Hi everyone, thank you so much for joining me on this webinar. Neuromuscular blocking agents getting a kick out of NMBAs. In this webinar, we are going to look at the neuromuscular junction and neurotransmission.
Discuss those neuromuscular blocking agents that we commonly use in practise, why we would want to be using them, and then also how to monitor a patient that has an MBA on board. So just having a look at an overview of muscle relaxation and anaesthesia, you can see here in the top right corner, we have the triad of general anaesthesia and these. Three things we like to accomplish when we induce a amnesia, we have analgesia, so pain relief, and we also have muscle relaxation.
So let's think about why muscle relaxation is part of the triad of general anaesthesia. Well, we want to provide muscle relaxation to provide balance anaesthesia. So, by providing balance anaesthesia, we can reduce the level of traction that's needed to open up surgical sites, for example.
And by doing that, we reduce any drug doses or, you know, high level of drug doses to facilitate opening up that surgical site. So, when we have less traction, we obviously have less postoperative pain, less postoperative inflammation at the surgical wound. And we must remember it is not actually an anaesthetic in itself, but we can use neuromuscular blocking agents or relax that muscle to facilitate our operation.
We could also relax the muscle as well to facilitate endotracheal intubation. So for example, a patient that is potentially at high risk of laryngospasm, we can relax the muscles and structures around the airway to facilitate this endotracheal intubation. We would usually otherwise do this with topical lidocaine, for example.
We also want to relax the muscles during anaesthesia so that we can perhaps provide effective IPPV or intermittent positive pressure ventilation for our patients undergoing anaesthesia. And this is really important where the breath needs to be regular and perhaps timed when the operating surgeon is in the thoracic cavity. We also might not want that patient to buck the ventilator or to fight against our ventilator.
Once again, it loops back into the balance anaesthesia part of why we want to relax muscle. We want this to assist, you know, provide some assistance in the surgical approach. So, for example, that laparotomy, when we open up the abdomen, we perhaps don't want those abdominal muscles to be really tight.
Same again with doing a thoracotomy. We don't want to be having excessive traction across the thorax or across the laparoscopic site. When we do a fracture repair, we might have, you know, in one of these injuries, some muscles tightening around, the fracture, where the fracture site is.
And it's not potentially going to let you, reduce the bad fracture any easier, because there still might be varying degrees of muscle fibrosis after the initial fracture has occurred. But it could, you know, it could still help us relax the muscles so that we could reduce a fracture. But also, we want the muscles to be really relaxed during anaesthesia for when we're doing things like microsurgeries.
So, for example, two really big ones, spinal anaesthesia and ophthalmic surgery as well, where, you know, small movements from the patient could potentially be quite catastrophic. And I think most of us are probably familiar with using NMBAs, and neuromuscular blocking agents, when we do cataract surgery, or when we're working on the cornea itself. When we provide general anaesthesia to our patients, that eyeball can roll away, or it can roll right out of view.
It often rolls ventromedly. So if we can centralise that eyeball by relaxing the muscle, then our operating surgeons can get a direct field of view. Also, if we have profound muscle relaxation as well, that I, that I actually protrude a little bit and makes it a bit easier to operate on.
So, how can we relax all of this muscle? Well, ideally, we relax just the skeletal muscle. We don't really want to be relaxing a smooth muscle.
We don't really at all want to be relaxing the cardiac muscle. So asking that question again, how can we relax the muscle so that we can do all the things that we just mentioned in the last slide? Well, there's a few ways we could provide deep general anaesthesia, this is going to reduce reflexes or voluntary muscle activity.
But what other effects does this have? What effects does deep anaesthesia have on our patients? Two big ones.
Cardiovascular effects and respiratory effects. So we're going to lose that contractility in our heart. We're going to get a vasodilation.
We could also get a profound hypoventilation as well, leading to hypocapnia. So this isn't an ideal choice. We could administer something like systemic benzodiazepine, which will reduce the muscle strength.
Alpha 2 agonists also do the same thing, but both of these drugs work centrally. So there's other effects again. We could use our volatile agent, to reduce muscle contractions.
We could provide local anaesthetic blocks to the area that we are operating on. But of course, if we wanted to operate on perhaps a complex fracture in the hind legs and we give an epidural, then both of our back legs aren't going to be at use. Another way that we can relax striated skeletal muscle is we could block something called acetylcholine, which is a neurotransmitter in the, peripheral autonomic nervous system.
So we could block ACH release from motor nerve terminals, and this is what can be achieved with botulism. Now, I don't know about you, but there's absolutely no way I'd be comfortable doing this on our everyday patient. So instead, we have, something we can do with neuromuscular blocking agents, and that is block this ACH.
On the postsynaptic muscle terminal. So that we don't get muscle movement. The good thing about this is it's profound.
It happens all over the body. It's massively predictable by dose. We, we have an idea on what doses to use, how long it's going to take our patient, if we, patient to recover, if we paralyse them.
And it's also reversible. We can stop this paralysis. We can stop this profound relaxation of the skeletal muscle.
And of course, antagonise it. So not only is it reversible because the body does its own metabolism, we can help speed this up with some antagonistic drugs. That is what we're going to be talking about today, and before we do that, I think we should really kind of zoom in, if you like, and have a look at the neuromuscular junction and the process of transmission.
So if we take our skeletal muscle here, I just use this photo to, well, this image, sorry, to show you this axon coming all the way down and then webbing out over the muscles. So, our skeletal muscle, which is what we want to relax, only contracts when there's a nerve impulse from the motor neuron, which you can see above. And that neuromuscular junction in the bottom of the page there.
