Neuromuscular Monitoring in Clinical Practice and Research

Thomas Fuchs-Buder Neuromuscular monitoring in clinical practice and research Thomas Fuchs-Buder Neuromuscular monit...

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Thomas Fuchs-Buder Neuromuscular monitoring in clinical practice and research

Thomas Fuchs-Buder

Neuromuscular monitoring in clinical practice and research With 50 figures and 16tables

~ Springer

Professor Thomas Fuchs-Buder, M.D. Departmentof Anesthesia and Critical Care Centre Hospitalier Universitaire de Nancy/Brabois 54511 Vandceuvre-les-Nancy, France

ISBN-13 978-3-642-13476-0 Springer Medizin Verlag Heidelberg Bibliographic information published by the Deutsche Nationalbibliothek. The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb .de. This work is subject to copyright laws. All rights are reserved, whether the whole or part of the mater ial is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broad-casting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965 in its current version, and perm ission for use mu st always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. Springer Medizin springer.com ein Unternehmen von Springer Science+Business Media © Springer-Verlag GmbH Heidelberg 2010

The use of general descriptive names, registered names, trademarks etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability:The publishers cannot guarantee the accuracy of any information about dosage or application contained in this book. In every individual case,the user must check all such information by consulting the pertinent literature. Cover design: deblik Berlin, Germany Production, reproduction and typesetting: TypoStud io Tobias Schaedla, Heidelberg, Germany Copy editing of German version : Bettina Arndt, Gorxheimertal, Germany English translation: Deborah A. Landry, B.A.,Gottinqen, Germany Printers: ML - Media Consult, Mannheim, Germany SPIN 12992713 Printed on acid-free paper

18/5135/DK - 5 43210

v

Foreword More than 25 years ago, at a time when neuromuscular function monitoring was only seldom used, it was documented that postoperative residual curarization (PORC), also referred to as residual paralysis, was frequent in three university hospitals in Copenhagen. The initial response of colleagues was that this finding most probably was due to insufficient training of anesthesiologists in Denmark and therefore did not apply to other departments in other parts of the world. Over the next years, it was documented that the high incidence of PORC was not solely a Danish problem: It was seen in other places of the world, when a neuromuscular block was not monitored and sufficient recovery of neuromuscular function was sought ensured using only clinical criteria, such as sustained eye opening, tongue protrusion or sustained head or arm lift. Soon it became apparent that the sole use of subjective evaluation of the response to peripheral nerve stimulation also did not exclude PORC and that the only reliable way to detect PORC was by the use of objective neuromuscular monitoring. This time the response among many anesthesiologists was that it might be true, but it did not matter, as PORC does not pose a threat to the patient. However, Professor Lars I. Eriksson and his group at Karolinska Hospital in Sweden showed that even moderate degrees of residual block decrease the chemoreceptor sensitivity to hypoxia. They also showed that PORC is associated with functional impairment of the muscles of the pharynx and upper esophagus, most probably leading to regurgitation and aspiration. Most recently, Dr. Eikermann and colleagues documented that partial neuromuscular block, even to a degree that does not evoke dyspnea or hypoxemia, may decrease inspiratory airway volume and can cause partial inspiratory airway collapse '. In accordance with this, it has been documented that PORC is a significant risk factor for the development of postoperative pulmonary complications and may lead to increase morbidity and mortality',", In spite of the above, many clinicians still do not monitor regularly. In USA it is still more the exception than

1 2 3

Eikermannet al. Am J Respir Crit CareMed.2007;175: 9-15. BergH et al. Acta Anaesthesial 5cand. 1997;41 :1095-1103. Murphy GS et al. Anesth Analg. 2008;107:130-137.

VI

Foreword

the rule that the anesthesiologists use a nerve stimulator. In UK 60% state that they never or seldom use a nerve stimulator and only 9-10% monitor neuromuscular function routinely.' Somewhat better is the situation in Denmark and Germany, where recent surveys have shown that 40-45% of all anesthesiologists use a nerve stimulator regularly. Personally, I support the notion recently expressed in an editorial in Anesthesiology that objective monitoring is an evidence-based practice that should consequently be used whenever a neuromuscular blocking drug is administered. I hope that this book will convince the skeptics by spreading the above message. At least the editor has done his share. I wish the book all the best of luck. Iergen Viby-Mogensen

4

GraylingM, Sweeney SP. Recovery from neuromuscular blockade: a surveyof practice. Anaesthesia. 2007Aug;62(8):806-809

