ketamine and dexmedetomidine in “wind-up” phenomenonketamine was developedin...
TRANSCRIPT
KETAMINE AND “WIND-UP” PHENOMENON
Ryan Dreikorn BSN SRNA York College of Pennsylvania / WellSpan Health Nurse Anesthesia Program
Objectives
Quick overview of the neuron and pain pathways
Go to “Receptorland”
Discuss traditional pain management techniques
Discuss the role of Ketamine in attenuating “wind-up”
Presenter
Presentation Notes
Ketamine was developedin 1962 Dexmeditomidine was developed in 2000
Wind-Up Phenomenon
Pain is pain and then its over.
Wind-Up phenomenon increases pain intensity
Wind-Up phenomenon increases pain duration
Wind-Up phenomenon is mediated and attenuated though the NMDA receptor
Presenter
Presentation Notes
When we say wind-up, or central sensitization, we are talking about a degree of neuroplasticity, in which the neurons actually change their physiology in response to prolonged exposure to nociceptive (or pain) impulses. What is mean by the neurons ability to change their physiology is that they can up and down regulate receptors to make it more easy for a painful impulse to be sent This means that when neurons make these changes, innocuous pain can be perceived by the person as noxious This also means that pain can linger long after the insult (surgery) is over We understand that narcotics, and to a minimal degree inhalational agents, can suppress nocicptive impulses to the brain, but today I want to talk to you about the antinociceptive effects of Ketamine and Dexmeditomidine, or precedex. Ketamine antagonizes the NMDA receptor, a receptor which is crucial in Wind-Up phenomenon, while precedex agonizes the alpha 2 receptor, which although not directly involved in Wind-Up can essential prevent or possibly reverse this process.
Wind-Up Phenomenon
Change in Neural Physiology Innocuous Stimuli Becomes Noxious Mediated by AMPA, NMDA, and NK1
Receptors Involves the Neurotransmitters Glutamate
and Substance P (SP) Brain Perceives Pain Even in the Absence of
Painful Stimuli Occurs Within One Hour
The Neuron
The Synapse
Presenter
Presentation Notes
Start with the basics Dendrite receive input from a broad area into a given neuron Dendrites can respond to both excitatory and inhibitory impulses by having excitatory and inhibitory receptors Dendrite can assist in spatial summation Dendrites are leaky to ions, and therefore require increased post synaptic potentials to transmit and impulse toward the soma The soma is the cell body of the neuron Soma contains the coding necessary for the neurons receptors, and neurotransmitters – we call this coding DNA Some neurotransmitters are synthesized in the soma Axon transmits impulses along the length of the neuron to the synapse Axon is covered in a myelin sheath on A fibers and left uncovered on slower C fibers carrying pain impulses Big money is in the synapse Synapse is where we can have the greatest effect Synapse is where neurotransmitters are released from the presynaptic neuron which inturn act on the post synaptic neuron to have an excitatory or inhibitory effect – we can either mimic the effect of neurotransmitters, or block their effect
First Order / Second Order
Presenter
Presentation Notes
When we talk about neurons, we need to understand that there are first order, second order, and in the case of the pain pathway, third order neurons. We have the axon of one neuron Then the dendrite of another neuron Then the all important synapse Making the lower neuron the first order neuron and the upper neuron the second order neuron In the pain pathway, the first order neuron is the one which lies in the periphery and receives the initial painful stimuli which it then passes on to the second order neuron which lies in the dorsal horn of the spinal cord. This impulse is then passed to the third order sensory neuron which lies in the brain.
Dorsal Root Ganglion
Presenter
Presentation Notes
With sensory neurons, the dorsal root ganglion is the actual cell body of the neuron and lies outside of the spinal cord. As you can see in this picture, this first order neuron is taking impulses from the periphery to the cord
Anterolater Spinothalamic Tract
Spinothalamic Tract (Simplified)
Presenter
Presentation Notes
This is a more understandable version of the Spinothalamic Tract Pain enters only the 1st order neuron through the dorsal nerve root It then synapses with the second order neuron, decussates, and continues up the cord where it synapses with the third order neuron in the thalamus Animation – This is probably were we have the greatest effect with our drugs
Spatial Summation
Presenter
Presentation Notes
Notice this one neuron is influenced by the axonic transmissions of multiple other neurons
Spatial Summation
What was incision?
