ryan dreikorn bsn srna york college of pennsylvania / wellspan health nurse anesthesia program
TRANSCRIPT
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KETAMINE AND DEXMEDETOMIDINE IN “WIND-UP” PHENOMENON
Ryan Dreikorn BSN SRNAYork College of Pennsylvania / WellSpan Health Nurse Anesthesia Program
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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”
Discuss the emerging research of Dexmedetomidine (Precedex) in attenuating “wind-up”
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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
Wind-Up phenomenon can be attenuated by the Alpha 2 receptor
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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
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The Neuron
The Synapse
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First Order / Second Order
Axon
Dendrite
First Order Neuron
Second Order Neuron
Synapse
Pain
Soma / Cell Body
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Dorsal Root Ganglion
First Order Neuron
Synapse
Free NerveEnding
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Anterolater Spinothalamic Tract
A bit much
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Spinothalamic Tract (Simplified)
Thalamus
Cerebral Cortex
1st Synapse
2nd Synapse
1st Order Neuron
2nd Order Neuron
3rd Order Neuron
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Spatial Summation
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Spatial SummationWhat 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.”
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Temporal Summation
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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.”
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Lois, Lois, mom, mom, mummy, mummy, muma, muma, ma, ma, mum, mum, mummy, ma
WHAT!?!?!
Persistent Low Intensity
HI!
Wind-Up Phenomenon
Persistent Low Intensity Temporal Summation
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Review Neuron Physiology and the Action Potential
Last Stop Before “Receptorland”
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Ionic Movement (Quick Review)
Intra-Cellular Fluid Extra-Cellular Fluid
Increased K+
Decreased Na+
Decreased Ca++
Decreased K+
Increased Na+
Increased Ca++C
ellu
lar
Mem
bra
ne
All In The Search For Equilibrium
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The Action Potential (Quick Review)
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Action Potential
Increases Na+ Permeability
Fast Na+ Channels
Impulse / AP Sent
Ca++
THIS CAN CHANGE
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Ah Finally, Receptorland
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Speaking The Local Dialect Ligands
Neuroplasticity Up-Regulation Down-Regulation
Ionotropic Receptors
Metabotropic Receptors
Nociceptors / Free Nerve Endings
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A Fiber & C Fibers (More Dialect)
C-Fiber
A-Fiber
C-Fiber Only
A-Fiber Only
XX
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Wide Dynamic Range Neuron
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alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA)
AMPA
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Neurokinin 1 Receptor (NK1r)
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N-methyl-D-aspartate (NMDA) Receptor
2nd Order Neuron
Intracellular
Extracellular
KETAMINE
AP
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Alpha 2 Receptor
Precedex
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Mu Opioid Receptor
Pres
ynap
tic
Post
syna
ptic
Pain Impulse
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Put The Pieces Together
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This Is Very Graphic Material
We Need to Build a Neuron
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Where Are We
You Are Here
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Our Neurons
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Postsynaptic / Second Order Neuorn
Presynaptic / First Order Neuorn
Threshold -45 Mv
RMP -65Mv
The Synapse
RMP -65Mv
Threshold -45 Mv
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Under General Anesthesia
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Masked Man With A Knife
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Initial Pain Impulses
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Postsynaptic / Second Order Neuron
Presynaptic / First Order Neuron
Threshold -45 Mv
RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Na+
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More Pain Impulses
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Postsynaptic / Second Order Neuron
Presynaptic / First Order Neuron
Threshold -45 Mv
RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Na+
Glutamate
Glutamate
Glutamate
Na+
Na+
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Increased Pain Impulses
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Postsynaptic / Second Order Neuron
Presynaptic / First Order Neuron
Threshold -45 Mv
RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Na+
Glutamate
Glutamate
Glutamate
Na+
Na+
Glutamate
Glutamate
GlutamateGlutama
teGlutamate
Glutamate
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NMDA Receptor
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Beginnings of Wind-Up Phenomenon