VII

Preface Compared to their precursors, the current generation of neuromuscular blocking agents features improved controllability. This improvement was accomplished by optimizing the metabolic pathways where, now, no more pharmacologically active metabolites are formed as well as by achieving more reliable elimination, even in patients whose organ function is limited. These properties have made it possible to reduce the risk of cumulative effects, particularly after repeated doses of relaxant. Notwithstanding these improvements, the pharmacodynamic action of today's neuromuscular blocking agents is still subject to pronounced individual variations. Both the onset and duration of action as well as neuromuscular recovery have only limited predictability in the individual patient. Moreover, the action of neuromuscular blocking agents is influenced by numerous external factors such as concomitant diseases, drug interactions and pharmacogenetic factors. In particular, the incidence of residual neuromuscular blockade - a proven risk factor for severe postoperative complications - continues to be unacceptably high. Even the most clinically relevant residual blockade is often imperceptible to anesthesiologists if they have to rely on their mere senses, and can generally only be made visible by neuromuscular monitoring. Thus, the willingness to reverse is also accordingly heightened . So, it is not surprising that the preclusion to monitor neuromuscular function counts as a critical, independent risk factor for the occurrence of postoperative residual blockades. While its benefits remain uncontested, the use of neuromuscular monitoring in clinical practice often lags behind expectations. The present textbook contains information that is essential for the judicious application of neuromuscular monitoring and also discusses the merits of neuromuscular monitoring in clinical settings. Special importance has been placed on a comprehensive presentation of acceleromyography. T. Fuchs-Buder

IX

Table of Contents 1

Principles of neuromuscular transmission

1

1.1

Physiological principles

2

1.1.1

Anatomical principles

2

1.1.2

Action potential

1.1.3

Acetylcholine

1.1.4

Postsynaptic nicotinic acetylcholine receptors

7

1.1.5

Presynaptic nicotinic acetylcholine receptors

9

1.1.6

Striated muscles

10

1.2

Pharmacological principles

11

1.2.1

Non-depolarizing neuromuscularblocking agents

11

1.2.2

Depolarizing neuromuscularblocking agents

15

1.2.3

Cholinesterase inhibitors

16

1.2.4

Selective relaxant binding agents drugs References

19 22

2 2.1 2.2

Principles of neuromuscular monitoring.....•......•.•.....• 23 Nervestimulation 24 Stimulation electrodes 26

2.3 2.3.1

Stimulation site/test muscle Ulnar nerve/adductor pollicis muscle

30 .31

2.3.2

Posterior tibial nervelflexor hallucis brevis muscle

32

2.3.3

Facial nerve/orbicularis occuli muscleor facial nerve/corrugator

.4

5

supercilii muscle

33

2.4

Anesthesia-relevant musclegroups

.37

2.4.1

Diaphragm

.38

2.4.2

Laryngeal muscles

.39

2.4.3

Abdominal muscles

.39

2.4.4

Extrinsicmuscles of the tongue and floor of mouth

.40

2.4.5

Pharyngeal muscles

.40

2.5 2.5.1

Stimulation patterns Singletwitch

.41 .42

2.5.2

Train-of-four

.43

2.5.3

Double-burst stimulation

.49

X

Table of Contents

2.5.4

Tetanic stimulation

.51

2.5.5

Post-tetanic count

.53 56

2.6

Assessment of stimulatory response

2.6.1

Simple nerve stimulators

56

2.6.2

Quantitative nerve stimulators

.59

References

.70

3

Clinical application ... . . ... .. . . •.. • . . •.... . . .. . . . . . . . . . .. . . . 73

3.1

Neuromuscular monitoring during anesthesia induction

3.1 .1

Neuromuscularblocking agents for anesthesia induct ion?

77

3.1 .2

Testmuscles and stimulation patterns

82

3.1.3

What level of neuromuscular block for intubation?

87

76

3.2

Intraoperative application of neuromuscular monitoring

90

3.2.1 3.2.2 3.3 3.3.1

Accumulation of NMBAs Stimulation patterns and test muscles Monitoring neuromuscular recovery Pathophysiological implicat ions of residual neuromuscular

91 9S 97

3.3.2

blockade Frequencyof residual neuromuscular blockade

98 106

3.3.3

Clinical implications associated with residual neuromuscular blockade

108

3.3.4

Stimulation patterns and test muscle

110

3.3.5

Prevention strategiesfor residual neuromuscular blockade

114

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 120 4

Acceleromyography . . • . • .. • • . • • • • . • . • • • • • • • . • • • • • • • • • • • • • • 124

4.1

Principles

126

4.2

The Accelograph and the TOF-Guard

127

4.3

TOF-Watch ~

130

4.3.1 4.3.2

TheTOF ratio algorithm Calibration modes

130 133

4.3.3

Nerve localization in regional anesthesia procedures

136

4.4

TOF-Watch ~

138

4.4.1 4.4.2 4.4.3 4.5

Short set-up instructions Brief overview Schemeof buttons and display symbols TOF-Watch" S

