2. INTRODUCTION
Red Indians used arrow poison to hunt their food,
using Curare as the poison. Unknown to them they
laid the foundation of blocking the NMJ.
Through subsequent ages new methods have been
studied and technique refined to produce a blockade
where we control the patient.
Curare was first used clinically in 1942 by Griffith and
Johnstone.
3. DEFINITION
The NMJ is a synapse at which an electrical impulse
travelling down a motor nerve, releases chemical
transmitter which cause the muscle to contract.
4.
5. PHYSIOLOGY OF
NEUROMUSCULAR TRANSMISSION
NMJ is specialised on the nerve side and on the
muscle side to transmit and recieve chemical
messages.
Each motor neuron runs without interruption from
the ventral horn of spinal cord to NMJ as a large
myelinated axon.
As it approaches muscle it branches to contact many
muscle cells together into functional group known as
Motor unit.
6. PARTS OF NMJ
The anatomy of NMJ consist of following parts:
2.Pre-synaptic membrane
3. Synaptic cleft
4.Post-Synaptic membrane
5.Contractile apparatus
• The nerve is separated from the surface of the muscle
by a gap of about 20nm called junctional cleft.
• Presynaptic membrane contains prejunctional
acetylcholine receptors and active zone.
7.
8. Synaptic cleft: Lies Between the muscle endplate
and nerve terminal which are held in tight alignment
by basal lamina.
Post synaptic membrane – acetylcholine
receptors: At the post synaptic membrane the area
overlying the nerve terminal is called muscle end
plate. The membrane here is thrown into primary and
secondary clefts.
At the shoulder of these clefts numerous
acetylcholine receptors are present.
9.
10.
11. The acetylcholine receptors are nicotinic and are of
following types
c. Junctional or mature
e.Extra junctional or immature
12.
13. Acetyl choline receptors/Post junctional receptors:
Present in the post junctional membrane of the motor
end plate & are of nicotinic type. These receptors
exist in pairs.
It consists of protein made up of 1000 amino acids,
made up of 5 protein subunits designated as alpha,
beta, delta and epsilon joined to form a channel that
penetrates through and projects on each side of the
membrane.
14. In the fetus gama replaces epsilon subunit.
Each receptor has central funnel shaped core which
is an ion channel, 4 nm in diameter at entrance
narrowing to less than 0.7nm within the membrane.
The receptor is 11 nm in length and extends 2nm
into the cytoplasm of the muscle cell.
The receptor has 2 gates, an Upper voltage-
dependent and a Lower time-dependent.
15.
16. When acetylcholine receptors bind to the pentameric
complex, they induce a conformational change in the
proteins of the alpha subunits which opens the channel
and occurs only if it binds to both the alpha binding sites.
For ions to pass through the channel both the gates
should be open.
Cations flow through the open channel, sodium and
calcium in and potassium out, thus generating end plate
potential.
Na ions are attracted to the inside of the cell which
induces depolarisation.
17. PREJUNCTIONAL RECEPTORS
These are nicotinic receptors that control ion channel
specific for calcium which is essential for synthesis
and mobilization of acetylcholine.
They contain protein subunits that are blocked by
non depolarising muscle relaxants resulting in fade
and exhaustion.
They are also blocked by aminoglycosides and
polymyxin antibiotics
18. EXTRAJUNCTIONAL RECEPTOR
These tend to be concentrated around the end plate,
where they mix with post junctional receptors but may be
found anywhere on the muscle membrane. In them, the
adult epsilon subunit is replaced by the fetal gamma
subunit.
They are not found in normal active muscle, but appear
very rapidly after injury or whenever muscle activity has
ended.
They can appear within 18hrs of injury and an altered
response to neuromuscular blocking drugs can be
detected in 24hrs of the insult.
19. When a large number of extrajunctional receptors are
present, resistance to non-depolarising muscle
relaxants develops, yet there is an increased
sensitivity to depolarising muscle relaxants.
In most extreme cases, increased sensitivity to
succinylcholine results in lethal hyperkalemic
receptors with an exaggerated efflux of intracellular
potassium.
The longer opening time of the ion channel on the
extrajunctional receptor also results in larger efflux.
20. CONTRACTILE APPARATUS
It is formed by thin actin , thick myosin filaments
tropomyosin & troponin.
The shortening of this apparatus causes the
contraction of the muscle
23. Ach (Synthesis, storage, release)
Synthesized in the Presynaptic terminal from substrate
Choline and Acetyl CoA.