What time was antibiotic
given?
What's my blood loss?
Patients awake!
How much Neo?
Now I understand
why they call this the
“Blood/Brain Barrier.”
Presenter
Presentation Notes
HB: Attempt to change white letter font to better match background
Temporal Summation
High Intensity Temporal Summation
TABLE
UP! NO,
DOWN! NO, UP! WHAT ARE YOU
DOING TO ME!?!? I’m going to show him an
“Action Potential.”
Lois, Lois, mom, mom, mummy, mummy, muma, muma, ma, ma, mum, mum, mummy, ma
WHAT!?!?!
HI!
Persistent Low Intensity Temporal Summation
Presenter
Presentation Notes
Or, temporal summation could caused by persistent low intensity stimuli from a small number of input sources This is largely were windup phenomenon occurs Temporal summation can even result in transmission along a neuron from stimuli that, on their own, would not have elicited an impulse.
Review Neuron Physiology and the Action Potential
Ionic Movement (Quick Review)
Intra-Cellular Fluid Extra-Cellular Fluid
Increased K +
Decreased Na +
Decreased Ca 2+
Decreased K +
Increased Na +
Increased Ca 2+ Ce
llula
r Mem
bran
e
Presenter
Presentation Notes
Before we understand the physiology of these receptors we need to understand how neurons transmit impulses, and in order to do that, we must understand why ions want to go were they go. Inward Na+ movement is the primary cause for depolarization of a neuron therefore allowing transmission of an impulse Outward K+ movement is the primary inhibitor of a neurons ability to depolarize and therefore this prevents transmission of an impulse Inward Ca++ does three actions of importance to us in out discussion: increases the likelihood a neuron will transmit an impulse, is necessary for the release of neurotransmitters, and activates intracellular machinery.
The Action Potential (Quick Review)
Presenter
Presentation Notes
This is why neurons transmit an impulse along their axon to excite the post synaptic or second order neuron For the purposes of our discussion today, we are mostly concerned with the left side of this diagram.
Action Potential
Increases Na+ Permeability
Fast Na+ Channels
Impulse / AP Sent
THIS CAN CHANGE
Presenter
Presentation Notes
The resting membrane potential represents the state of the neurons in your patient under GA who has not yet been cut with a knife Then you have a stimulus The stimulus opens Na+ channels. The degree or channel opening is often related to the intensity or repedity of the stimulus (temporal summation), or the diffuse area of the stimulus (spatial summation). The Na+ raises RMP to threshold at which point depolarization occurs and the impulse is sent along the neuron Notice however, that depending on the permeability to Na+, RMP can increase or decrease making it harder or easier to illicit an impulse But wait….. We forgot about the calcium – When the AP reaches the synapse, it causes the opening of voltage gated Ca++ Channels which allow for the influx of Ca++ which causes the release of neurotransmitters.
