’s blood vessels to become constricted (and you thought your dad was weird). 

 

In the late 1890’s scientists were hot on the track of the active substance causing these changes and there was a big race to be the first person to isolate the active compound and be able to synthesize it.  Otto von Furth in Strasburg isolated what he (incorrectly) thought was the active compound and called it ‘suprarenin’.  In 1897, the American John Abel, who we’ll come back to a bit later, isolated what he (also incorrectly) thought was the active compound and gave it the name ‘epinephrine’.

 

DISCOVERY

 

Then, at the beginning of the new century, in 1901 Jokichi Takamine, a prolific chemical researcher in Japan, correctly isolated the pure form of the active substance and called it adrenaline choosing the name that the British had previously invented for the as-yet-undiscovered active substance known to come from the adrenal gland[i]. 

 

Actually, in order to obtain the patent, Takamine called it ‘adrenalin’ (with no e) to differentiate it from the commonly used British name adrenaline (with an e), but that was for a legal loophole to allow the patent.  Everyone uses the ‘e’ now.  Also, interestingly, Takamine had to fight a lawsuit against him which put forward that naturally occurring hormones can’t be patented.  Takamine won, setting (for good or bad) a very influential legal precedent for medical science and the pharmacological industry which later became such a huge part of our modern society.

 

By discovering the exact chemical formula for adrenaline, Takamine became the first person to ever isolate any pure hormone from natural sources and it was the discovery and knowledge of hormones which set in motion the research that eventually led to an understanding of the previously inscrutable process of neurotransmission over 70 years later. 

 

Takamine had as fascinating history – his father was an actual Samurai who had learned Dutch and was one of the first people in Japan to study and practice western medicine.  The father encouraged his son to follow in his footsteps, but Jokichi decided he could make more of a difference as a chemist and, in addition to isolating adrenaline, he made many other remarkable discoveries with fertilizers, alcohol fermentation, and carbohydrate digestion that eventually earned him the epithet ‘The Japanese Thomas Edison[ii]’.

 

But let’s get back to the American John Abel who was the highly respected first professor ever of chemistry at John Hopkins university who had isolated what he called ‘epinephrine’.  Abel was incensed by Takamine’s accomplishment, feeling he had been unfairly scooped, and continued to claim (to his death bed) that he was the first to correctly discover the active substance.  Partially due to the ongoing, and somewhat unresolvable dispute between these two, and partially due to a very strong xenophobic backlash against Takamine in America (they burned down one of his factories!) Americans continued to call the substance epinephrine (the name Abel had chosen) while the rest of the world uses the name Takamine chose, and calls it adrenaline.  That’s why paramedic students today are faced with the fact that there are two names for the chemical C9H13NO3 – depending what part of the world you are from.  As if medicine isn’t confusing enough! 

 

Incidentally, both of the words epinephrine and adrenaline (and suprarenin too, come to think it) etymologically mean the same thing, only in different languages. Adrenaline is derived from the Latin ad (above) + renes (the kidney – the same word we get ‘renal’ from). Epinephrine, in ancient Greek comes from epi (above) and nephros (the kidney – the same word we get ‘nephron from), so both words mean ‘above the kidney’ – which was known to be the source of the chemical long before anyone isolated it.

 

To make it even more confusing, researchers later discovered and isolated another hormone from the adrenal medulla (and as it turns out, from sympathetic nerve endings as well) that was very similar to adrenaline.  In fact, it was so similar it took over 30 years to realise that the two chemicals were actually different.  It was only then that researchers realised that the early medical experiments with what they thought was pure adrenaline were hampered by the fact that their samples were actually mixtures of the two.  The new compound (with the formula C8H11NO3) that had very similar physiological effects to adrenaline, was eventually named noradrenaline (but the Americans - continuing Abel’s pique - determined to call it norepinephrine).  The reason it is called ‘NORadrenaline’ is because it was discovered that adrenaline is actually produced by the removal of one carbon and two hydrogen atoms from noradrenaline, meaning noradrenaline is a physiological precursor to adrenaline.  The ‘nor’ originally was used in chemistry to denote the ‘normal’ version of a compound[iii].  Thus ‘normal-adrenaline’ is converted in the body to produce ‘adrenaline’, and the two are very, very similar.

 

Both noradrenaline and adrenaline are used in paramedicine to treat our patients.  Adrenaline is a vastly more common drug than noradrenaline for paramedics to use.  Almost every paramedic carries adrenaline, and we use it for respiratory, allergic and cardiac conditions (more on this later). 