CAT
CHOLINE + ACETYL CoA ACETYL CHOLINE
COMT
50% Carrier Facilitated Transport Release
CHOLINE + ACETYL CoA ACETYL CHOLINE
Synaptic Cleft
24. Different pools of acetylcholine in the nerve terminal
have variable availability for release
c)The immediately releasable stores, VP2: Responsible
for the maintainance of transmitter release under
conditions of low nerve activity. 1% of vesicles
e)The reserve pool, VP1: Released in response to nerve
impulses. 80% of vesicles
g)The stationary store: The remainder of the vesicles.
25. Each vesicle contains approx 12,000 molecules of
acetylcholine, which are loaded into the vesicles by an
active transport process in the vesicle membrane
involving a magnesium dependent H+ pump ATPase.
Contents of a single vesicle constitute a quantum of
acetylcholine.
Release of acetylcholine may be
f) Spontaneous or
g)In response to a nerve impulse.
26. When a nerve impulse invades the nerve terminal,
calcium channels in the nerve terminal membrane are
opened up.
Calcium enters the nerve terminal and there is
calcium dependant synchronous release of the
contents from 50-100 vesicles.
The number of quanta released by each nerve impulse
is very sensitive to extracellular ionized calcium
concentrations. Increased calcium concentration
results in increased quanta released.
27. To enable this, vesicle must be docked at special
release sites (active zones) in that part of the terminal
where the axonal membrane faces the postjunctional
acetylcholine receptors.
These are vesicle from the immediately releasable
stores
28. Once the contents have been discharged, they are
rapidly refilled from the reserve stores.
The reserve vesicles are anchored to actin fibrils in
the cytoskeleton, by vesicular proteins called
synapsins
Some calcium that enters the axoplasm, on the arrival
of the nerve impulse binds to calmodulin, which
activates protein kinase-2 which phosphorylates
synapsins, which, in turn dissociates the vesicle from
the actin fibrils allowing it to move forward to the
release site.
29. Docking of the vesicle and subsequent discharge of
acetylcholine by exocytosis, involves several other
proteins.
Membrane protein called SNAREs ( Soluble N-
ethylmatrimide sensitive attachment proteins) are
involved in fusion, docking, and release of
acetylcholine at the active zone.
SNARE includes – synaptic vesicle protein
synaptobrevin, synataxin and SNAP-25.
30.
31.
32. The released acetylcholine diffuses to the muscle type
nicotinic acetylcholine receptors which are
concentrated at the tops of junctional folds of
membrane of the motor end plate.
Binding of acetylcholine to these receptors increases
Na and K conductance of membrane and resultant
influx of Na produces a depolarising potential, end
plate potential.
The current created by the local potential depolarise
the adjacent muscle membrane to firing level.
33. Acetylcholine is then removed by acetylcholinesterase
from synaptic cleft, which is present in high
concentration at NMJ.
Action potential generated on either side of end plate
and are conducted away from end plate in both
directions along muscle fiber.
The muscle action potential in turn initiates muscle
contraction
34. STRUCTURE OF NA CHANNEL
This Na channel is cylindrical
Has membrane protein
Its two ends act as gates
Both should be open to allow passage of ions.
Voltage dependent gate is closed in resting state and
opens only on application of a depolarising voltage,
remains open as long as the voltage persists
35.
36. The time dependent gate is normally open at rest
closing a few milliseconds after the voltage gate opens
and remains closed as long as the voltage gate is open
It reopens after the voltage gate closes.
The channel is patent, allowing sodium ions only
when the gates are open.
37. POSSIBLE CONFIGURATION OF Na CHANNELS
• Resting state: Voltage gate closed
Time gate open
Channel closed
• Depolarization: Voltage gate open
Time gate open
Channel open
• With in a few milliseconds: Voltage gate open
Time gate closed
Channel closed
• End of depolarization: Voltage gate closed
Time gate open
Channel closed
38. ROLE OF CALCIUM
The concentration of calcium and the length of time
during which it flows into the nerve ending, determines
the number of quanta release.
Calcium current is normally stopped by the out flow of
potassium.
Calcium channels are specialized proteins, which are
opened by voltage change accompanying action
potentials
39. Part of calcium is captured by proteins in the
endoplasmic reticulum & are sequestrated.