Ah Finally, Receptorland
Speaking The Local Dialect
Ligands
Neuroplasticity Up-Regulation Down-Regulation
Ionotropic Receptors
Metabotropic Receptors
Nociceptors / Free Nerve Endings
Presenter
Presentation Notes
A ligand is anything which binds to a receptor to cause an action, where it is excitatory or inhibitory in nature Up regulation of cellular receptors involves increasing the number of receptors expressed on the cell surface that are allowed to interact with ligands therefore increasing the effectiveness of that receptors ligands Upregulation can be adaptive and maladaptive for our use, however in the neurons transmitting pain impulses it is generally bad. Downregulation of cellular receptors involves decreasing the number of receptors expressed on the cell surface that are allowed to interact with ligands therefore decreasing the effectiveness of that receptors ligands. Down regulation can go either was with pain, however if we down regulate opioid Mu receptors, this would decrease the effectiveness of opioids. Ionotropic Receptors are those which directly allow the movement of ions across the cell membrane when activated. The ionotropic receptor we are all most familiar with is the NAchR which directly allows Na+ into skeletal muscle to initiate the contraction cycle Metabotropic receptors are those which activate other intracellular signaling pathways which result in a response An example of a metabotropic receptor is one we use daily, the alpha 1 adrenergic receptor. Activation of this receptor releases its intracellular alpha subunit which then activated phospholipase C, which cleave PIP2 to IP3 and DAG which increase intracellular Ca+ resulting in smooth muscle vascular contraction. Free nerve endings are located in the periosteum of bone, and around organ capsuls, and they only report pain Nociceptors however are located everywhere with large concentrations in the skin and tendons and they report tissue damage – although it feels like pain
A Fiber & C Fibers (More Dialect)
C-Fiber
A-Fiber
C-Fiber Only
A-Fiber Only
Presenter
Presentation Notes
This graph depicts pain impulses sent along A fibers (the spike) and C fibers (the hump). A-fibers are fast myelinated nerve fibers which carry more discriminate messages from the periphery, including that of some types of fast pain impulses with high localization. They respond to impulses fast and when the impulse has concluded they rapidly cease transmission. A fibers generally do not display windup phenomenon C fibers are slower unmyelinated nerve fibers and they are what we are mostly concerned with as they transmit most of our slow pain impulses generated during surgical manipulation. As you can see they are slower to respond but yetr maintain the impulse for a longer period of time We have all at one time placed our hand on something hot, or in hot water and quickly pulled it away. Have you ever wondered why is kept hurting for that extra 2 seconds after you pulled it away? This graph explains why, and it also explains the beginnings of wind-up phenomenon.
Wide Dynamic Range Neuron
Presenter
Presentation Notes
In the periphery, there are too many sensory neurons to carry input from each nociceptor You cant just randomly connect a bunch of first order sensory neurons to afferent second order neurons or you would never be able to tell where the pain was coming from The solution is a neuron called the wide dynamic range neuron, a type of nocieptive C fiber, which acts like a telegraph operator. It send impulses received from a large area of sensation to the brain with a reasonable degree of point discrimination It accomplishes this goal be coding the impulses so that, when received by the brain, they can be deciphered for location and also intensity. We will talk more about this later and see why this neuron can create huge problems for us.
alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA)
AMPA
Presenter
Presentation Notes
The AMPA is the most important ligand gated ionotropic receptor to us in the pain pathway. The neurotransmitter glutamate is released from the first order neuron which then binds to the AMPA receptor which allows for the influx of Na+ into the second order neuron, thereby allowing it to reach threshold and cause depolarization. Unfortunately, this receptor can be opened spontaneously by intracellular mechanisms in the absence of glutamate during wind-up phenomenon. This spontaneous opening can allow the transmission of pain impulses in the absence of painful stimuli. To a small degree, this receptor is blocked by Ketamine.
Neurokinin 1 Receptor (NK1r)
Presenter
Presentation Notes
Neurokin 1 or NK1 receptors are ligand gated metabotropic receptors that are activated by the neurotransmitter Substance P Substance P is also released from the first order neuron at the same time as glutamate Activation of this receptor can then cause activation of the NMDA receptor and spontaneous activation of the AMPA receptor – More on this later NK1 receptors are also called Tachykinin receptors due to their ability to up regulate with hours
N-methyl-D-aspartate (NMDA) Receptor
2nd Order Neuron
Intracellular
Extracellular
Presenter
Presentation Notes
This is the N-Methyl D-Aspartate receptor is a ligand and voltage gated ionotropic receptor which has been identified as a key element in windup phenomenon The NMDA receptor is activated by glutamate binding to it as well as spontaneous activation from intracellular mechanisms from activation of the NK1 receptor Once activated it allows Na+ and Ca+ to enter the cell While Na+ directly increases resting membrane potential, thereby making it easier for this neuron to transmit and impulse, increased intracellular Ca++ further increases RMP and participates in spontaneous opening of the AMPA receptor which further raises RMP Now we see the beginnings of the wind-up phenomenon – we’ll put all the pieces together shortly This is were KETAMINE comes in. Ketamine binds to an allosteric site which changes the shape of the receptor, and therefore prevents glutamate from binding to it. Fortunately wind-up does not happen every time there is glutamate binding to the NMDA receptor and this is because it is “clogged” by a magnesium ion. This magnesium ion, however, can be unclogged by depolarization of the neuron, thereby allowing glutamate to bind and activate the channel. The NMDA receptor has “slow channel kinetics,” which means that once its open, it tends to remain in an open state longer than most channels, thereby having a prolonged effect. While found on multiple different types of neurons, this receptor has a large population on C-fibers which carry nociceptive impulses
Mu Opioid Receptor
Presenter
Presentation Notes
Mu opioid receptors are ligand gated receptors that can either be metabotropic or ionotropic depending on their location. Mu receptors are found presynaptically, and postsynaptically Regardless of their mechanism, the final result is increase membrane permeability to K+, allowing it to leave the neuron, which decreases RMP making it more difficult to reach depolarization threshold Click – The bad part about Mu Opioid receptors is that they begin to downregulate after 24 hours of prolonged activation – the mechanism is currently unknown.