That is, that junction is between the motor neuron and the muscle. So it's like a chemical synapse. It's a junction, and it is so small, it's only about 20 nanometers across.
It's tiny. So that's why I'm going to just zoom in on it and we'll have a bit of a closer look. So let's start with just what normal, impulse would look like.
OK, you can see from the top of this image here, we have our normal myelinated motor neuron, which is coming from the spinal cord, and it's carrying an electrical impulse down to the skeletal muscle, which is the second half of this image. When we have a depolarization within the nerve terminal, you can see that we've got some calcium up here, let me just circle it there, we've got some calcium here. That is going to come down the axon, come down the nerve fibre, activate these channels here, which is going to release these little sacs, these little vesicles of acetylcholine.
Now this, remember, is a neurotransmitter. OK, this is going to transmit a message from the nerve onto the muscle. OK, so when there's a vesicle of ACH is released, it crosses this pre-synaptic side, and it goes through the synapse and it binds onto the post-synaptic synaptic side.
And in particular, we want to focus on these nicotinic receptors just here. It is a ligand gated ion channel, so the ACH comes from the nerve terminal here, across the synapse and it binds onto here. When it binds onto these Nicotinic receptors here.
We have an action potential that is generated, and the muscle fibre eventually contracts. So what we have is these will open and we have potassium that moves out, out of the cell here. We have, sodium that moves into the cell, and then further down stimulates calcium to be released in that muscle fibre, and then we get a depolarization, which causes the muscle fibre to move.
So this is a really zoomed in important way to understand the neuromuscular junction. You'll also see here on this post-synaptic side. That it's, it's highly folded.
So look how it goes up and down and up and down and up and down. And that is just to increase the contact area between the pre-synaptic side and the post-synaptic side, from where the nerve terminal is to the muscle. It's just this really highly folded area.
And you'll see here that the receptors, you know, they're quite, they're up, they're up quite high. What happens with this ACH, this little wee caramel coloured, neurotransmitter, it's binding to the top of this, this receptor here up nice and high. And then further down, which is what we call the Crips.
So further down in the creps, you'll see this little purple, purple bit here, which is, acetylcholine esterase. And S. Rase means break down, doesn't it?
So what we have here is when that ACH crosses the nerve terminal into, you know, across the neuromuscular junction and onto the nicotinic receptor there, eventually, once it's finished binding, which is only for about 2 milliseconds, or we've got lots of ACH that never actually bound, we have these, these acetocholine erases just here. Which then come across, they break down the ACH, they then take it back up to the top of the nerve terminal, you know, package it all up, ready for the next time that nerve fires. Now if we wanted to zoom in even further, now to look at the receptor itself, so now we're going to zoom in and have a look at this receptor here.
Let's scroll down to here. We've really zoomed in now, haven't we? This is the nicotinic receptor, which is really important when we're working with neuromuscular blocking agents.
OK. As you can see here, there's 5 glycoprotein subunits. We've got 2 alphas, 1 beta, 1 delta.
Subunit here, there's 5 little subunits, and what happens is when that ACH when that neurotransmitter comes across that neuromuscular junction, it must bind to 2 alpha units for that channel to open, these 2 alpha units. Once that channel opens, we've got, you know, we've got that sodium rushing in, we've got that potassium rushing out. We've changed the membrane potential.
We've changed and we've depolarized that cell, and therefore that muscle contraction occurs. So 2, in the normal world, 2 ACH neurotransmitters must bind to those two, alpha subunits to open that channel. However, when we give our neuromuscular blocking agent drugs, only one, you know, only 1.
Alpha subunit has to be bound to. Otherwise, in the natural world, it's kind of an all or nothing phenomenon. You know, if you've just got one ACH bound to one of those subunits, nothing's going to happen.
So it needs to be two in the natural world and that all or nothing phenomenon. So having a look at the drugs themselves, they are the only true peripherally acting muscle relaxation drugs. Like I said before, we could use things like volatile agents.
We could use things like benzodiazepines. We could use things like alpha 2 agonists, but they work centrally as well. So we're only using neomuscular blocking agents to work on the periphery.
And it's An antagonist to this ACH receptor to bind to it and compete to get there. It's going to interfere with that post-synaptic side of the nicotinic ACH receptor, which we can see here written as NACHR. OK.
It's highly ionised. It stays in the extracellular fluid. It doesn't cross the blood-brain barrier, which is why we don't get any central effects.
It does, however, it is, you know, is able to cross, the placenta. However, from the literature we have, we can't quite see that the foetuses are actually affected by this. And we have two different types of neuromuscular blocking agent drugs.
We have some called non-polarizing drugs and also depolarizing drugs. The ones we are going to focus on today are just the depolarizing drugs, the, Sorry, the, the non-depolarizing drugs, apologies for that, just the non depolarizing drugs, and I'm going to explain the difference between them on the next slide. So the non-polarizing drugs, these compete with ACH, with that neurotransmitter, to get onto that post-synaptic side of the receptor.
And once they bind onto that receptor, they don't activate it. So it does not make the channel open. It does not allow for those electrolytes to change, to create a depolarization wave.
And these are the most common ones that we use. Thankfully, it does not activate it, which you can see in the top picture there. In the bottom picture with a depolarizing agent, we don't commonly use this in veterinary anaesthesia, but what they do is they bind to the receptors, open them, and then allow this influx of, sodium and the, and the efflux of potassium to come out, and you get this huge wave of depolarization that perhaps just lasts for a few, seconds to minutes and, and the body goes really rigid.