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Postsynaptic / Second Order Neuron
Presynaptic / First Order Neuron
Threshold -45 Mv
RMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Na+
Glutamate
Glutamate
Glutamate
Na+
Na+
Glutamate
Glutamate
GlutamateGlutama
teGlutamate
Glutamate
Na+
Na+
Na+
Na+ RMP -60Mv
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Wind-Up Phenomenon
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Presynaptic / First Order Neuron
Threshold -45 MvRMP -60Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Glutamate
Na+
Glutamate
Glutamate
GlutamateGlutama
teGlutamate
Glutamate
Na+
Na+
SPSP
SP
SP
SPSP
SP
SPSP
SP
Phospholipase-C
DAG
PKCNa+
Na+ Na
+
Ca++RMP -50Mv
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Wind-Up Phenomenon
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Presynaptic / First Order Neuron
Threshold -45 MvRMP -50Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Glutamate
Na+
Glutamate
Glutamate
GlutamateGlutama
teGlutamate
Glutamate
Na+
Na+
SPSP
SP
SP
SPSP
SP
SPSP
SP
Ca++
CaMKII
Na+
Na+
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Hyperalgesia / Allodynia
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Presynaptic / First Order Neuron
Threshold -45 MvRMP -50Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Glutamate
Na+
Glutamate
Glutamate
GlutamateGlutama
teGlutamate
Glutamate
Na+
Na+
SPSP
SP
SP
SPSP
SP
SPSP
SP
Ca++Na+
Na+
Pain
Pain
Pain
Pain
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Wind-Up on the WDR Neuron
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Traditional Opioids
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Presynaptic / First Order Neuron
Threshold -45 MvRMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Na+
FentanylFentanyl
Fentanyl
Fentanyl
Fentanyl
K+
K+ K
+
K+
K+
K+
K+
K+
RMP -75Mv
RMP -75MvRMP -65Mv
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Opioid Problem
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Presynaptic / First Order Neuron
Threshold -45 MvRMP -75Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Na+
FentanylFentanyl
Fentanyl
Fentanyl
FentanylK+ K
+K+
K+
Pain
Pain
Pain
RMP -75MvRMP -65Mv
Glutamate
Glutamate Glutama
teGlutamate
Glutamate
Na+
Na+ Na
+
Glutamate
Na+
RMP -65Mv
SP
SP
SP
SPSP
SP
NK1r
NK1r
SP
SPSP
SP
SP
SP
SP
SP
SP
Na+
Na+
RMP -60MvRMP -55MvRMP -50Mv
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Opioid Problem
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Presynaptic / First Order Neuron
Threshold -45 MvRMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
FentanylFentanyl
Fentanyl
FentanylK+
K+
K+
K+
SP
SP
SP
SP
SP
SP
I’m out of gas!
Help!
NK1r
NK1r
SP
SP
SPSP
SP
SP
SP
SP
SP
SP
SP
SP
Pain
Pain
Pain
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Ketamine
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Presynaptic / First Order Neuron
Threshold -45 MvRMP -60Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
GlutamateGlutama
teGlutamate
Glutamate
SPSP
SP
SP
SPSP
SP
SPSP
SP
Na+
Na+
Ketamine
Na+
Na+
Ca++
RMP -75Mv
RMP -50MvRMP -65Mv
FentanylK+
K+
RMP -65Mv
FentanylK+
K+
FentanylK+
K+
FentanylK+
K+
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Ketamine Without Opioids
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Presynaptic / First Order Neuron
Threshold -45 MvRMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
GlutamateGlutama
teGlutamate
Glutamate
SPSP
SP
SP
SPSP
SP
SPSP
SP
Na+
Na+
Ketamine
Na+
Na+
Ca++
RMP -75Mv
Ca++
CaMKII
Na+
Na+
RMP -55Mv
FentanylK+
K+
NK1r
NK1r
Fentanyl
FentanylK+
K+
FentanylK+
K+
FentanylK+
K+
RMP -65Mv
RMP -60MvRMP -55Mv
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Practicality of Ketamine
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How Much Ketamine?
Less Painful Procedures 0.25mg / Kg Prior to Incision 0.125mg / Kg every 30 minutes
Painful Procedures 0.5mg / Kg prior to Incision 0.25mg / Kg every 30 minutes
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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
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What about Dexmedetomidine
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Alpha 2 Receptor α2 agonist binds with the receptor
Gi α subunit is released from the β and γ subunits inhibits adenylate cyclase decreases cAMP decreased PKA decreased membrane permiability to ions K+ efflux hyperpolarization Inhibition of Ca++ entry No vesicles
out
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More On the Alpha 2 Receptor
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Dexmedetomidine Mechanism of Action
NMDAr MUr
MUr
α2rAMPArNK1rMUr MUr
α2r
Threshold -45 MvRMP -65Mv
Glutamate
Glutamate
Glutamate
Glutamate
Glutamate
Na+
Glutamate
Na+
Glutamate
Glutamate
SPSP
SP
SP
SPSP
SP
SPSP
SPPrecedex
Precedex
RMP -65Mv
↓Adenylate Cyclase
↓ cAMP↓PKA
↓Ca+
↓Na+ ↑K+
K+ K+
RMP -75Mv
↓Adenylate Cyclase↓ cAMP↓PKA
↓K+
K+ K+
RMP -75Mv
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Presynaptic or Postsynaptic
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Effect of Dexmedetomidine on Attenuation of Nociceptive
Impulses
WithoutWind-Up
FormalinInducedWind-Up
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Practicality of Dexmedetomidine
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The Anesthetists Toolbox
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Questions
References Available Upon Request