 

Noradrenaline, on the other hand, is a very ‘high end’ drug usually only used by paramedics doing interfacility critical care transfers.  Noradrenaline is run by IV pump and used to constrict blood vessels in order to maintain a patient’s blood pressure.  It’s a tricky drug to use and unless you are a paramedic working at that level, you won’t have to worry about it.  For people just learning about pharmacology the important point to remember is that adrenaline and noradrenaline are not the same thing, even though they do sound pretty similar.

 

 

 

Adrenaline                                                  Noradrenaline[iv]

 

POST DISCOVERY

 

In the early 1900’s a fellow by the name of Solomon Solis-Cohen was injecting the newly discovered adrenaline extract into asthmatics and noting a remarkable recovery in what was previously an intractable condition[v].  By 1910 articles in the Lancet were describing the use of adrenaline in which the author "claim[ed] marvellous results in the treatment of the paroxysm of asthma by the hypodermic use of preparations from the suprarenal glands. One injection of 10 minims (About 600 mcg) [vi] of 1:1000 solution [1 mg in 1 mL) is all that is required, but may be repeated if other attacks supervene."[vii]

 

Adrenaline actually became a popular fad for a while – believed to cure just about everything, and its popularity even led to the invention (for the first time) of the glass ampoule to house it safely as a liquid. That’s where all of our modern glass ampoules began.  It was one of the most common medications carried in a doctors ‘little black bag’ and it transformed surgery due to its ability to vasoconstrict a bleeding vessel and assist with stopping the bleed.  It was used in many disciplines and, as noted, was revolutionary in the treatment of asthma, as well as anaphylaxis.  Today, it’s not only paramedics that carry adrenaline around in the community.  Adrenaline auto-injectors (called either an EpiPen® or Anapen® depending on whether you are an American or not) are carried by countless citizens so that they can inject adrenaline into themselves in a medical emergency.

 

So much for history.

MECHANISM OF ACTION

 

How does adrenaline work in the body?  What’s it’s mechanism of action? There are actually four answers to this, because adrenaline does 4 different things.

 

The first thing it does, in no particular order, is act on the blood vessels.  In particular it acts on specific receptors in the blood vessels as an agonist.

 

ALPHA ONE RECEPTORS

 

In our blood vessels we have receptors that, when stimulated, cause our blood vessels to constrict.  These receptors are called alpha 1 receptors, so alpha one agonists will cause our blood vessels to constrict.  That’s pretty useful!  If you’re bleeding a lot then using an alpha one agonist can constrict your blood vessels to help slow, or even stop, the bleeding.  In fact, as I mentioned at the beginning of the podcast, this was one of the first medical uses of adrenaline that was discovered in surgery.  Also, if someone has lost control of their blood vessels and they dilate the vessels all over the body, causing their blood pressure to plummet, then using adrenaline as an alpha one receptor agonist to constrict the blood vessels can help to raise their blood pressure back up to a safer level.  So, you can immediately see why adrenaline is useful for someone in shock.

 

It’s also useful if you’re intentionally injecting a drug, like an anaesthetic, into someone’s tissue and you want the anaesthetic to stay in that area and not be carried away by the blood to rest of the body.  So, if you’re a dentist, using an anesthetic like lidocaine to numb someone’s mouth so you don’t hurt them, you would use lidocaine with a bit of adrenaline mixed in to help keep the lidocaine localized, in the gums where you injected it. 

 

In the emergency department you’ll hear that lidocaine is often referred to simply as ‘lidocaine with’ or ‘lidocaine without’.  They’re referring of course to whether it is lidocaine with adrenaline or lidocaine without adrenaline. 

 

You can see why we might want to use lidocaine with adrenaline – it’s pretty handy to keep the lidocaine in a restricted area, just like the dentists do.  Can you imagine when we might be forced to use ‘lidocaine without’?

 

The answer is that if we inject adrenaline into an area with a limited blood supply going into it, like at the base of a finger for example, we might cut off the blood supply to the entire finger and kill it.  So generations of medical students have been admonished to learn that you never use lidocaine with adrenaline on a patients’ nose, toes, fingers, or hose.

 

As paramedics, we use adrenaline’s alpha 1 receptor agonistic properties when we give patients in cardiac arrest adrenaline intravenously, or IV.  Contrary to what most people think, we’re not actually using adrenaline to try and restart the heart during cardiac arrest.  Instead, we’re using the alpha 1 receptor agonist effects to shut down the peripheral circulation, the circulation in the arms and the legs, so that the blood we’re pushing around during CPR perfuses the vital organs in the torso and head.  We don’t really care as much about saving someone’s toes as we do about saving their heart and brain. 

 

You can think of adrenaline then, as a chemical adjunct to CPR.  By agonising the alpha one receptors in the periphery, we ensure CPR compressions more effectively perfuse the patient’s vital organs.  The usual adult dose in cardiac arrest is 1 mg of adrenaline IV every 3 to 5 minutes, except in some special situations like, for example, when the patient is hypothermic.