And actually, they use this agent in particular. It's called suximonium. They use it in humans, every single time we are orotracheally intubated.
So just to stop a laryngo spasm, this is what we get. And the effect itself only lasts for 5 minutes. But for us in veterinary medicine, we very rarely need to intubate our patients like this.
So we are just needing, non-polarizing drugs which are going to last a lot longer than 5 minutes. Now as a safety margin, it's amazing to see how you know, beautifully orchestrated our whole body is. For a safety margin to block.
This effect with this non-polarizing drugs to, to, to make the skeletal muscle no longer move, we must block at least 70% of the postsynaptic nicotinic receptors in the body to, to somewhat see a degree of paralysis. And by paralysis, I mean that skeletal muscle relaxation. 70% is quite a lot.
And then when we block up to 90% of them, we've got this complete blockade where our body literally will not move at all. So you can see here, we actually only need about 25 to 30% or so of these nicotine receptors, you know, bound to an activated in, in the normal world for neurotransmission to occur. So there's a huge, enormous safety margin that we have here.
So we do need to block quite a lot of them to keep our patient really still for the procedure. Having a look at the two different types of drugs that we have available, we have, aminosteroids, and these are really stumpy fat molecules that you can see there, in the top right of the screen. And these drugs, they're metabolised by the liver, and they're excreted in the urine or in the bile as well.
And we do have some active metabolites. We also have some, which is a very fun word to, to, pronounce. So benzyoquinolines, which are long spiny molecules.
And you can see that as well. You know, you've got the amino steroids, which is really stumpy and fat, and must be metabolised by some of our organs. And then we have this really long spindly molecule, which is actually broken down in the plasma by an esterase and also by something called Hoffmann's elimination, which I'm going to talk about.
The thing is with these drugs, it can also cause a histamine response. So when we give this drug, we must give it really slowly, over a perhaps a minute or so, and preferably if we can dilute it, we're less likely to see this histamine response. And you'll see the drug here that I've, I've just highlighted at tracurium, this is our most commonly used.
Neuromuscular blocking agent in small animal anaesthesia. And this is the one that in the videos coming up, is being used on our patients. But in the meantime, I'm going to show you also some of the other drugs that we have available to us, because they might be familiar, especially if you are studying, a postgraduate certificate, they will talk about this.
So here are all the drugs that we have on, you know, at our hands that we can use, Aurum, which I've highlighted in yellow because it is the most commonly used one. We also have vecuronium, pancuronium, rockcuronium, Mavericum. We have so many different types of drugs that we can use, but atracurum is definitely the most commonly used one.
However, these agents, it is really important to know that none of them are licenced in animal and veterinary medicine. So when we are performing a procedure, be mindful that we need to discuss this with our client, that these are drugs that of course we have literature and lots of studies on, but they are still not licenced. So let's have a look at Aurum here because it is our most common one.
We've got a byproduct that is produced. OK. This byproduct here, sorry, laudanzacine, this byproduct can actually have, an effect on the central nervous system, and it could cause seizures, but this is when we give, a lot of it for a very long period of time, perhaps as a CRI.
So it's quite unlikely to, to have any kind of clinical effect in the small doses that we use for in our day to day procedures. The great thing about it is we don't really have any cardiac effects a apart from perhaps if there's a histamine release, and we do in our body can break it down by something called Hoffman's elimination, which is what I mentioned on the previous slide. So this type of elimination, this does not require kidneys or liver involvement to be metabolised.
So it's really great for our patients that potentially have kidney or liver disease. So it uses pH and temperature to, to, to degrade it. And also we have some non-specific esterases in our blood.
Remember, esterasers for breaking it down. Considering that we use a lot of neuromuscular blocks when we do ophthalmology procedures, and especially during cataract procedures, cataracts are commonly seen in our older pets, and these are the pets that probably do have a degree of organ function change. So that's why it's such a fantastic drug that we can use because we know it's literally gonna be down to the blood, to the plasma, to a nice normal pH and nice normal patient temperature to break this drug down.
We do not have to wait on our organs. That might be performing a bit slower to get through the drug. So therefore metabolise it so we can recover our patient.
As I mentioned before, this is a drug where you can get a histamine release. So that is when we give a really large volume of this drug, and we rapidly administer it. So my advice, what I used to do is I would just dilute it quite slowly, and I'd give it nice and slow over one minute.
Our other three drugs there that you can see, you can see that they are aminos. I've just tried to list that on the left hand side there. These are our amino drugs here.
And they're all quite similar, and I think one of the big take home points is that they do require the kidney and the liver at different points to metabolise and to excrete that drug. Down the bottom, you will see another benzoyl drug, which is quite similar to our Atracurium. It's really rapid.
It works very, very quickly. You can see here the onset is quite similar to Acurium. 11 minute, 60 seconds for this drug to work.
But have a look over at the duration of action for this drug. So 12 to 20 minutes, you know, 15 or so minutes, compared with, you know, up to about 30, 35, 40 minutes for Acurum. So it works really quickly, but it doesn't last for very long.
So perhaps it's not actually going to be that useful. When we're doing our procedures, which are not, you know, known to be short procedures. Cataract procedures do take a bit of time, spinal procedures do take a bit of time.
So there's really no kind of advantage over using, this kind of drug instead of achicurium. You might also hear of a drug called cisatchiurum. So it's just a more potent form.