Remaining part is removed out of the nerve by the
Na/Ca antiport system
The sodium is eventually removed from the cell by
ATPase
40. ACETYLCHOLINESTERASE
This protein enzyme is secreted from the muscle, but
remain attached to it by thin stalks of collagen,
attached to the basement membrane.
Acetylcholine molecules that don’t interact with
receptors are released from the binding site & are
destroyed almost immediately by
acetylcholinesterase, in <1 ms, after its release into the
junctional cleft.
41. PHYSICAL CHANNEL BLOCKADE
Various drugs can block the neuromuscular junction
and prevent depolarisation.
Blockade can occur in two modes
d)Blocked when open
e)Blocked when closed
42. OPEN CHANNEL BLOCK
In this, the drug molecule enters a channel which has
been opened by acetylcholine.
This is use dependent block
Physical blockade by a molecule of an open channel
relies on the open configuration of the channel and the
development of this is proportional to the frequency of
channel opening.
43. This mechanism may explain the synergy that occurs
with certain drugs such as local anaesthetic,
antibiotics and muscle relaxants.
In addition, the difficulty in antagonizing profound
neuromuscular blockade may be due to open channel
block by the muscle relaxants
44. CLOSED CHANNEL BLOCK
The drugs occupy the mouth of the channel and prevents
ions from passing through the channel to depolarise the
end plate.
Tricyclic drugs and naloxone may cause physical blockade
of a closed by impending interaction of acetylcholine with
the receptor.
For drugs interfering with the function of the
acetylcholine receptor, without acting as an agonist or
antagonist, the receptor lipid membrane interface may
also be another site of action.
Eg: Volatile agents, Local anaesthetic and Ketamine
45.
46. INTRODUCTION
Neuromuscular monitoring is based on two important
issues:
1. on the variable response to muscle relaxants and
2 because of the narrow therapeutic window.
There is no detectable block until 75 to 85% of receptors
are occupied and paralysis is complete at 90 to 95%
receptor occupancy.
Neuromuscular monitoring permit optimal surgical
relaxation and reverses the block spontaneously or
revesed quickly with antagonists.
47. Residual neuromuscular block is a major risk factor
for many critical events in the immediate
postoperative period such as ventilatory insufficiency,
hypoxemia and pulmonary infections.
The most satisfactory method is by peripheral nerve
stimulator and observation of evoked response in the
muscle supplied.
48. FEATURES OF
NEUROSTIMULATION
Key features of exogenous nerve stimulation are:
• Nerve stimulator: A battery powered device that delivers
depolarizing current via the electrodes.
• Pulse width: Is the duration of the individual impulse
delivered by the nerve stimulator.
• Each impulse should be <0.5msec and 0.1sec in duration
to elicit nerve firing at a readily attainable current. Pulse
width >0.5msec extends beyond the refractory period of
the nerve resulting in repetitive firing.
49. • Current intensity: Is the amperage(mA) of the
current delivered by the nerve stimulator. The
current output of most stimulators can range from
0-80mA.
• Supramaximal current: Is approximately 10-20%
higher intensity than the current required to
depolarize all fibres in a particular nerve bundles.
50. • Submaximal current: A current intensity that induces
firing of only a fraction fibres in a given nerve bundle
and is less painful
• Stimulus frequency: The rate (Hz) at which each
impulse is repeated in cycles per second (Hz).
• Single twitch is commonly repeated at 10 second
intervals i.e. 0.1 Hz and
• Tetanic stimulation commonly consists of 50 impulses/
sec i.e. 50 Hz.
51. ELECTRODES
Surface Electrodes: They contain gel conducting
surfaces for transmission of impulses to the nerves
through the skin. With careful skin preparation the
threshold for which response is generally <15mA.
Needle Electrodes: Subcutaneous needles deliver the
impulse in the immediate vicinity of the nerve. These
are highly effective because they bypass the tissue
impedance so that the tissue impedance is typically
<2000 Ohms.
52. Single twitch: This is the simplest form 0f
neurostimulation entailing a single twitch at 0.1 to
0.12 msec.
Single twitch is delivered at a supramaximal current,
it induces a single nerve action potential in each fiber
of the nerve bundle.
During nondepolarizing block the response to single
twitch stimulation is not reduced until atleast 75 to
80% of receptors are occupied and therefore does not
detect block of less than 70%.
53.
54. Train of four(TOF):
This is a popular mode of stimulation for clinical
monitoring of neuromuscular junction first described by
ali et al.