 

However, the laudable and extremely important PARAMEDIC2 paper, published in 2018 has cast doubt on whether or not we should be continuing to administer adrenaline in cardiac arrest, so in the future we may not continue to use adrenaline this way.

 

BETA 1 RECEPTORS

 

That covers alpha one receptors.  Now let’s turn to Beta 1 receptors. The second thing that adrenaline does is act on different receptors that are found only in the heart.  These receptors are called beta 1 receptors.  So we talked about alpha one receptors in the blood vessels, but now we’ve switched to talking about beta one receptors, in the heart. 

 

When adrenaline binds with beta 1 receptors in the heart it causes four separate things to happen.  First, it causes the heart rate to speed up.  Second, it causes the heart muscle – or myocardium - to beat more powerfully.  Third, it causes the electrical signals in the heart to move more quickly through the myocardium, and fourth, it causes the heart to become more electrically irritable – which can lead (in extreme cases) to dangerous electrical dysrhythmias in the heart.

 

Chronotropy

 

Let’s dive somewhat deeply into some more medspeak.  In medicine, we refer to heart rate as chronotropy.  Chronos was the Greek God of time, and the root word ‘trope’ means ‘to turn’.  So, when we are referring to how often the heart ‘turns’ in a set amount of time, which is the heart rate, we say we are talking about ‘chronotropy’.  And the substances which affect heart rate are referred to as chronotropes. Chronotropes that speeds up the heart (like adrenaline) are considered to be ‘positive’ chronotropes whereas chronotropes that slow down the heart (like, for example, digoxin) are considered to be negative chronotropes.

 

Inotropy

 

Inotropy, on the other hand, refers to how powerfully the heart muscle contracts. In Greek the ‘ino’ prefix denotes ‘fibres’ or ‘sinew’ and (again) the root ‘trope’ means ‘to turn’.  So, an inotrope is something that ‘turns the fibres’ of (in this case) your heart, and makes it beat more or less powerfully.  Inotropes that increase the strength of contraction (like adrenaline) are considered to be ‘positive’ inotropes whereas inotropes that decrease the strength of contraction (like, for example calcium channel blockers) are considered to be ‘negative’ inotropes.

 

It’s important to remember that chronotropy (meaning rate) and inotropy (meaning strength) are very different effects. Digoxin, for example, is a negative chronotrope (it slows yours heart down) and a positive inotrope (it makes your heart contract more powerfully).  So, you’ll often see patients with heart failure taking digoxin in order to slow their heart down and make it stronger.

 

Dromotropy

 

The third effect that adrenaline has on the beta one receptors in the heart is referred to as dromotropy.  Dromotropy refers to how quickly the electrical signals in the heart can travel through the electrical bottleneck between the atria and ventricles – which we call the A (atria) V (ventricle) node.  In Greek the prefix ‘dromo’ means to run a trail or track.  So, a dromotrope is any agent that changes how fast the electricity can run through the ‘track’ of the AV node. Any agent which increases the speed of electrical conduction through the AV node is called a ‘positive’ dromotrope, and any agent that slows the speed of electrical conduction through the AV node is called a ‘negative’ dromotrope.  Adrenaline is a positive dromotrope, it speeds up electrical conduction through the AV node. 

 

Probably the most common negative dromotrope that paramedics use is adenosine which temporarily blocks the electrical impulses going through the AV node completely, and which can completely stop the heart for up to 30 seconds.  We use adenosine to try and slow down hearts that are beating dangerously fast.  Adenosine is the myocardial pharmacological tool for turning it off and turning it on again when it isn’t working.

 

Irritability

 

The last thing adrenaline does in the heart is increase electrical irritability.  To explain this think about the fact that all the cells in the heart have to depolarise in a coordinated manner in order to stimulate the heart to contract in a coordinated manner.  If the heart cells don’t cooperate with each other, if they don’t all wait their turn, then the heart won’t work properly.  Patient’s with increased myocardial irritability can start getting premature ventricular complexes or even have a ‘runaway’ rhythm like ventricular tachycardia – which is potentially deadly.  So, increased myocardial irritability can be life threatening.  That’s one of the downsides of using adrenaline on a patient, especially if they already happen to have a weak heart.   And it’s one of the dangers we have to consider carefully before we treat anyone with adrenaline.

 

Let’s pause and recap. We’ve spoken about adrenaline’s first effect on the alpha one receptors in the blood vessels.  Then, secondly, we spoke about the four different effects that adrenaline had on the beta one receptors in the heart – positive chronotropy, positive inotropy, positive dromotropy and increased irritability.  Those are the first two major effects of adrenaline – in the blood vessels and in the heart.