And the great thing about it is we don't get this byproduct that's form, and it's still nice and independent of kidney and liver function, but still, it doesn't really have any other benefits over aurum for everyday use. Now, when we give these drugs, when we give these non-polarizing drugs, if you remember back to our picture where I had the non-polarizing and then the depolarizing at the bottom, non-depolarizing, so these drugs are going to bind to the post-synaptic nicotinic receptors, and no effect is going to be seen. So we're not going to get this big rigidity.
No effect is going to be seen, except we're going to eventually lose muscle tone. And of course, this happens in a very specific order all over the body. So let's quickly have a look at that with this muscle tone.
First of all, you can see that we go from muscles of facial expression down to jaw muscles, you know, muscles from the tail, the neck, and then the distal limbs, more of the proximal limbs, then we get onto our abdominal intercostals and our diaphragmatic muscle, eventually gets paralysed. So if you imagine, Not all muscles are equally sensitive to neuromuscular blocking agent drugs, so it's not all gonna happen at once, it's going to happen nice and slowly, and I always pictured it from the outside of the animal to the inside of the animal. OK.
It's usually those really smart, sorry, small and fast contracting muscles that, that block first. And that diaphragm, you can see down the bottom there, it's the most resistant to neuromuscular blocking agents. Thank goodness, we need our diaphragm to live.
But it might actually also become paralysed, perhaps a little bit earlier because of it's really high blood supply that it has. So it gets a really rapid delivery of the drug. So it could be the last to fully block, and it is actually going to be the first that comes back of all of our muscle actions.
But look where the pharyngeal muscles are. So way up the top here, compared to our diaphragm. So, although our patient might regain the ability to, to ventilate properly, once we extubate them, they still might not actually be ready for that.
OK. So if we, if we block in this order, we recover in this order. We recover backwards there.
You might think, well, actually, I, perhaps I could give a really low dose of a neuromuscular blocking agent, and therefore, my patient will still be able to breathe. And of course, I think there's probably a degree of you actually being able to do this. Is that ethical though?
Is it ethical to potentially put our patient at risk where they are unable to breathe? If we use our pulse ox under anaesthesia, of course, we're probably still gonna get a normal oxygen saturation because our patients are receiving 100% oxygen. But what we might not see from our diaphragm and our intercostal muscles not working very well is that level of CO2 creeping on up, OK, because of that hypoventilation.
So, of course, you're just gonna be looking at their oxygenation, you think, that's fantastic. They still look great, and I haven't even needed to ventilate them. But what's the CO2 like?
Are they actually showing us that they're struggling to breathe? In this video that I have here, I have recorded just a normal spontaneously breathing patient. I have then administered the neuromuscular blocking agent.
So what I want you to do is I want you to look down on this white line here, and I want you to see, well, first of all, at the, the fall and the trace of the capnogram as our patient becomes paralysed, and also our in tidal creep down as well. They're starting to fall because they're just not able to take those big deep breaths to get the CO2 out. Another thing I want you to focus on is TV over here.
So this is tidal volume. You'll see in my 7 kilogramme dog, that's got a tidal volume of 10 mL per kilogramme, spontaneously ventilating fantastically well. Nice normal volumes here, nice normal idle CO2.
But watch these two as I inject the neuromuscular blocking agent and try and guess when that blocking agent is taking full effect. Right before the video ends, you will see me, well, I will turn on the ventilator, and then you will see a really big spike here in the idle CO2 and also this tidal volume increase back up. So I have given a neuromuscular drug to my patient, trying to keep that eyeball central in a ophthalmology, ophthalmology procedure, but I have also managed to paralyse that patient's respiratory muscles as well, and I need to intervene.
I need to take over. So let's have a little wee look there. So you can see that Tanograph trace is is falling.
The patients still trying to breathe. Their effort is just a lot less. And have a look over on the left-hand side of the screen at that tiny little tidal volume.
And notice nothing else changes, heart rate does not change. The blood pressure is quite static. It's on, non-invasive, blood pressure monitorings are osciometric, but nothing really changes.
And I need to intervene now. My patient is no longer breathing. Look at that normal oxygen saturation though in yellow, 100%.
And here, I've turned the ventilator back on. That CO2 shoots up. We start to see on the left-hand side, you will see that really big tidal volume that I've just managed to give to my patients, 16 mLs.
OK. If we are providing neuromuscular blocking agents to our patients, we need to be ready to ventilate them, whether it's manual or machine. So someone give IPPV or the ventilator.
So people, what are the challenges for the 80? Well, it's, we, our welfare and ethical concerns around doing this is we must not be using a paralysis drug, like our neuromuscular blocking agents. If there is any doubt on our patient's anaesthetic depth or the adequacy of ventilation on board.
OK? The neuromuscular blocking agents, they are not anaesthetics. They are not analgesics.
They are going to paralyse the patient, and they will not be able to respond or move appropriately if they are in pain or if the depth of anaesthesia is not accurate. So therefore, how are we going to monitor our patients' anaesthesia? Well, We can have a look at, you know, we're, we're not gonna be able to access a skeletal muscle anymore.
So even things like a palpable blink, it's useless to us now. We need to start looking at signs from our autonomic nervous system. So the heart rate, the blood pressure, is that increasing?
Any chance we can notice sweating very, very difficult in our patients? Is there any changes in salivation or lachrymation? Is there, any change in anal tone as well?
Quite difficult. Let's Focus on the autonomic changes. So, autonomic nervous system changes, our heart rate and our blood, our blood, pressure as well.