Four successive stimuli are delivered at 2 Hz (every
0.5sec). In the presence of non depolarizing relaxants,
the margin of safety is decreased such that some end
plates in train of four progressively fade.
In the absence of non depolarizing block, the T4/T1 ratio
is approximately one.
For complete recovery T4/T1 ratio should be more than
0.9
55.
56.
57. ADVANTAGES OF TOF STIMULATION
This pattern of stimulation can be applied at anytime
during the neuromuscular block and can provide
quantification of depth of block without the need for
control measurement before relaxant administration.
It is more sensitive to lesser degree of receptor
occupancy than single twitch.
58. The relatively low frequency allows response to be
evaluated manually or visibly.
There is no post tetanic facilitation therefore can be
repeated every 10 to 12 sec.
It may be delivered at sub maximal current which is
less painful and is associated with same degree of
fade.
59. TETANIC STIMULATION
High frequency stimulation (50Hz or more) results in
sustained or tetanic contraction of the muscle during
normal neuromuscular transmission despite
decrement in acetylcholine release.
During tetanus, progressive depletion of acetylcholine
output is balanced by increased synthesis and transfer
of transmitter from its mobilization stores.
60. The presence of nondepolarizing muscle relaxants
reduces the margin of safety by reducing the number of
free cholinergic receptors and also by impairing the
mobilization of acetylcholine within the nerve terminal
there by contributing to the fade in the response to
tetanic and TOF stimulation.
A frequency of 50Hz is physiological as it is similar to
that generated during maximal voluntary effort. Fade is
first noted at 70% receptor occupancy.
It has been shown that tetanic response to 50 Hz for five
sec is sustained when TOF ratio is greater than 0.7.
61.
62. DISADVANTAGES
• Is post tetanic facilitation which depends on
frequency and duration of block
• It is very painful and therefore not suitable for
unanaesthetised patients.
63. DOUBLE BURST STIMULATION
TOF ratio of less than 0.2 to 0.3 is difficult to detect
even by trained observers.
To improve the detection rate, a new mode of
stimulation which consist of two short tetani,
separated by a interval long enough to allow
relaxation, evaluating the ratio of second to first
response has been proposed.
Many patterns have been suggested but the most
promising one consists of two train of three impulse
of 50 Hz separated by 750msec.
64.
65. POST- TETANIC COUNT (PTC)
Tetanus at 50 Hz for five seconds is applied followed 3
sec later by single twitch stimulation at 1 Hz.
The number of evoked post-tetanic twitches detected
is called the post-tetanic count (PTC).
PTC is a prejunctional event, the response can vary
with the nondepolarising muscle relaxant used.
A PTC of 8 to 9 indicated imminent return of TOF.
66.
67. APPLICATION OF PTC
Evaluating the degree of neuromuscular blockade
when there is no reaction to single twich or TOF as
after administration of large dose of nondepolarizing
muscle relaxant.
PTC can also be used whenever sudden movement
must be eliminated (Ophthalmic Surgery).
Elimination of responses to tracheobronchial
stimulation requires intense neuromuscular blockade
of zero PTC.
68. PTC can be used during continuous infusion of
intermediate nondepolarizing muscle relaxant as a
guidance to intensity of neuromuscular blockade.
PTC predicts time to reappearance of first response to
TOF stimulation
69. MONITORING SITES
The specific nerve-muscle site utilized for monitoring
has drawn interest in the recent years because of the
variability among muscle groups in sensitivity and
onset time
70. Relative sensitivities of muscle groups to
nondepolarizing muscle relaxants
MUSCLES SENSITIVITY
Vocal cord Most Resistant
Diaphragm
Orbicularis oculi
Abdominal rectus
Adductor pollicis
Masseter
Pharyngeal
Extraocular Most sensitive
71. ULNAR NERVE
The nerve is most commonly used for neuromuscular
monitoring in the perioperative period.
The ulnar nerve innervates the adductor pollicis, abductor digiti
mimimi, abductor pollicis brevis and dorsal interosseous
muscles.
One stimulating electrode is typically placed more than 2cm
proximally on the volar forearm or over the olecranon groove.
The recording electrodes are placed over the appropriated
muscle.
72.
73.
74.
75.
76. FACIAL NERVE:
The response to the stimulation is monitored
commonly at the orbicularis oculi (contraction of
eyebrow) and orbicularis oris(contraction of the lip)
77. NERVES OF THE FOOT
The posterior tibial nerve may be stimulated as it
comes behind the medial malleolus, caused plantar
flexion of the great toe and foot.