 

BETA 2

 

The third thing adrenaline does is act on the lungs.  In the lungs, we have different receptors again, which are called beta two receptors.  So, just to be clear, we have alpha one receptors in the blood vessels, beta one receptors in the heart, and beta two receptors in the lungs. 

 

Before you get confused about which beta receptors are where, you’ll be happy to know that clever medical students from previous generations have come up with a simple mnemonic to remember that the heart has beta one receptors and the lungs have beta two receptors.  If you remember that you have one heart, and two lungs, it will be easy to remember that our one heart has beta one receptors and our two lungs have beta two receptors.

 

When the beta two receptors in our lungs are stimulated they cause our airways to dilate, and to therefore be able to move more gas in and out of our lungs.  Adrenaline is a very powerful beta two receptor agonist.  Therefore, it causes the bronchi and bronchioles of the lungs to open up, or (in medspeak) it causes our patients to ‘bronchodilate’.  That’s really useful when our patients are in life threatening bronchoconstriction or bronchospasm, and that’s why paramedics give adrenaline to patients with life threatening asthma, anaphylaxis, or any other dangerous, bronchoconstrictive emergency.

 

Incidentally, most paramedics carry another beta 2 receptor agonist to help bronchodilate their patients.  That drug is called Ventolin (that’s the trade name) or salbutamol (which is the generic name).  In the United States it’s also called Albuterol. Salbutamol – which is what I’ll call it here -  works the same way that adrenaline does in the lungs – by stimulating the beta two receptors to initiate bronchodilation, and a lot of patients carry salbutamol puffers around with them every day for when their asthma starts acting up.  My youngest daughter has one, for example. However, salbutamol has a much weaker effect on alpha one and beta one receptors.  So, giving a patient salbutamol doesn’t constrict their blood vessels, or affect their heart anywhere near as much as adrenaline does. 

 

If you think of salbutamol as a gentle nudge to the alpha and beta receptors, then adrenaline is a powerful kick with a heavy boot.  It’s a much stronger agonist.  That’s why we tend to use salbutamol as our first agent in milder asthma, but we switch instead to adrenaline in life threatening asthma. In these instances, we’ll often administer anywhere from 200-500 micrograms of adrenaline into a patient intramuscularly, aiming primarily to have it exert its beta two effects in the lungs, to dilate the airways and allow the patient to breathe more effectively.

 

Let’s take a minute again to recap what we’ve covered so far, because I know it’s a lot.

 

Adrenaline has alpha one receptors effects, which means it causes our blood vessels to constrict, which is very useful to help increase blood pressure, decrease bleeding, or make CPR more effective by ensuring the blood we’re pumping stays in the core, and doesn’t go out to the arms or legs very much.

 

Adrenaline is also a powerful beta one receptor agonist.  Beta one receptors are in the heart – remember, we have ONE heart – and when they are stimulated they do four things; they increase inotropy (heart strength), chronotropy (heart rate), dromotropy (conduction speed through the AV node) and irritability (the amount of electrical misfiring we get in the heart). 

 

Ok, alpha one, beta one, beta two.  We now have the first three effects sorted.

GRANULOCYTES (MAST CELLS AND BASOPHILS)

 

The fourth and final major effect of adrenaline in the body occurs at two different places dispersed throughout the body.  In order to understand how this works we have to start with an understanding of how our body responds to an invasion of foreign microorganisms. If foreign bacteria or viruses or other microorganisms get into our body our body attempts to fight them off in a very, very complicated form of chemical warfare.  In fact, chemical warfare is a very good analogy for what happens.

 

Let’s try using another metaphor to explain this.  Imagine you’re a general in charge of protecting your city from foreign invaders.  In order to make this metaphor fit even better, I’m going to say that the city you’re charged with protecting is Venice, which, as we all know uses waterways as it’s principle transportation infrastructure, instead of roads, much like how our bodies use the bloodstream. 

 

Imagine that you’ve had a lot of time to prepare for the coming invasion and you’ve managed to prepare a bunch of booby-traps to stop the invaders.  Let’s imagine what would happen.

 

 

At the beginning of the invasion the attackers come sailing in through the water in various canals, or they parachute into the buildings on land throughout the city.  The water based attacks are the blood, and the attack on the buildings are the body’s cells.  In response, you send out your massive navy ships, bristling with guns and soldiers and you start attacking the invaders.  But the invaders are smart, and they’re small, so they start sailing into the smaller canals, or hiding in the middle of the buildings they’re in, in an attempt to outsmart you, figuring your large navy ships can’t get into the smaller canals easily.  But you’re smarter!  You already realized they might do this, so you have set small mines throughout the city to cause explosions which end up making the canals larger for your ships.  Those mines are set into the actual earth of the city, but there are also mines floating in the canal as well.  Obviously, all those detonating mines wreak havoc on the city, but it’s worth it, because it allows you to get your large warships where they need to go to kill all the invaders and keep the citizens safe.