One thing I like to do when I used to, you know, be using neuromuscular blocking agents every single day in practise, is I would look at my, anaesthetic machine and, in particular, my entitled or fresh inspired levels of induction agent or maintenance agent that I have. And in this particular patient on the screen, I'm using sevoflurae. And I know that typically, the Mac fluorine in dogs is going to be 2.3%.
So I know giving it about 2, 2.1%, making sure that their end title value to assess MAC is about 2, 2.1%.
I know that they're, they're pretty likely to be. Adequately anaesthetized based on those percentage percentages, so not only could we have a look at our autonomic changes, so our increase in heart rate or blood pressure, The best way we can monitor our neuromuscular block and if it's, if it's working adequately is by using a nerve stimulator. So we can stimulate different nerves around the body and we can measure what remains of the neuromuscular junction transmissions.
So remember I said we need to block quite a lot, we need to block about 70% of these neuromuscular, Junctions so that we can see this paralysis. So we're actually going to use a nerve stimulator, elicit a kind of a stimuli across the nerve, watch them twitching occur in their muscle, and engage by what's left over. And hopefully this will start to make a little bit more sense as we go through, and I've got some videos for you.
We know that we're not going to be looking at how our diaphragm's moving. We know we can no longer have a look at the way that our chest wall is moving, and we know that our jaw tone, our eye position, palpibral reflexes, reflexes. We now, we've paralysed our patients, so we add to different nerves around the body, so we're going to look at a nerve stimulator next.
And we can have a look at the electrical activity of the muscle to see how well blocked it is, the tension of the muscle. How much tension is that muscle under? Is it actually blocked and relaxed or not?
We can have a look at low frequency sounds of the muscle contractions. And all of these, these are not often performed these in general practise settings or referral settings. These are quite commonly used in research settings.
Or we could use something where we measure the acceleration of a moving part. So if we have a neuromuscular blocking agent on board, we paralyse that patient, we then put a nerve stimulator on them, we watched this muscle move, and we can now get an idea on how much is blocked and how, how many spare receptors we've got left over, basically. Cause of course, we don't want our, our patient to spontaneously, unblock or get, get movement of its muscle back.
Especially, imagine doing spinal surgery and a patient starts to twitch or a buck, for example. Or if we're in the thorax and we're trying to work and some really fine areas around the heart, and then suddenly our patient starts breathing erratically again, or that eyeball that the surgeon's operating on has started to roll away from you. We really don't want this to occur.
We really want to make sure that everything is blocked adequately, and this is what we use our nerve stimulator for. So this is exactly what I'm going to show you in the next slide or two. Now just before we move on to the next slide here, you can see that I've said, well, You know, of course we would love to use a neuromuscular and a nerve stimulator, sorry, to see if our neuromuscular blocking agent is working, of course, but what if we look at muscle tone?
Well, I've I've told you it's not exactly Accurate. It's very subjective. I might not see something or I might not be able to palpate something in the same way that you could.
But I just wanted to show you some really cool little wee thing that you might actually see on your Kapnograph as your patient's block is wearing off. And it's called a Carrere cleft. So if you see this little wee notch on your capnograph, during anaesthesia, what this is is a diaphragm, slightly twitching.
We know it's one of the last muscles to be paralysed and one of the very first to come back. So as our block is wearing off and our patient is regaining function over their skeletal muscle again, this little diaphragm twitches. So it's quite cool.
Looking at our nerve stimulator. OK. We've got, I've got two different types of nerve stimulators here, which I'm going to show you, but we need to put these nerve stimulators over some commonly used nerves, being the ulnar nerve, the dorsal buckle branch of the facial nerve, and the perineal nerve.
So, of course, we want to make sure that our eyeball's nice and centralised, for example, but we're not gonna be able to access the face when we're doing an ophthalmology procedure. So we're going to use the leg, and we're just going to elicit this stimulation over muscle in the leg in the hopes that it's also going to give us information about general skeletal muscle control over the whole body. So looking at the ulnar nerve, if we put a, a positive and negative electrode over the ulnar nerve, we will get carpal flexion and it will move.
The good thing is, this doesn't interfere with ocular surgery, which is the most common reason we use these, neuromuscular blocking agents for. So this is a good option, good option for you if you can access that area, and there's not a big microscope in the way, for example. We can also place this, nerve stimulator, so positive and a negative probe around the buckle branch of the facial nerve, and we'll see this little way, this twitch and this retraction of the nay as well.
And we place this kind of quarto ventral to the medial campus, the lateral to the eye. Or most commonly, we use the perineal nerve, which is down by the knee. So it's a branch of the sciatic nerve.
And when we stimulate this nerve, the hock will move. It will flex. And the good thing about this one as well is patients are typically on their back for ocular surgery at the other end of the table to us.
So this is one that you will see quite a lot in my images. Now, you'll see, especially on the top, nerve stimulator that we have there, we have got a red and a black electrode, and then on the bottom cough watch, we also have a, white and a black electrode. So I've just put here where those go.
If we put the nerve stimulator and the, and the needles going through the skin over the nerves, we, we need to put the, the white or the red electrode, more proximal, and then the negative, the black electrode at the distal end. Just to show you those 3 nerves here. So we've got the ulnar nerve.
You can see with this particular type of to watch. You can see the red and the black electrode there, and it's on the medial side of the ulnar nerve. So when we attach this underneath the skin over the top of the nerve, not at all deep in the muscle bed, when we put our, topwa or our nerve stimulator to elicit this or to produce this, this nerve stimulation, that, that muscle's going to move.