Put The Pieces Together
This Is Very Graphic Material
Presenter
Presentation Notes
When I have been asked to explain windup phenomenon in the past, I found I needed to be able to draw it out on a piece of paper in order to make it visual for people and myself to understand it. We’ll use this PowerPoint as our giant piece of paper.
Where Are We
You Are Here
Our Neurons
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv
RMP -65Mv
RMP -65Mv
Threshold -45 Mv
Under General Anesthesia
Presenter
Presentation Notes
So you have your patient under general anesthesia and there has been no surgical stimulation at this time. This is the most effective time to give pre-emptive analgesia with opioids and Ketamine We can also give Ketamine which will mildly act on Kappa receptors to decrease RMP but mostly will act on the NMDA receptor to prevent increases in RMP and the hump we noted earlier.
Masked Man With A Knife
Presenter
Presentation Notes
Then this masked man comes into the room and attacks your patient with a knife!
Initial Pain Impulses
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv
RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+ Na+
Presenter
Presentation Notes
Now the nociceptors of the skin are transmitting impulses to the first order neuron which is passing through the soma or dorsal root ganglion of the nerve and onto the synapse where it begins to secrete glutamate. As you can see, the glutamate is binding to the AMPA receptor, causing it to open and allow Na+ into the post synaptic neuron This raises resting membrane potential closer to threshold. Nothing occurs in the first 10 milliseconds
More Pain Impulses
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv
RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+ Na+
Glutamate
Glutamate
Glutamate
Na+ Na+
Presenter
Presentation Notes
However, as the concentration of glutamate increases in the synapse, it is able to increase the amount of Na+ in the post synaptic neuron until it reaches the threshold for that given neuron (about -45mv). At that point an action potential is sent along the neuron and the brain perceives pain
Increased Pain Impulses
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv
RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+ Na+
Glutamate
Glutamate
Glutamate
Na+ Na+
Glutamate
Glutamate Glutamate Glutamate
Glutamate
Glutamate
Presenter
Presentation Notes
This is were our problems begin. First, as the pain impulses continue to present to the synapse, the concentration of glutamate begins to increase which increases the frequency at which the AMPA receptor opens, therefore increasing the influx of Na+ and making it easier to create an AP. Also, this increased glutamate is free to bind to other receptors, such as the NMDA receptor.
NMDA Receptor
Presenter
Presentation Notes
Now, remember in our discussion of this receptor there are two key points that prevent activation of the NMDA receptor every time we perceive pain. The first being the need for increased levels of glutamate in the synapse to bind to the rector At the same time, and action potential must be occurring inside that neuron to remove the magnesium ion which blocks the channel However, now that the masked man is attacking our patient with a knife while making an incision, there is plenty of glutamate being supplied to the synapse to allow for both, the action potential from AMPAr activation as well as direct glutamate binding. The one thing not in our favor, however, is that this receptor demonstrates slow channel kinetics, so it will remain open even after the AP has concluded and the glutamate has left the site.