138 139 140 150

models

XI

Table of Contents

4.5.1 4.5.2

Short set-up instructions Briefoverview

150 151

4.5.3 4.6

Scheme of buttons and displaysymbols TOF-Watch@ SX

152 164

4.6.1 4.6.2 4.6.3

Short set-up instructions 164 Brief overview . . . .. . . . .. . . . . . .. . . . . . . . . . . . .. . .. . . . .. . . . . . . . . .. . . . 165 Scheme of buttons and display symbols 166

4.6.4 4.7

Scheme of buttons and display symbols FAQS

168 179

4.7.1

Can acceleromyography also be used in infants?

179

4.7.2

Isneuromuscular monitoring painful for patients?

180

4.7.3

What to observewhen attaching TOF-Watch" nerve

4.7.4

stimulators? Iscalibration reallynecessary?

182 184

Can neuromuscular monitoring with the TOF-Watch" nerve stimulator prevent residual blockade?

190

4.7.5 4.8 4.8.1 4.8.2 4.8.3

Acceleromyography in research Neuromuscular monitoring for scientific purposes: What should anesthesiologistsgenerally look out for? Particulars of performing acceleromyography Guidelines for measuringonset and time profile of neuromuscular blockade Concluding remarks References

193

Subject Index

205

194 197 198 200 202

XIII

List of abbreviations a ACh Ag/AgCI AMG ASA ATPase RR

·C Cal OBS OUR

ED, s ECG EMG F

FAQS FVC

Hz ICU IDS

K' m mA IIC MEF MIF MMG MR Na+ NMBA NMT NPW PMG PPW

PTC R T(l )

TOF

Acceleration Acetylcholine Silver/silver chloride Acceleromyography AmericanSociety of Anesthesiologists Adenosine triphosphatase Recovery room Degrees Celsius Calibration software Double-burststimulation Duration Effective dose(doseof a musclerelaxant that inducesa 95% blockade) Electrocardiogram Electromyography Force Frequentlyasked questions Forced vital capacity Hertz IntensiveCare Unit Intubation Difficulty Score Potassium ion Mass Milliampere Microcoulomb Maximumexpiratoryflow Maximuminspiratory flow Mechanomyography Muscle relaxant, an older term for neuromuscular blocking agent (NMBA) Sodium ion Neuromuscular blocking agent Neuromuscular transmission Negative predictivevalue Phonomyography Positive predictive value Post-Tetanic Count Ramus (First)stimulatory response after train-of-four stimulation Train-of-four

1

Principles of neuromuscular transmission

1.1


1.1.1


- 2

1.1.2

Action potential

1.1.3

Acetylcholine

1.1.4

Postsynaptic nicotinic acetylcholine receptors

1.1.5


1.1.6

Striated muscles

- 2

- 4 - 5 - 7 - 9

- 10

1.2


1.2.1

Non -depolarizing neuromuscular blocking agents

1.2.2

Depolarizing neuromuscular blocking agents

1.2.3

Cholinesterase inhibitors

1.2.4

Selective relaxant binding agents drugs References

- 22

- 11

- 16 - 19

- 11

- 15

2

Chapter 1 . Principles of neuromuscular transmission

1.1


1.1.1


Motor neurons and motor units Motor neurons are the efferent neural pathways that innervate the muscles of the body and are thus involved in all voluntary and involuntary movements. It is the motor neurons that actually conduct the impulses to the muscles. The motor neuron nuclei and cell bodies are located in the anterior horn of the gray matter of the spinal cord, while the metabolic and chemical processes primarily take place in the cell bodies. Axons exiting the vertebral canal from every spinal cord segment travel along the spinal nerve to the motor endplates of the muscle fibers in the target supply area where they divide off into several branches. For better insulation and more rapid conduction of impulses, the axons of motor neurons are encased in a myelin sheath. The myelin sheath is interrupted by regularly spaced nodes of Ranvier. In the vicinity of the nodes of Ranvier, the axon is in direct contact with the extracellular space. While each individual motor neuron innervates several muscle fibers, an individual muscle cell is innervated by a single axon only. A motor unit comprises all muscle fibers innervated by a single motor neuron as well as the motor neuron itself. The motor unit is the smallest functional unit; several hundred motor units make up a nerve-muscle ensemble. The contractile strength of a muscle is determined by the number of recruited (i.e., activated) motor units. The number of muscle fibers innervated by one motor unit differs depending on the function of the target muscle and varies between 5 and 1000. As a general principle, small motor units supply approx. 5-15 muscle fibers only and thereby enable very refined motor control. The outer eye muscles are examples of small motor units. By contrast, large motor units supply up to 1000 muscle fibers, and their motor control is correspondingly less refined. For example, the quadriceps muscle constitutes a large motor unit.