Same thing when we put it over the dorsal buckle branch of the facial nerves. You can see here on the left hand side, we've just placed the needles through the skin right over where the nerve sits, and we're just using some IV caps there so that nobody gets a needle stick injury. And then we go and place our electrodes over the top of it.
And in this instance, this person is using, some really soft crocodile clips to clip onto the metal part of the needle, that is going through the skin over the top of the nerve that we want to stimulate. And most commonly, like I said before, we've got the perineal nerve, and you can see here on the left-hand side, this dog is lying on its back and we're coming and looking at it from the side. Our red electrode is more proximal, our black electrode is more distal.
Same again for this dog in the middle that's laying on its left lateral side. So we're looking at the right side. And then we have this kitty cat here on the right hand side as well.
So we are, you know, this is facing onto it's, what's lay on its right lateral side, isn't it? And we've got two needles under the skin, over the top of the perineal nerve, and our electrodes from our nerve stimulator plant on top, the top of it. So let's think about the types of nerve stimulation we can produce.
OK, so we've got, with our machines, 4 typical, typical types of stimulations that can be. Supplied from that nerve stimulator to the muscle. We've got our train of 4, and this is, it produces something called fade, which we quite like and I'm going to explain further.
OK, so our, the motor neuron that we've put the neuromus sorry, the nerve stimulator over. It's stimulated by 4 bursts of equal electrical pulses. OK?
And every time we, we stimulate that muscle 4 times, we will get 4 different types of muscle contractions. Now, remember, if we have paralysed this patient, hopefully, we don't get any twitches at all. So that, pre-synaptic side of the neuromuscular junction, that is also blocked there are nicotinic receptors on that side as well, not just on the post-synaptic side.
We do have some pre-synaptic neuromuscular receptors. And when we give our neuromuscular blocking agent drug like our Achiurum, it not only will block the, post-synaptic side, but there actually is a little bit of blockage from the pre-synaptic side. So remember when I said we have our esterases that take the ACH that's cross the neuromuscular junction back up.
To the presynaptic side and package it all up to go again for the next time. Well, our neuromuscular blocking agent, as we have an increase in, block, will also have this pre-synaptic side affected. So they can't repackage that ACH.
They can't get it really in package up to, to push out for the next lot of contractions that are coming through. So when we have fade, so if you can see here on the, on the left-hand side image, with, with 4 equal stimuli being given, so we've got 1234. Of course, we get 4 equal contractions.
But when we give our neuromuscular drug and we start to get fade, you can see it starts to sit down, 1234. And we call the first twitch T1 and the last twitch T4. OK, so what we have is this incomplete, block.
So so far we haven't blocked everything. We're still able to recycle some of that ACH back up into the presynaptic side to cross anemuscular junction again. And we've got this desirable problem.
What's happening is we have this desirable blocking occurring. On our neuromuscular junction. Ideally, we end up with no kicks whatsoever, but what we see is we're slowly losing strength in our kicks because our post-synaptic side is blocked.
And also, there's a problem now with the pre-synaptic side packaging up the ACH to go again. This is desirable. It's happening, OK?
It's happening. And then eventually, as you can see here on the last image, we've got T4 completely gone. So we've just got T1, T2, T3, and T4 is completely gone.
So this is great news. Another way that we can stimulate this muscle is with tetany, and this is really unpleasant. It's quite a high frequency that goes on for about 5 seconds and it's quite painful, and it's really hard to assess fade because you've just jolted that muscle continuously for 5 seconds.
It's not commonly used. And then we have double ber stimulations, DBS, and we give just 2. Two really short bursts of muscle stimulation, and we're able to see if they're higher or lower.
If that T2, for example, is higher than the first twitch that's come through. We also have this, functionality to give one single nerve impulse discharge. But it, it tells us what the post-junctional side is doing of that membrane.
Like, oh, how blocked are those postjunctional sides across the synapse, but it's not really giving us any information on what's happening on the pre-junctional side. And so usually we most commonly will be using our trainer for or our DBS. Now, we will use fade, and especially this train of 4, so this 1234.
We will start to look at what we call a TOF ratio or a percentage of T4 compared to twitch 1, the first twitch. So T4 compared to T1. Because as you can see, as we get this progressive block occurring, we start to lose our T1, sorry, our T4, but also our T4 might just be a certain percentage of our T1.
OK, so this is how we can use a train of forward of 4 to see fade occurring here. So usually Between, you know, if that height of T of T4 is a certain height of T1, in this case, 40 to 50%, we might be able to also see or feel that patient's twitch. If that fourth twitch, if it's present, is, is, well, actually, if that 4th twitch is gone completely.
This is really good news. We're starting to get a full-on block, but you can see we haven't blocked all of our receptors. We lose T4 when about 80 to 70, 80 to 85% of our neuromuscular junctions are blocked.
And then eventually, as we start to creep on up, once we get over 95%, 90%, we end up with absolutely no twitches. But the thing is, we must remember, when we're using a tough watch, it's giving us information on this T4 to T1. So what happens when we don't have A T4 anymore, our top watch is going to say 0 because there's no height here, but we still might see some twitches occur.
OK. Having a look at two of our really common nerve stimulators that you might see, you might just be using the normal nerve stimulator, which is visual only. We're only going to see, if we go back to that last slide, we're only going to be able to see twitches.