Beginnings of Wind-Up Phenomenon
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv
RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+ Na+
Glutamate
Glutamate
Glutamate
Na+ Na+
Glutamate
Glutamate Glutamate Glutamate
Glutamate
Glutamate
Na+ Na+ Na+ Na+
RMP -60Mv
Presenter
Presentation Notes
Now we see our resting membrane potential has increased to -65mv, so it’s a little bit easier to create an AP and a pain impulse to the brain. This means that it will now take less painful stimuli from the 1st order neuron, and less glutamate in thee synapse to elicit a pain impulse
Wind-Up Phenomenon
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv
RMP -60Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Glutamate
Na+
Glutamate
Glutamate Glutamate Glutamate
Glutamate
Glutamate
Na+ Na+
SP SP
SP
SP
SP SP
SP
SP SP
SP
Phospholipase-C
DAG PKC Na+
Na+ Na+
Ca++ RMP -50Mv
Presenter
Presentation Notes
Unfortunately, now that we have all this glutamate released, Substance P starts to be released and it acts in the NK1 Receptor Now, The NK1 receptor’s action is mediated by that of the NMDA receptor in that activation of the NK1 receptor must activate the NMDA receptor to obtain a response. Activation of the NK1 receptor causes activation of Phospholipase C, which activated Diacylglycerol, which activated protein kinase C which activates the NMDA receptor, thereby allowing the influx of Na+ and Ca++ This further raises RMP so that it takes even less glutamate to bind to AMPA receptors to elicit an action potential This means that a small amount of nociceptive impulses are necessary for the brain to perceive significant pain. Wait a minute…. Ca++, whats that have to do with this?
Wind-Up Phenomenon
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv RMP -50Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Glutamate
Na+
Glutamate
Glutamate Glutamate Glutamate
Glutamate
Glutamate
Na+ Na+
SP SP
SP
SP
SP SP
SP
SP SP
SP
Ca++
CaMKII
Na+ Na+
Presenter
Presentation Notes
So now we have activation of the NMDA receptor which is allowing for increased Na+ into the post synaptic neuron therey increasingh the RMP and bringing it close to threshold Activation of the NMDAr also allows for the influx of Ca++ which then binds to calcium-calmodulin dependant kinase 2 which can then cause spontaneous activation of the AMPAr This means that even in the abscesses of painful stimuli, this second order neuron will send painful impulses to the brain.
Hyperalgesia / Allodynia
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv RMP -50Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Glutamate
Na+
Glutamate
Glutamate Glutamate Glutamate
Glutamate
Glutamate
Na+ Na+
SP SP
SP
SP
SP SP
SP
SP SP
SP
Ca++ Na+ Na+
Pain
Pain
Pain
Pain
Presenter
Presentation Notes
Now we have this neuron with a relatively high RMP, making it easier to elicit nociceptive impulses Additionally, there is spontaneous activation of the AMPAr meaning that pain impulses are being submitted to the brain in the absence of painful stimuli Now, the neuron starts to down regulate its Mu receptors So now, your fentanyl won’t work anymore whoa
Wind-Up on the WDR Neuron
Presenter
Presentation Notes
When this gets really grizzly is when Wind-Up phenomenon occurs on the WDR Neuron, it allows the pain to be percieved by the brain over a move more broad area of the body. As we can see from the picture an area of local insult results in hyperalgesia to a large area of the body Eventually this will progress to allodynia where innocuous stimuli is perceived as noxious
Traditional Opioids
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv
RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+ Na+
Fentanyl Fentanyl
Fentanyl
Fentanyl
K+ K+
K+ K+ K+ K+
K+ K+
RMP -75Mv
RMP -75Mv RMP -65Mv
Presenter
Presentation Notes
So what we can do is attempt to give our patients preemptive analgesia with opioids This works well but you need significantly high doses of opioids to attenuate windup phenomenon Opioids work by agonizing Mu receptors and therefore allowing K+ out of the cell If we let a positively charges ion out of the cell we make the cell more negetive thereby decreasing RMP and taking it farther from threshold This means that you need more painful stimuli in order to initiate a pain impulse
Opioid Problem
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv
RMP -75Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+ Na+
Fentanyl Fentanyl
Fentanyl
Fentanyl K+
K+ K+
K+
Pain Pain Pain RMP -75Mv RMP -65Mv
Glutamate
Glutamate Glutamate
Glutamate
Glutamate
Na+ Na+ Na+
Glutamate
Na+
RMP -65Mv
SP
SP
SP
SP SP
SP
NK1r
NK1r
SP
SP SP
SP
SP
SP
SP
SP
SP
Na+ Na+
RMP -60Mv RMP -55Mv RMP -50Mv
Presenter
Presentation Notes
So what we can do is attempt to give our patients preemptive analgesia with opioids This works well but you need significantly high doses of opioids to attenuate windup phenomenon Opioids work by agonizing Mu receptors and therefore allowing K+ out of the cell If we let a positively charges ion out of the cell we make the cell more negetive thereby decreasing RMP and taking it farther from threshold This means that you need more painful stimuli in order to initiate a pain impulse
Opioid Problem
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv
RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate Fentanyl
Fentanyl
Fentanyl
Fentanyl K+ K+ K+
K+ SP
SP
SP
SP
SP
SP
I’m out of gas!