 

Let’s now apply that metaphor to our bodies.  The canals are obviously analogous to the bloodstream, and the large navy ships are the white blood cells that fight off invasive microorganisms.  Let’s focus on the mines I mentioned in the metaphor.  Throughout the tissue of our bodies we have cells called Mast cells.  Mast cells are filled with a huge variety chemicals that – altogether – cause inflammation in our body.  The inflammation causes our blood vessels to dilate allowing more blood, and therefore more white blood cells, to enter into an area that’s being attacked.  The inflammation also makes the walls of the blood vessels more permeable so that white blood cells can actually leave the blood stream through the vessel walls and enter into our tissue, if there are foreign microorganisms there.  So, when the Mast cells are triggered we experience a great deal of inflammation in that area due to the chemicals that sit waiting within them.  There are quite a few different chemicals, and they each have slightly different effects.  If you’re really keen on doing a deep dive you can learn about these different chemicals like cytokines and chemokines, but you don’t need to in order to understand how adrenaline works. 

 

Just know that we have Mast cells in our tissue that release what we can just call ‘inflammatory mediators’ as a catch all term.  We also have other cells floating in our blood that release inflammatory mediators as well, and these are called basophils.  So, both mast cells and basophils store inflammatory mediators, in small granule sacks inside themselves, waiting for something to come along and trigger them so that they can explode their granule sacks, release the inflammatory mediators and cause the inflammation which allows the body to fight off invasive microorganisms.

 

ANAPHYLAXIS

 

But here’s the thing about inflammation.  Sometimes our body gets a bit trigger happy and start exploding WAAAY more of these mast cells and basophils than we need. This chain REACTION of exploding inflammatory cells starts to threaten our health more than the actual invaders ever could.  For example, this could happen if you are stung by a bee and your body, sensing the foreign bee venom, starts exploding millions of mast cells and basophils causing so much widespread inflammation throughout your entire body that your blood pressure starts to drop dangerously due to vasodilation, and your vessels start to leak fluid into your skin giving you itchy red spots across your body, and your airways start to shut closed because of all the swelling going on due to the inflammation.  This is, of course, the deadly condition of anaphylaxis – a dangerously out of control and exaggerated response to invasive microorganisms in the body. 

 

What to do …?

 

Well, if only we had a drug that could constrict the overly dilated blood vessels, and also speed up the heart help to help increase our blood pressure, and that could also cause our bronchioles to dilate to make it easier to breathe.  And while we’re wishing for the moon, why not ask for a drug that ALSO stabilises the membranes of mast cells and basophils so that it is much more difficult for them to explode and release excessive amounts of their inflammatory mediators.

 

Of course, that’s exactly what adrenaline does.  In addition to its alpha 1, beta 1 and beta 2 receptor agonist effects, it’s fourth and final effect is to stabilise the membranes of mast cells and basophils so that they don’t release as many inflammatory mediators.

 

Adrenaline is the perfect drug to treat anaphylaxis, and that’s why so many people with deadly allergies carry small cartridges with them filled with about 500 mcg of adrenaline that they can inject into their muscles in a life threatening anaphylactic emergency.

 

ADMINISTRATION

 

As paramedics, we carry our adrenaline in glass vials – not auto injectors.  To treat our patients, we inject adrenaline into the thigh.  Specifically, we inject it into the meaty muscle on the front, outer (or, anterolateral) part of our thigh, which is the vastus lateralis muscle.  We aim for the medial third of the vastus lateralis, which means roughly in the middle of the space between your knee and your hip.  It’s possible to inject right through clothing, but if you can avoid it that’s better.  We want to make sure we get right into the muscle, and we want to keep our needle clean – clothing can interfere with both of those objectives.  But if you’re patient is dying then, as we say in Canada – giv’er!  Which means, inject it directly through their clothes in order not to waste time.  If you’re injecting adrenaline into a child’s thigh then it’s a good idea to hold the child down securely because they can injure themselves if they move while you have the needle in their vastus lateralis. 

 

If your patient is obese, and you think you might not get the needle through the fat layer and into the muscle, which is where you want it, it’s better to inject into the lower half of the vastus lateralis because there is usually less fat there.  If the patient is very, very obese than an injection into their calf might be your best option, for the same reason.

 

 

In roughly 30% of patients you might have to give a second injection.  If you do you should change to a clean needle, and give the second injection in the other leg.  If we put too much adrenaline into one spot in the body we risk shutting down the blood to that area because of adrenaline’s alpha 1 effects and killing the tissue by depriving it of perfusion.