You know, what kind of height are those twitches if they're present, if we can pick up on them and if we can see them, we're only going to get kicks. Whereas if we have the top watch, it's really good. It gives us this visual and percentage ratio of the twitch height.
So it tells us the twitch height of T4 to T1. And I quite like a topwa because we get two bits of information here. What is the height of this 4th twitch, which is pretty much almost unblocked, isn't it?
What is the height of this 4th twitch to T1? And also it just also just moves that leg and we can start to visualise the four kicks themselves. So I've got 2 patients here and we have these 2 patients laying on their back.
We're using the perineal nerve, and I'm going to show you what it looks like when we put a nerve stimulator on them with no block on board. So we should start to see complete normal nerve transmission creating this muscle contraction. Four equal movements there, same with this little dog.
OK. So now it's ready to rock and roll, OK? We've got our nerve stom set up.
Let's start to block this patient. But let's quickly just summarise, are we ready to block? Before we even anaesthetize this patient, we really need to check if the equipment is ready.
Do we have enough drug? Do we have a neuro, do we have a nerve stem that's got battery in it? Is the anaesthetic machine all ready to go?
Is our ventilator piped in all of the tubings correct? We would induce and maintain anaesthesia as normal, place the nerve stimulator before we block this patient, get some baseline data. What is this patient like before we paralyse them?
Remember, we're unable to, monitor them with any types of reflexes or blinking or pedal reflexes or movement. Start ventilation for this patient, and then we can paralyse them. And throughout the surgery, we just need to monitor that neurotransmission and redose appropriately, if we start to see fade occurring.
If you know, if it's coming back, if we start to get some twitches, we need to redose appropriately. And that is usually done with about a third of the loading dose from our drug that we initially, gave. So, for example, if we gave Aurum, 0.2 mg per kg for our patient when we started, we might just want to top up with a 0.05 or even a 0.1 mg per keg, depending on how long you've got left of your procedure.
So here, I've got a video of a patient that is showing us fade, so that neuromuscular block is starting to work. OK, could you see those first muscle twitches quite high, and they get less and less and less. This is desirable.
This is a good thing to see when we have administered that neuromuscular blocking agent before eventually there will be no twitches. Let's just play it one more time. And we've got another patient here which is showing fade with a train of force, the 4 electrical impulses coming through.
4 crutches there of the patient's leg, and then we also have the double berth, so that 12. And remember, these are the types of nerve stimulation where we can see that fade. We want to see the neuromuscular junction progressively become, you know, not, susceptible to that ACH, that neurotransmitter that's been released.
And then eventually we'll have this full, fully blocked patient here. OK. We gave 4 twitches, absolutely nothing happened to our foot.
Wonderful. A patient must have over 90% of their neuromuscular junctions all blocked. So how will you monitor this?
We can draw the twitches, you can just do lines which show the block progressing and then coming back. And, or you could just write the percentage of your top watch. But just remember, your top watch is showing you T4.
In comparison to T1. And we could lose our T4, our 4th twitch, at around, you know, 80, 85%. So then we're just gonna end up with 000.
So now that you've done your procedure, your skeletal muscle was perfectly relaxed so we could perform our our ocular surgery, so we could work on the spinal cord without our patient moving. Now we want to get our patient back from having their entire skeletal muscle system paralysed. So, let's start looking at the recovery for the last few slides.
To antagonise the neuromuscular blocking agent, we've got to be very careful about it. Eventually, the neuromuscular blocking agent will wear off. It will become, you know, it will get metabolised, and then what will happen is because that neuromuscular, we've also, affected the presynaptic side of that neuromuscular junction.
We will be able to release that neurotransmitter, that ACH, across the synaptic cleft. It might still not be able to bind to that post-synaptic side to continue that muscle transmission, but eventually, it's going to build up in that neuromuscular junction. OK.
And just like everything in pharmacology, often where there is more, will win. So eventually, we will be able to get that, that ACH across the junction, binding and creating skeletal movement. OK.
And we can also speed this up when our patient has at least one twitch back. We don't want to go trying to antagonise this block when we have a completely paralysed patient. Remember, they only need about 20 to 30 of their neuromuscular junctions working.
So we kind of need to make sure that we have at least one twitch back indicating that there's 70 or or or less, blocked. So normally, we have this, if you remember back to our picture of the neuromuscular junction, we have this acetocholine esterase, which is in the concentrated part of the neuromuscular junction. This will rapidly hydrolyze that ACH, bring it all the way back to the top of the nerve terminal to be released again.
And what we do when we give a neuromuscular antagonist. Drug to stop the neuromuscular drug from working. They don't actually work on the drug themselves.
What they do is they stop the anti, cholineisterases from breaking down the ACH. So if I can't break it down to repackage it at the top of the nerve again, it just builds up again in that neuromuscular junction. And of course, where there is more, it's probably going to win.
So the drugs that we use, Irahonium and also neostigmine, most commonly, it's probably going to be neostigmine. So how, how do we often use this one? Well, you, you will know, if you've done these before, you don't just use them on your own.
You do need to give them with another drug. So let's have a look at these two. When we give our anticholinesterase drugs, So our neosymine, our herohonium, which are going to stop ACH from being brought up, repackaged and broken down to go ahead for the next lot of nerve stimulation or nerve transmission.
When we give these drugs to stop ACH. Be broken down, it means we also build up ACH in other areas of the body, and in particular around the muscarinic receptors, which are on the autonomic ganglia, OK, of the parasympathetic nervous system. If you remember our parasympathetic nervous system, this is a slow it down nervous system.