Help!
NK1r
NK1r
SP
SP
SP SP
SP
SP
SP
SP
SP
SP
SP
SP
Pain Pain Pain
Presenter
Presentation Notes
So now we have given some fentanyl and that has hyperpolarized out neuron, but remember we said that SP is co-released along with glutamate so while you have decreased RMP with your fentanyl, Glutamate on the AMPAr and SP on the NMDAr are increasing RMP X2. Additionally, NK1 receptors have the ability to up-regulate themselves within hours The opioids have still helped a great deal but over any type of duration of pain impulses, they are loosing the war. Attenuating pain with narcotics alone is a little like fighting off an invading army who has ships attacking from the see, fighter planes in the sky, and infantry come in the back door, and all you can do is fight off the infantry with your tanks. Te only problem is that eventually your tanks start running out of gas, and the ships make landfall, and the aircraft start blowing up the town.
Ketamine
Ketamine
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv RMP -60Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate Glutamate Glutamate
Glutamate
Glutamate
SP SP
SP
SP
SP SP
SP
SP SP
SP
Na+ Na+
Ketamine
Na+ Na+ Ca++
RMP -75Mv
RMP -50Mv RMP -65Mv
Fentanyl K+ K+
RMP -65Mv
Fentanyl K+ K+ Fentanyl K+ K+ Fentanyl K+ K+
Presenter
Presentation Notes
The point here is that while opioids work well at first, but their mechanism of action is being usurped by other intracellular actions. Additionally, with prolonged painful impulses there is down regulation of Mu receptors. This is where the research is showing Ketamine comes into play The Achilles heal of the NMDA receptor and NK1 receptor associated wind-up phenomenon is an open NMDA receptor If we block the NMDA receptor with an antagonist, such as ketamine, we can do two helpful things. First, we decrease the permeability of Na+ which decreases RMP Second, we decrease the channel permeability to Ca++ which inhibits Calcium-Calmodulin Dependant Kinase which then inhibits spontaneous activation of the AMPAr Together these actions greatly attenuate windup phenomenon
Ketamine Without Opioids
NMDAr MUr
MUr
AMPAr NK1r MUr MUr
Threshold -45 Mv RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate Glutamate Glutamate
Glutamate
Glutamate
SP SP
SP
SP
SP SP
SP
SP SP
SP
Na+ Na+
Ketamine
Na+ Na+ Ca++
RMP -75Mv
Ca++
CaMKII
Na+ Na+
RMP -55Mv
Fentanyl K+ K+
NK1r
NK1r
Fentanyl K+ K+ Fentanyl K+ K+ Fentanyl K+ K+
RMP -65Mv
RMP -60Mv RMP -55Mv
Presenter
Presentation Notes
This however does not suggest that ketamine alone will attenuate nocicptive impulses in the surgical patient. While you have blocked the sodium and Ca++ entry from the NMDA receptor with Ketamine (click) this still allow SP for bind to the NK1r and release a small amount of Ca++ which activates Calcium-Calmodulin Dependant Kinase which will phosphorelate the AMPAr and then increase RMP. Additionally, in response to repetitive stimulation, NK1 receptors up regulate very rapidly so their effect can become cumulative within hours. For this reason, adequate narcotics must be administer in combination with Ketamine for best results as they can act presynaptically to hyperpolarize the 1st order neuron and decrease the amount of SP and glutamate released. When the NMDA receptor is blocked by ketamine, and you decrease the amount of glutamate and SP released from the first order neuron, coupled with increasing the amount of K+ leaving the second order neuron, you make it very difficult for the second order neuron to elicit an AP Additionally, as you have noted from the slide, there is now a decreased ammount of SP to interact with NK1r so they have not upregulated themselves
Practicality of Ketamine
Presenter
Presentation Notes
It was told to me by a doctorial prepared research professor in my graduate studies, that is take 17 years for research to become practice. In preparing for this presentation I discovered that there is a considerable amount of research showing opioid sparring effects and anti-nociceptive effects of ketamine as well as its ability to directly attenuate windup phenomenon. Ketamine has been shown to attenuate wind-up phenomenon in research articles for over 20 years with some of the most promising research emerging in the early 1990’s Still this remains the Bermuda triangle of anelgesia as this research seems to be published….. And then disappear.