 

It’s also possible to administer adrenaline down an endotracheal tube.  Although we typically don’t do that so often anymore it may be helpful if you aren’t able to achieve an intramuscular injection for some reason. 

 

Adrenaline can be administered through an intravenous line, or an intraosseous line, although we typically administer a slightly lower dose, and this is a technique that’s usually reserved for more highly trained paramedics.  The best veins to use are the largest possible ones – ideally a central line – but we don’t usually do those as paramedics, so use the largest vein you can find in the arm.  We try to avoid using veins in the legs, especially in the elderly, or anyone suffering from vascular diseases (like diabetic endarteritis, arteriosclerosis or atherosclerosis).  It’s also really, really important to make sure you are in the vein before you inject the adrenaline.  So flush the line and make sure it’s running smoothly, and there isn’t any swelling or coolness at the IV site that might indicate your needle is in the tissue instead of the blood vessel.  A useful double-check is to take your IV bag and lower below the level of the patient’s arm.  You should see blood starting to back up the IV line.  If you don’t, you might not be in the vein.

 

If you end up injecting adrenaline into a patient’s tissue, instead of in the vein – a situation we would describe by saying that you’ve injected the adrenaline interstitially, or perhaps by saying that the adrenaline has extravasated – meaning it’s left the blood vessel, then this is a dangerous situation that threatens the tissue you’ve filled with adrenaline.  If it happens, you should get a syringe and gently draw back on the IV to remove as much of the adrenaline as you can from the patient.  Don’t try to flush the line, you want to get the adrenaline out, not push it in further.  Once you’ve gotten all that you can out, discontinue the line and remove the IV catheter.  Elevate the limb, so it drains, and put a heat pack onto the IV site to that the blood vessels there vasodilate and remove as much of the adrenaline as possible. 

 

Because the adrenaline will be exerting a very powerful, local alpha 1 receptor agonist effect and shutting down the blood vessels you’re going to want to use an alpha 1 antagonist.  In other words, a drug that blocks the alpha 1 receptors and interferes with adrenaline’s ability to cause vasoconstriction.  A common drug for this purpose is phentolamine which is a is a long-acting alpha-receptor antagonist.  However, most paramedics don’t carry phentolamine, so if we inject adrenaline interstitially our response should be to aspirate as much as we can, raise the limb, put a heat pack on it, and transport to the hospital and notify them of what has happened so that they can get the phentolamine ready at the hospital.

 

VASOPRESSOR

 

So, injecting adrenaline interstitially is dangerous because of its local alpha 1 effects, but there are situations where we rely on adrenalines alpha 1 agonist effects systemically to help our patients, and that is in normovolemic hypotenstion.  Let’s explain that means. 

 

Hypotension simply means that their blood pressure is low … and there are three main reasons why someone’s blood pressure could be low.  The first might be that they’ve lost a lot of blood.  Having a low volume of blood is described as being hypovolemic.  So low blood pressure due to low blood volume is described as hypovolemic hypotension, and that’s the hypotension that we’re most used to thinking of.  But there are two other reasons why someone’s blood pressure might be low.  It could be that the patient’s heart is not pumping powerfully enough.  They might have plenty of blood in their blood vessels, but without a working heart they’re still going to have low blood pressure.  This would be an example of normovolemic hypotension. If someone’s heart stops beating completely, and they die, they won’t have any blood pressure, even though they probably have a normal amount of  blood in their body.  This is probably the most extreme example of normovolemic hypotension, but’s definitely an illustrative one.

 

Another example of example of normovolemic hypotension occurs when a patient has a normal amount of blood in their vessels, and their hearts are beating well, but their blood vessels are dangerously dilated throughout their body and they are hypotensive because of the vasodilation. Sepsis is a perfect example of this situation.  Imagine someone who was feeling perfectly fine, with plenty of blood in their veins, but then they get an infection in their blood, and the chemicals produced by that infection causes their blood vessels to massively vasodilate.  They’ve got plenty of blood, and their heart is fine, but their wide-open blood vessels make it impossible for them to maintain an adequate blood pressure.

 

In this case, administering a slow, steady infusion of adrenaline will stimulate the patient’s alpha 1 receptors to cause vasoconstriction throughout the body and help raise the blood pressure.  However, before you try this it’s critically important to ensure that the patient first of all has an adequately beating heart, and second of all, that they have a normal amount of blood in their veins.  If they don’t, you need to fix those situations first, before you start an adrenaline infusion.

 

There are actually lots of drugs that you could use to constrict blood vessels – drugs that we call ‘vasopressors’ – and which one to use depends on the drugs available to you and your local practice guidelines, but just about everyone carries adrenaline and an IV bag of normal saline, and it’s definitely the drug of choice for anaphylactic hypotension, so I’ll describe how to run an adrenaline drip for vasopression. 