Neuromuscular endplate The synaptic junction between motor neuron and muscle fiber is termed the neuromuscular endplate. Presynaptically, the neuromuscular endplate

3 1.1 . Physiological principles

consists of microscopically visible synaptic processes shaped like bulbs at the distal end of the axon. This motor neuron terminal contains the transmitter substance acetylcholine (ACh) stored in vesicles. Postsynaptically, the motor endplate consists of a specially structured portion of the muscle fiber membrane (D Fig. 1.1) which is garlanded by primary and secondary grooves. Most of the nicotinic ACh receptors are localized on these bulblike structures and have a density ranging between 10,000-20,000 per flm2• The distance between two neighboring ACh receptors is approximately 10 nm. In total, an endplate will contain an average of around 2 x 106 ACh receptors. As with other synapses utilizing acetylcholine as a transmitter, the ACh-cleaving enzyme acetylcholinesterase is available in their direct vicinity. Deep within these grooves, numerous voltage-gated sodium channels are found. These sodium channels playa key role in the generation of action potentials [1]. The pre- and postsynaptic membranes of the motor endplate are separated by a narrow synaptic gap measuring a mere ±50 nm.

Schwann cells

Mitochondria Axolemma Basement membrane Sarcolemma

a Fig. 1.1. Depiction of a motor endplate

1

4


Key points - - - - - - - - - - - - - - - - - - - - - - - - , -

A single motor neuron innervates several muscle fibers. A motor unit is made up of a single motor neuron and all of the muscle fibers it innervates.

-

The neuromuscular end plate consists of the distal end of the axon and a specially structured muscle fiber membrane; the two structures are divided by the synaptic gap.

-

The nicotinic ACh receptors are located on bulb-like processes of the muscle fiber membrane.

1.1.2 Action potential In principle, we differentiate between two types of excitable cells: nerve cells that can transmit impulses and muscle cells that react to these impulses by contracting. An action potential is defined as the change in membrane potential occurring transiently and in characteristic form in excitable cells when excited from their resting potential. In the resting state, the intracellular space of nerve cells contains significantly more potassium ions (K+) than sodium ions (Na-), while, at the same time, an overabundance of sodium ions prevails in the extracellular space. As a result of this uneven ion distr ibution across the intra-and extracellular spaces, a potential differential is created which gives the interior of the cell a negative charge. This is defined as the resting potential . A nerve cell has a resting potential of around -70 to -90 m V. The potential differential is maintained by a constant flow of Na- being pumped from the cell while K+ moves into the cell. The integral membrane protein Na"-K+ ATPase plays a key role in this process. When a sufficient electrical, mechanical or chemical stimulus is applied, the ion conductance at the nerve cell membrane changes. As a result, the resting potential shifts in a positive direction , i.e., towards zero; this capacitance change causes depolarization. Activation of specific voltage-gated sodium channels occurs as soon as the depolarization of the axon membrane has exceeded a threshold of around -15 mV. The transient massive influx of Na" that results ultimately generates an action potential. In myelinated axons, the voltage-gated Na" channels are localized exclusively at the nodes of Ranvier. The action potential at the surface of the axon is transmitted from node to node . As soon as the action potential reaches the

5

1

1.1 . Physiological principles

presynaptic nerve terminal, the voltage-gated Ca" channels are activated and acetylcholine is ultimately released by the inflowing calcium ions. In humans, an action potential lasts for approx. 1 ms. The maximum conductance velocity of an action potential for myelinated axons is usually stated as 100 m/s.

o

Nerve stimulators based on the principle of electromyography (see below) measure the compound action potential of one or several muscles. Key points - - - - - - - - - - - - - - - - - - - - - - - - , -

An action potential is triggered by a massive influx of Na+. In myelinated axons, like motor neurons for example, voltage-gated Na+ channels are localized exclusive ly at the nodes of Ranvier.

-

At the presynaptic nerve terminal, the action potential activates an influx of calcium and thereby acetylcholine release.

1.1.3

Acetylcholine

Synthesis and metabolism Acetylcholine (ACh) is produced in the axon terminals from choline and acetyl-coenzyme A. This reaction is catalyzed by the enzyme choline acetyltransferase which is synthesized in the neurons. Acetyl-coenzyme A is formed as a conversion product of pyruvate during glucose metabolism assisted by mitochondrial enzymes. Choline is taken up by nerve cells with the help of specialized transport molecules. This step is considered the limiting factor in acetylcholine synthesis. After its release, ACh is hydrolyzed to choline and acetate by acetylcholinesterase. Some of the choline produced can later be reabsorbed by the presynaptic structures (D Fig. 1.2). Almost half of the choline required for ACh synthesis is recovered in this way.