OK. We could get a bradycardia, brady arrhythmias, to the point of asystole, actually, we could get a bronchoconstriction and we could get an increase in broncho secretions. So of course, we don't just want to give these drugs, these two idiohoniums or these neurostigmines to help build up ACH in the neuromuscular junction where neuromuscular blocking agents have been working, because they are going to affect other parts of the body, the muscarinic receptors as well.
Wow. OK. Everything can start to go really, really slow, really, really low.
So that's why we concurrently give these antimuscarinics, your atropine or your glycopyrolate. OK. It's going to block the effect at the muscarinic receptors.
It's gonna block the bradycardia, the Brady arrhythmias, for example. So you could give both at the same time, both either atropine and Irahonium all in one go, or the glycopyrolate and the stigmine all in one go. I prefer, first of all, to give the antimuscarinics, the glycopylate or the atropine first, to bring up that heart rate, to, you know, that tachycardia is not gonna be as detrimental as what the bradycardia will be.
And then I will antagonise the block. Now the reason we pair these two together is atropine and Irahonium, they work really quickly with quite a short duration of action, compared to glycopyrolate which work quite a bit slower, but they also last for a bit longer. And you'll remember that the way in which we did initially paralysed these organs and these muscle structures, it's going to work back in a different direction now.
So we're going to hopefully get movement on our diaphragm, come back, and then eventually, the muscle will start moving again around in the face and where, our swallowing reflexes all are. And then if we look at our nerve stimulator, we should get this really nice, completely unblocked patient again. So we've gone and blocked them and we've been monitoring that really, really well.
And then eventually, let's have a look at this video of this patient that has been antagonised. Everything works normally again, fantastic. We've blocked that patient, we've antagonised that drug, and now their skeletal muscle is working.
Now their diaphragm is working, they will be able to swallow when we extubate them. So our last two slides that we have here on the recovery of a patient with, that has had a neuromuscular agent on board. When we're prepared to recover these patients with one twitch before we give the antagonni, that they don't have an acid-based disturbance, that they don't have a depth of anaesthesia that is also so deep they're going to struggle to recover.
OK, if we have a really cold patient, this is going to slow their circulation, it's going to slow the metabolism down. It's going to lengthen the action potential of, of our ACH as well to be released. If we have an acidosis, this is going to slow down the speed of that Hoffmann's elimination, so our esterases and everything that's going to be breaking down the acurum and the plasma, it's gonna slow that really down.
It's gonna slow it down quite a lot. And also our volatile agents, they can actually potentially, potentialtiate the neuromuscular blocking agent. Through vasodilation, through also depressing our central nervous system, through changing the way the muscle tone acts anyway.
And of course, we, we do not want them to have any kind of electrolyte disturbances as well. These electrolytes are part of normal, Electrolyte and ion influx and efflux if you wish, when we have a depolarizing action on the muscles, so we don't want any kind of electrolyte abnormalities either. Now initially we thought we.
We might not have to antagonise these drugs if our patient looks like they're breathing. Is that really ethical though? If it looks like they're breathing, their intercostal muscles and the diaphragm are obviously moving, but we know that that pharynx, those pharyngeal muscles might not come back till later on.
They're one of the last to come back. So we could extubate a patient that's got really good thoracic movement. That actually ends up not being able to, to move and open their airway.
So it's not very ethical. And then we also talk about something called recuration, which is where that neuromuscular block starts to come back on board after we've antagonised it. It's quite, it's uncommon.
Because our drugs work so long, you know, our glycopyrelate and yammine, they, they work for quite a wee while. And the drugs that we produce, the neuromuscular blocking action with, so our Aurum, they're only intermediate length drugs. So usually our patients don't often wreck your eyes or become reparalyzed in the recovery period.
I've only seen this once. So when we're recovering our patient, I'm really looking for any types of sign of respiratory distress, and I'm using my pulse ox and my catnograph up the nose during the recovery period. But before we terminate this patient's anaesthesia, it is so important.
That they must be fully recovered from the neuromuscular block before we wake them up. We do not need a paralysed, conscious patient, and this is why we do not remove our nerve stimulator until we are convinced, and our top what shows us that our twitch number 4 is the same height as twitch number 1. So just in summary, when we go to recover our patient, are there signs of recovery before we give those antagonising drugs?
You know, is there a chest wall movement? Does the patient seem a little bit more rigid? Is the surgeon somewhat fighting to, get, surgical access cause that muscle tone's improved?
OK, then we can start to give our anti-cholinesterase drugs and our anticholinergic drugs as well. Monitor our train of 4 or use our double berth stimulation. Do not remove the nerve stimulator until you are convinced your patient has fully recovered.
I've done this once. I've antagonised the patient, and then in a rush, I removed the nerve stimulator. How am I ever supposed to tell how well that patient has actually become antagonised if I can't put it back on a nerve cause it's not moving?
OK, wean them off the ventilator that I've been on to reduce their minute volume, create a hypercapnic situation where they start to breathe again. Recover them from their anaesthesia, and then when we move them into the recovery room, extubate them, use the pulse ox, can they maintain oxygen saturation, use the Capnograph, put this up the nose, are there any signs of hypoventilation because their CO2 has risen. So thank you very much for listening to this webinar.
I appreciate it is quite a lot to take on board, but I would really encourage you to just get quite familiar with the neuromuscular junction itself, and then perhaps just focus in particular on drugs like Aurum, because it's our most common drug, and our reversal agents being glycopyrolate and neosymine. Thank you.