 

The first step is to get a vial with one milligram of adrenaline in it.  Adrenaline concentration is still often described using ancient apothecary terminology for some reason, but we’re trying to stop this.  Adrenaline often comes as 1 mg in 1 mL of fluid – which in the older, obsolete terminology is described as being ‘adrenaline, 1 in 1000’.  It also comes as 1 mg in 10 mL – which in the older, obsolete terminology is described as being ‘adrenaline, 1 in 10,000’.  Again, we’re trying to stop using this terminology because it’s confusing and it leads to errors, but you’ll still hear it.

 

Whether you use 1 mg of adrenaline in 1 mL of fluid, or in 10 mL of fluid doesn’t matter – it’s still the same amount of adrenaline.  It’s similar to whether you have a gram of sugar in a tablespoon or water or in a cup of water – it’s still one gram of sugar.

 

So take 1 mg of adrenaline and put it into a one litre bag of normal saline solution.  This makes a mixture of 1 mcg of adrenaline per 1 mL of fluid.  Then, run the bag wide open until the blood pressure comes back up.  Once it does, cut back the flow to about 2 drips a second.  If the blood pressure stays up, or increases, cut it back to about one drip per second, and keep on adjusting the flow until your patient is maintaining the pressure you want.

 

Doctors and nurses will probably shudder to hear that we do this, and that’s very understandable, because the ideal way to run an infusion – any infusion – properly is with an IV pump so that you can very carefully control your infusion rate and be precise.  But most paramedics don’t have IV pumps, and there’s no reason for our patients to die because of it, so crudely adjusting IV infusions like this is how we do it in the field, even though it is definitely less than an ideal situation. 

 

ASTHMA

 

There are some other situations in which we, as paramedics, normally use adrenaline. I mentioned previously that around 1900 Solomon Solis-Cohen had realised that injecting about 600 mcg of adrenaline into a patient helped relieve asthma.  And adrenaline is still routinely suggested as a medication to help alleviate asthma.  Typically, paramedic CPGs recommend that paramedics initially treat asthmatics with salbutamol and another drug called ipratropium bromide – both of which we’ll cover in another podcast – and if THOSE drugs don’t work, to then try treating the patient with adrenaline.  Using adrenaline this way, despite the fact that every paramedic is taught to do it, is actually considered an ‘off label’ use of adrenaline, which means that the manufacturer of adrenaline doesn’t actually recommend it.  It doesn’t mean that they say you shouldn’t use it this way, it just means that they don’t specifically recommend that you should.  Additionally, you might be surprised to hear that neither the National Asthma Council Australia (NACA) or the Global Initiative for Asthma (GINA) recommend adrenaline for asthma unless there is a clear component of anaphylaxis.  So again, what paramedics do is not entirely standard, but that’s how we do it in the field.  I’m sure there’s a good paper there exploring the discrepancy if you’re interested in writing it.  If you do, let me know!  The reason we use adrenaline in this case is, ostensibly at least, for its powerful beta 2 receptor agonist effects.

 

 

BRADYCARDIA

 

We’ve talked about using adrenaline in anaphylaxis, and as a vasopressor in sepsis or other vasodilatory emergencies, and for asthma as well.  The last thing we use adrenaline for as paramedics, is bradycardia.

 

If our patient has a heart rate that is too slow to maintain a sufficient blood pressure – if they are bradycardic – then we will want to try and speed up their heart rate.  Administering adrenaline is one way to do this.  Typically, we would try some other things first, like using atropine, or transcutaneous pacing, but if those don’t work then we’re going to fall back on our adrenaline.  In this case, it’s the beta 1 effects of adrenaline that we are relying on to increase chronotropy.

 

Our method of administration in this case is the same method of titrating to effect that we used for its vasopressor activity.  We put 1 mg into a 1000 mL bag and we titrate to effect.

 

CONTRAINDICATIONS

 

Let’s talk now about the contraindications to adrenaline – the times when we shouldn’t use it.  Generally, we only use adrenaline in life-threatening emergencies, so if we feel we need to use it, then we go ahead and use it.

 

 

 

ADVERSE EFFECTS

 

However, there are adverse effects that we need to be mindful of.  Because adrenaline’s alpha one receptor effects raise blood pressure we need to be careful of using adrenaline in anyone who is already dangerously hypertensive, who might be suffering disproportionately from relatively mild hypertension, or who could possibly suffer from any increase in their current blood pressure.  Such patients would include the normotensive or mildly hypertensive pregnant patient or stroke patient. 