How Much Ketamine?
Less Painful Procedures 0.25mg / Kg Prior to Incision 0.125mg / Kg every 30 minutes Infusion 0.25mg/kg/hr Last dose 30 min prior to emergence
Painful Procedures 0.5mg / Kg prior to Incision 0.25mg / Kg every 30 minutes Infusion 0.5mg/kg/hr Last dose 60 min prior to emergence
Presenter
Presentation Notes
Bolus on shorter cases (approx 40 min) – 0.1 – 0.5mg/kg, 0.25mg/kg, Infusion on longer cases – (bolus of 2mcg/kg) 20mcg.kg Proposed administration scale (scale is for racemic Ketamine and can be decreased by 70% for S(+) Ketamine) Painful procedures 0.5mg/kg prior to incision 0.25mg/kg every 30 minutes or 500mcg/kg/hr Procedures lasting longer than 2hr administration of ketamine should stop 60 before emergence to prevent prolonged recovery Less painful procedures 0.25mg Bolus prior to incision 0.125mg/kg bolus every 30 minutes or 250mcg/kg/hr Last dose of ketamine should not be given within 30 minutes of emergence to prevent prolonged recovery
Myths of Sub-Anesthetic Ketamine Ketamine and emergence phenomenon
Ketamine and PONV
Ketamine and ischemic heart disease
Using high dose narcotics do not need ketamine
Presenter
Presentation Notes
Emergence phenomemon was not seen with increased incidence in patients who had received sub anesthetic doses of ketamine prior to surgical incision, pre-incisional with ketamine infusion, or at the conclusion of surgery, or even in those who had ketamine incorporated into their PCA Much of this attenuation in windup phenomenon may likely be due to the use of benzodiazepines as well as the diminished doses of the agent No increases in PONV was seen in patients who had sub anesthetic doses of ketamine prior to surgical incision, pre-incisional with ketamine infusion, or at the conclusion of surgery with those who did not have ketamine. Infact some research states that the ketamine may actually decrease the amount of PONV as SP is released from the second order neuron in the brain and therefore may increase nausea, as well as from histamine releasing opioids (morphine and dilaudid) used to treat postoperative pain. Ketamine and ischemic heart disease….. Well, honestly the jury is still out on this one. Ketamine increased HR by blocking the parasympathetic muscurinic receptors on the heart as well as increasing the release of norepinepherine which acts at B1 receptors on the heart thereby increasing rate and contractility. This is infact a dose related response, and therefore low, sub anesthetic, doses are generally not associated with an increase in myocardial oxygen consumption. However, the fact remains that this CAN be a side effect of this agent. Conversely, the prolonged release of catecholamine associated with postoperative pain can have the same effect. Unfortunately, Narcotics are only attenuated a multifatorial problem occurring in the synapse, and while high dose narcotics are significantly advantageous, pain is still sneaking in the back door throughout the surgery. Ketamine, along with adequate doses of opioids have been shown to significantly attenuate postoperative pain as well as decrease the amount of postoperative narcotics used.
The Anesthetists Toolbox
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As anesthetists, we are provided with a number of excellent tools in our toolbox. As our practice evolves, we may soon be realizing some new uses for some old tools, such as ketamine, and some new tools, such as precedex. It is in the best interest of our patients that we are aware of these tools so that we may impart on our patient our best clinical effort to provide them with analgesia long after we leave them. Thank you for your time
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