Storage and release Essentially, acetylcholine is stored in vesicles in the presynaptic nerve terminals. Each one of these presynaptic vesicles contains approx. 10,000 acetylcholine molecules. A large portion of these vesicles is located in the vicinity of the synaptic gap, parallel to the postsynaptic bulbs of the motor endplate and thus directly opposite the ACh receptors . Individual vesicles empty spontane-

6


AcetylCoA + Choline

Acetylcholine

D Fig. 1.2. Acetylcholine synthesis

ously into the synaptic gap, but this spontaneous release is not sufficient to trigger a muscle contraction. It is not until the action potentials arrive at the motor neuron and trigger an influx of Ca2+ into the nerve ending that several hundred vesicles synchronously release their acetylcholine into the synaptic gap. The binding of ACh to the postsynaptic nicotinic ACh receptor results in depolarization. This depolarization of the postsynaptic membrane at the neuromuscular junction is termed the endplate potential which ultimately results in a muscle contraction. Only a small proportion of the vesicleslocalized directly at the presynaptic membrane (around 1%) are directly available for neuromuscular transmission. This region is called the active zone. Most of the other presynaptic ACh vesicles form a reserve pool that is recruited, as needed, for example during high-frequency, repetitive stimulation. The recruitment of this reserve pool is mediated by intracellular calcium. Key p o int s - - - - - - - - - - --

-

-

-

-

-

-

-

-

-

Acetylcholine is stored in presynaptic vesicles, with each of these stores containing approx. 10,000 acetylcholine molecules. Only an infinitesimally small proportion of the presynaptically stored acetylcholine is directly available for neuromuscular transmission . Calcium is required for recruitment from the reserve pool. -

--,

Acetylcholine (ACh) is synthesized from choline and acetyl-coenzyme A.

The binding of acetylcholine to postsynaptic nicotinic Ach receptors generates an end plate potential.

7

1

1.1 . Physiological principles

1.1.4 Postsynaptic nicotinic acetylcholine receptors

Structure The nicotinic acetylcholine receptor is regarded as the prototype ligand-gated ion channel. Receptors of the excitatory amino acids (glutamate and aspartate), of the inhibitory amino acids (GABA and glycine) as well as of certain serotonin receptors, in particular, the 5-HT 3 receptors, all belong to the same receptor family as the nicotinic acetylcholine receptor. Activation of these receptors leads to a rapid elevation in the cell's permeability for Na" and Ca2+, and is associated with a conformational change [2). All ligand-gated ion channels are oligomers. Most of them are pentamers, i.e., made up of five subunits. The nicotinic acetylcholine receptor similarly consists of five subunits : alongside two identical a subunits , there is one p, 0, and one E or y subunit, depending on the receptor type (aFig.1.3). The subunits are arranged in a ring that forms a huddle around the ion channel located in the interior. Each of the two a subunits has a molecular weight of 40 kDa. The total molecular weight of the nicotinic acetylcholine receptor is 250 kDa [3). Each of the five subunits has an extracellular and intracellular portion on the postsynaptic membrane, with the main portion of this receptor lying in the extracellular space (aFig. 1.3).

Acetylcholine binding sites

+ t

4nm ~==:\

a Fig. 1.3. The N-choline receptor

Intracellular space

8


Differentiation and classification The composition of the nicotinic acetylcholine receptor changes as the body develops from prenatal to adult. The mature, or adult, acetylcholine receptor is only found in the junction of the neuromuscular endplate. The fifth element in its pentamer structure is an e subunit. By contrast, embryonal muscles possess an immature, fetal receptor subtype, where the e subunit is substituted by a y subunit. This ely exchange is responsible for important differences between the two receptor subtypes. For example, the fetal acetylcholine receptor has a much greater sensitivity to agonists where as little as a 10- to 100-times lower dose of acetylcholine or succinylcholine is enough to trigger depolarization. By comparison, fetal acetylcholine receptors have a lower sensitivity to non-depolarizing neuromuscular blocking agents. The half-life of the fetal receptor subtype is about 20 hours; that of mature receptors, several days to weeks. Moreover, the fetal subtype exhibits a much longer receptor opening time. If function of the motor neuron is impaired or when prolonged periods of immobilization, denervation, severe burns or infection occur or whenever chronic therapy with non-depolarizing neuromuscular blocking agents is given as part of an intensive treatment regimen, the mature muscle goes back to producing an abundance of fetal receptors. Initially, these new acetylcholine receptors form in the peripheral regions of the motor endplate (= peri junctiona l) , then later are also present outside the endplate over the entire surface of skeletal muscle (= extrajunctional) .

o

When there is a massive increase in extrajunctional fetal receptor subtypes after periods of immobilization, denervation or burns, an excessive release of potassium will take place after administration of the acetylcholine agonist succinylcholine. This can lead to a hyperkalemic cardiac arrest.