 

Patients who are in thyrotoxicosis, or diabetic patients, or patients with narrow angle glaucoma shouldn’t receive adrenaline unless it’s required for life saving measures.  The thyrotoxic patient is already getting too much sympathetic stimulation from thyroid stimulating hormones.  Adrenaline causes the body to release sugar into the blood stream, so it can cause hyperglycemia, which might be deleterious for diabetic patients who are already hyperglycemic. 

 

Patients with a condition called pheochromocytoma have tumours on their adrenal glands which are filled with adrenaline.  When the adrenal glands are stimulated by adrenaline that you have given – which we call exogenous adrenaline – the tumours can release massive amounts of adrenaline in response leading to an adrenaline overload.

 

 

Patient’s with Parkinson disease might temporarily have increase psychomotor agitation or temporary worsening of symptoms.

 

In addition, rapid IV administration of adrenaline may cause death from cerebrovascular hemorrhage or cardiac dysrhythmias.

 

But again, it’s important to emphasize that NONE of these conditions should ever stop you from administering adrenaline to a patient in a life-threatening emergency who requires it.  If your patient is in anaphylaxis, or deadly bronchospasm, or septic shock refractory to fluid treatment, or profoundly bradycardic refractory to atropine and pacing, then you give adrenaline without hesitation unless you have a more appropriate medication on hand.

 

DRUG INTERACTIONS

 

Beta Blockers – cardioselective beta blockers may diminish effects of adrenaline, non-cardioselective beta blockaded patients may experience hypertension.

 

Will probably increase the sympathomimetic effects of cocaine and cannaboids.

 

 

Patients on Monoamine Oxidase Inhibitors, which are used to treat depression and some phobias, should be administered adrenaline with caution.  The reason for this is simple, monoamine oxidase is a substance in the body which breaks down adrenaline, so if they are taking monoamine oxidase inhibitors it means that they won’t be able to break down adrenaline properly and they’ll effectively end up being overdosed.

 

So, that’s how adrenaline works.  We’ve gone from bizarre dads feeding adrenal glands to their helpless children while measuring the effects on their blood pressure, to a transpacific feud which is still reflected in the two different names that adrenaline has, to the creation of glass ampules, to the first patent of a naturally occurring hormone, to the amazing discovery of neurotransmission, and the ubiquitous presence of adrenaline in every clinic, emergency department and paramedic kit bag around the world.

 

You will use adrenaline in your career as a paramedic.  This will be your best friend when confronted with asthmatics, anaphylactics, and those in vasodilatory shock and maybe even those with symptomatic bradycardia refractory to other treatement.  I’ve gratefully used adrenaline to save lives and you will too.  I hope this podcast has helped you to understand not only it’s fascinating and unexpectedly  diverse history, but also the effects it has on our body at a cellular level, and how we can harness those effects to save lives and reduce suffering.

 

Thanks for listening, and until next time, keep on studying, keep on caring, and keep safe out there.

 

 

[i] Yamashima, T. (2003). Jokichi Takamine (1854–1922), the samurai chemist, and his work on adrenalin. Journal of Medical Biography, (May). Retrieved from http://jmb.sagepub.com/content/11/2/95.short

 

[ii] Adrenalin and cherry trees. Joan Bennett.

http://pubs.acs.org/subscribe/archive/mdd/v04/i12/html/12timeline.html

 

[iii] Gaddum JH (June 1956). "The Prefix 'Nor' in Chemical Nomenclature". Nature 177 (1046): 1046. Bibcode:1956Natur.177.1046G . doi:10.1038/1771046b0

 

[iv] Taken from: http://en.wikipedia.org/wiki/Nor-

 

[v] Sneader, Walter, "Drug Discovery: A History," 2005, Wiley, Great Britain

 

[vi] About 600 mcg.  Taken from: http://www.convert-me.com/en/convert/volume/minim.html
 

[vii] Melland, Brian, "Some Therapeutic Suggestions: Asthma Paroxysms," Therapeutic Notes, volumes 17 and 18, 1909 and 1910, Park Davis and Company (this text is from "Therapeutic Notes, who quote it from an New England Medical Monthly, July, 2010.  The original article referred to here was published in Lancet, May 21, 1910)

 

 

Other references:

 

http://brainimmune.com/the-discovery-of-adrenaline/
 

http://hardluckasthma.blogspot.com.au/2013/03/1893-1933-how-does-epinephrine.html

 

Bennett MR. One hundred years of adrenaline: the discovery of autoreceptors. Clin Auton Res 1999; 9:145-159.

 

http://www.the-aps.org/mm/Publications/Journals/Physiologist/1980-1989/1982/April.pdf  - see page 76.

 

http://www.asthmahandbook.org.au/acute-asthma/clinical/add-on-treatment

 

https://ginasthma.org/2018-pocket-guide-for-asthma-management-and-prevention/