The peroneal nerve and lateral popliteal nerve elicit
dorsi flexion of the foot
78. ASSESSMENT OF EVOKED RESPONSE TO
NEUROMUSCULAR STIMULATION
Visual or tactile assessment: Visual or tactile methods of
evaluation of the evoked response to stimulation is the
simplest means of assessment
During recovery of neuromuscular function all responses
of TOF can be felt.
An estimation of TOF ratio may be attempted but the
method is not sensitive enough to exclude possibility of
residual neuromuscular blockade.
Fade is usually undetected until TOF ratio values are less
than 0.5
Greater sensitivity for fade detection is achieved with DBS
79. RECORDING DEVICES FOR MEASURING
NEUROMUSCULAR FUNCTION
Compound muscle action potential: It is the
cumulative electrical signal generated by the
individual action potentials of the individual muscle
fibres.
Electromyogram(EMG): It records the compound
MAP via recording electrodes place near the mid
portion or motor point of the muscle.
The latency of the compound MAP is the interval
between stimulus artifact and evolved muscle
response
80. The amplitude of the compound MAP is proportional
to the number of muscle units that generate an MAP
within the designated time interval (epoch) and this
correlates with the evoked mechanical responses.
This method is used mostly for experimental studies
81. ACCELEROMYOGRAPHY
This technique used a miniature piezoelectric
transducer to determine the rate of angular
acceleration.
This is a nonisometric measurement and there are
less stringent requirements for immobilization of
arm, fingers and thumb and also no preload is
necessary.
However recording of tetanic responses is not
possible as the movement is an essential component
of accelerography.
It is a simple method useful in operating room and in
the intensive care unit.
82. CLINICAL APPLICATION
To differentiate depolarising block and Non-
depolarising block
To see efficacy of depolarising block after
administration of drug and to judge whether the
patient is fully relaxed
To see whether the pt is out of effect of block of
depolarising muscle relaxed
As a guide to administer first dose of non-depolarising
muscle relaxant
As a guide to see whether completeness of non-
depolarising neuromuscular block
83. As a guide to for starting of reversal of non-
depolarising block
To see a completeness of recovery
As a guide for incremental doses administration of
non-depolarising muscle relaxant
To differentiate respiratory paralysis i.e. central or
peripheral due to nueromuscular block
To diagnose overdose of sedatives cerebral
depressants or muscle relaxants
84. To diagnose phase II block after suxamethonium
To diagnose various neuromuscular disorders
To diagnose site of nerve injury
To diagnose electrolyte imbalance or disturbances
affecting NM Transmission
As a guide in diagnosis of prolonged apnea or
recovery after balanced anaesthesia
85. WHICH PATIENT SHOULD BE MONITORED
By the foregoing discussion, it would seem prudent to
monitor NMJ in all pts receiving NMBs.
Such monitoring is advisible particularly in conditions
where the pharmacokinetics and pharmacodynamics
of NMBs are altered significantly as listed below:
Several renal, liver disease
Neuromuscular disorders such as myasthenia gravis,
myopathies , and upper and lower motor neuron
lesions
86. Pts with severe pulmonary disease or marked obesity to
ensure adequate recovery of skeletal muscle function.
Neuromuscular blockade achieved with continuous
infusion of NMBs
Pts receiving long-acting NMBs
Pts undergoing lengthy surgical procedures
87. LIMITATIONS OF NEUROMUSCULAR
MONITORING
Despite the important role of NMJ monitoring in
anaesthesia practice, it is necessary to use a
multifactorial approach for the following reasons:
Neuromuscular responses may appear normal despite
persistence of receptor occupancy y NMBs. T4:T1
ratio is 1 even when 40-50% of the receptors are
occupied.
Because of wide individual variability in evoked
responses some pts may exhibit weakness at TOF
ratio as high as high as 0.8 to 0.9
88. The established cut-off values for adequate recovery
do not guarantee adequate ventilatory function or
airway protection
Increased skin impedence resulting from
perioperative hypothermia limits the appropriate
interpretation of evoked responses
89. REFERENCES:
ð Millers text book of anesthesia,7th
ed.
k Clinical anesthesia,Barasch
s Morgan`s principles of anesthesia
l Textbook of physiology,Ganong.
i Snell`s Textbook of anatomy.
Guyton & Hall Textbook of physiology.
x RACE 2005 & 2002
x ISACON 2009
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