Activation The binding sites for acetylcholine are located at the subunit contact sites. However, of the five possible contact sites, only the a/y contact site on the fetal receptor and the two alo contact sites of the adult receptor have the ability to bind ligands (agonists or antagonists). This receptor functions according to the »all or nothing prlnciple« and opens as soon as acetylcholine or an agonist (e.g. succinylcholine) occupies the two a-subunits. The central ion

9

1

,., . Physiological principles

channel opens as a result of an allosteric change in the conformation of the macromolecule, which thereby becomes permeable to the cations Na' and K+. As soon as a certain number of channels have opened and the threshold potential at the endplate has been reached. a muscle contraction is triggered. Key points - - - - - - - - - - - - - - - - - - - - - - - - , -

The postsynaptic, nicotinic acetylcholine receptor is made up of five subunits. The fetal receptor subtype contains two a subunits in combination with one ~, 6, and V subunit.

-

During the first weeks of life. a switch from the V to the E subunit ereates the adult receptor subtype. However, immobilization and/or burns can also cause the postsynaptic nicotinic acetylcholine receptor to form fetal subtypes later in life. Two acetylcholine molecules must bind in unison at the receptor for activation to take place.

-

1.1.5

Activation causes an ion channel in the center of the receptor to open.


Presynaptic nicotinic acetylcholine receptors are also thought to exist alongside the postsynaptic nicotinic acetylcholine receptors described above. With great probability, this subgroup differs in structure and pharmacological properties from the postsynaptic nicotinic receptors. Low concentrations of agonists (e.g. acetylcholine, nicotine) force acetylcholine to be recruited presynaptically from the reserve pool. Likewise, repeated neuromuscular stimulation forces the recruitment of acetylcholine from the reserve pool. This increased acetylcholine release is required to maintain the stimulatory response after repeated stimulation and explains why an exaggerated stimulatory response occurs after tetanic stimulation (post-tetanic facilitation).

o

Unlike succinylcholine, non -depolarizing neuromuscular blocking agents in hibit acetylcholine recruitment at the presynaptic nerve terminals . This inhibition is attributed with causing the fading observed after TOFor DBS followinq the administration of non -depolarizing neuromuscular blocking agents.

10

Chapter 1 . Principles of neuromu scular transmission

Key points - - --

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Presynaptic nicotinic acetylcholine receptors facilitate the recruitment

-

They differ in structure and pharmacological properties from postsyn-

--,

of acetylcholine. aptic acetylcholine receptors.

1.1.6 Striated muscles Histologie

A skeletal muscle cell has a diameter of 10-100 urn, a length of up to 20 em and features several nuclei. A muscle fiber is made up of several hundred myofibrils. The myofibrils contain repeating assemblies of myosin and actin filaments arranged with overlapping filaments of troponin and tropomyosin threaded around the actin filament [2].

Electromechanical coupling

Inside the muscle fiber, action potentials release Ca2+ from the sarcoplasmic reticulum . This cancels the inhibitory action of the troponin, thereby allowing actin and myosin to react with each other, and finally triggering a contraction. The contraction is over with the reuptake of the Ca2+ into the sarcoplasmic reticulum. As a general rule, every above-threshold endplate potential at the muscle triggers an action potential. On the one hand , the refinement of motor control is accomplished by recruitment (i.e., excitation of several motor units) and on the other hand by a change in the frequency of the action potentials. Action potentials occurring in rapid succession induce a summation of contractions that finally reaches the strongest tension at a peak frequency; this is referred to as a tetanic contraction . To avoid summation effects, it is best to not alter the stimulation frequency intraoperatively. A transient increase in measured muscle strength occurring after a tetanic stimulus can take as long as several minutes before the actual level of neuromuscular blockade is re-achieved. This phenomenon has direct implications for neuromuscular monitoring: By achieving supramaximal stimulation, it is ensured that the same (maximum) number of motor units is always recruited intraoperatively and

11

1

1.2 . Pharmacological principles

maintains the baseline strength at a constant level. Intraoperative changes in muscle strength thus directly reflect the action of the NMBA. Key po ints - - - - - - - - - - - - - - - - - - - - - - - - , The action potential activates voltage-gated, specific Cal>channels; this leads to a massive release of Cal>from the sarcoplasmic reticulum. Cal>cancels the inhibitoryaction of troponin, allowingactin and myo sin to react with each othe r and trigger a musclecontraction. - A muscle action potential just lasts a few milliseconds. while the ensuing musclecontraction lasts 100-200 ms.

1.2


Neuromuscular blocking agents (NMBAs), also referred to as muscle relaxants, are classified as depolarizing or non-depolarizing, depending on their mechanism of action. The group of non-depolarizing NMBA is further subdivided according to basic chemical structure into aminosteroids (e.g. rocuronium) and benzylisoquinolines (e.g. atracurium) . Succinylcholine is the only depolarizing drug of clinical relevance. Previously, only cholinesterase inhibitors were available to reverse the action of non-depolarizing neuromuscular blockers. Now, sugammadex, a modified y-cyclodextrin belonging to the group of oligosaccharides, offers an additional option in this sector. Sugammadex selectively prevents the effects of the steroidal NMBAs, rocuronium and vecuronium, by a process of encapsulation. Due to their mechanism of action, the drugs of this new class are called selective relaxant binding agents.

1.2.1

Non-depolarizing neuromuscular blocking agents

Mechanism of action In principle, non-depolarizing neuromuscular blocking agents act as competitive antagonists at the postsynaptic nicotinic acetylcholine receptor. They bind to the same receptor subunits (u/o and/or u/y) as the physiological agonist acetylcholine. Unlike acetylcholine, however, they do not induce

12


a conformational change at the receptor and consequently no open ing of the central ion channel either. While the channel opening frequency is reduced, the condu ctance and opening time of the ion channel are not affected. Non-depolarizing neuromuscular blocking agents inh ibit electrical and mechanical phenomena equally. However, the ratio of excitation of the synapse and the elicited muscular contraction is not influenced. Muscle contraction is triggered every time an excitation of th e synapse occurs; compared to drugs like dantrolene that do not act on synaptic impulse tran smission, but only inh ibit subsequent Ca2+ release and thereb y prevent muscle contractions. Since acetylcholine needs to bind both a -subunits in order to trigger activation of the receptor, it is sufficient for the non-depolarizing neuromuscular blocking agent to block just one of these two subunits to prevent activation of the postsynaptic acetylcholine receptor actors. Thus, non-depolarizing neuromuscular blocking agents only block the receptor, but do not induce depolarization [4]. In addition to their action at the postsynaptic acetylcholine receptor, non -depolarizing neuromuscular blocking agents also inhibit presynaptic acetylcholine receptors at the nerve terminals and thereby impair the recruitment of acetylcholine.

Features of non-depolarizing blockades The neuromuscular blockade observed after administration of non-depolarizing relaxants is characterized by a marked reduction in the stimulatory response after repeated stimulation. This fading can be observed particularly after TOF, tetanic stimulation or DBS. The reason for this is attributed to the binding of non-depolarizing neuromuscular blocking agents to presynaptic acetylcholine receptors, resulting in inhibition of the recruitment of acetylcholine from the reserve pool. Non-depolarizing blockades are additionally characterized by what is

called »post-tetanic potentiation«. After tetanic stimulation, a stimulator y response can be observed briefly that is more pronounced than the previous one. This phenomenon is thought to be due to an increase in the presynaptic release of acetylcholine that is accompanied by a subsequent increase in the acetylcholine concentration at the motor endplate. In other words, there is a transient change in the ratio of acetylcholine to non-depolarizing neuromus-

13 1.2 . Pharmacological principles

cular blocking agent in favor of acetylcholine. The competitive mechanism of action of the non-depolarizing relaxants causes a transient reduction in the neuromuscular blockade and thus leads to an increase in stimulatory response. The extent of this post-tetanic potentiation depends on the duration and intensity of the tetanic stimulation and amounts to around 3 minutes after a 5-second stimulation at 50 Hz. Safety margin

An action potential arnvmg at the presynaptic nerve terminal releases much more acetylcholine than is required to induce a postsynaptic action potential of the muscle fiber. In the muscles of the extremities, only around 30% of acetylcholine receptors at an endplate need to be activated to trigger action potential, whereas as little as 10% of the receptors are needed at the diaphragm. Accordingly, 70% or even 90% of the receptors can be blocked without this blockade limiting neuromuscular transmission. This phenomenon is referred to as a neuromuscular safety margin . As a general rule, the entire span of a non -depolarizing block - from complete blockade to complete recovery - takes place within a very limited range of blocked receptors: - At the beginn ing. when the NMBA is first injected, this safety margin has to be overcome before initial signs of neuromuscular blockade become evident. Accordingly,the initial amounts of non-depolarizing neuromuscular blocking agent have to be large enough. - If secondary relaxation is required intraoperatively. however a large proportion of the acetylcholine receptors may still be occupied by the relaxant, although no blocked action may be detectable. In that case, accordingly low amounts of the NMBA will be sufficient to reinstate and maintain a complete blockade. Typically, 25% of the initial dose is given to achieve secondary relaxation. Here, larger amounts would easily lead to overdosage and correspondingly prolong the effect. - At the end of the intervention, more than 70% of the receptors may still be occupied by NMBA,without any signs of a neuromuscular (residual) blockade being detectable. During this phase, however, even minor changes in the ratio of acetylcholine to non-depolarizing neuromuscular blocking agent tipping it away from acetylcholine can lead to clinically relevant recurarization.

1

14


Sequence of neuromuscular blockade Once a sufficient dose of NMBA has been injected, flaccid paralysis is induced. As a general rule, small, rapid-moving muscle groups like those of the eye and pharyngeal muscles are affected earlier than those of the extremities, neck and trunk muscles. The intercostal muscles required for respiration and the diaphragm are the last to be paralyzed. The effect usually subsides in reverse order ; the diaphragm is the first muscle group to regain its function . This fact can also be observed in clinical application. If conscious patients are injected with low, subparalytic doses of a non-depolarizing neuromuscular blocking agent, as is still sometimes done nowadays according to the occasionally applied priming principle or precurarization, dimin ished accommodation and difficulties in swallowing appear as the initial and, frequently, also the only signs of the onset of relaxation. Of particular clinical importance is the order of the blockade during neuromuscular recovery, where a dysfunction of the muscles of the eyes and of the upper airways is noted , although residual blockade is no longer detectable in the muscles of the extremities (e.g. adductor pollicis muscle) - muscle groups frequently used for neuromuscular monitoring. In this context, incomplete neuromuscular recovery, particularly when it occurs in the muscles of the upper airways, can put the patient at significant risk. Key points - - - - - - - - - - - - - -- - - - - - - - - , -

Non-depolarizing neuromuscular block ing agents act as competitive antagonists at the nicotinic acetylcholine receptor ; they bind to the same receptor subunit as acetylcholine.

-

Over 70% of the acetylcholine receptors at the motor endplate must be occupied by non -depolarizing neuromuscular block ing agents before

-

The non -depo larizing block is character ized by a marked reduction

initial signs of a neuromuscular blockade become evident. in the stimu lato ry response after repeated stimu lat ion . Called fad ing , this phenomenon is util ized by several stimulation patterns (among others TOF st im ulation and DBS) for mon itoring neuromuscular recovery. • Post-tetanic potentiations is another prope rty associated with non depolarizing neuromuscular blocking agents. After tetanic stimulation, a transien t increase in the concentration of acetylcholine occurs at the motor endplate.

1S


1.2.2

1

Depolarizing neuromuscular blocking agents

Mechanism of action

Unlike non-depolarizing agents, succinylcholine causes depolarization of the postsynaptic membrane. Similar to the action of acetylcholine, the central ion channelof the postsynaptic acetylcholine receptorinitially opens during a depolarization block(alsocalled phase-Iblock). Amongother events, an outfluxof K" takes place in line with the concentration gradient. Under physiological conditions, the resultant increase in extracellular K+ is around 0.1-0.5 mmol. Under pathological conditions - like prolonged immobilization, denervation, severe burns or infection - immature acetylcholine receptors proliferate in the periand extrajunctional region of the motor endplate. This proliferation not only increases the number of acetylcholine receptors but also their sensitivity to agonists.In addition,theseimmaturereceptors havea muchlongerchannelopening time. When such conditions prevail, administration of succinylcholine can lead to exaggerated potassium release followed bylife-threatening hyperkalemia. Features of depolarization blockades

Typically, the neuromuscular blocking action of succinylcholine is preceded by muscle fasciculations. Both the fasciculations and the subsequent neuromuscular blockade take place in a similar order as described for non-depolarizing drugs, namely, starting with the eye and facial muscles, the block propagates to the extremity, neck and trunk muscles. Additionally, a large proportion of patients experience myalgia after succinylcholine. To date, the causes of myalgiaare not fully understood, but appear to have no direct relationship with fasciculation [5]. Compared to the action of non-depolarizing neuromuscular blocking agents, no fading is observed after TOF, DBS or tetanic stimulation in patients with SUCCinylcholine-induced depolarization block.Thus, all four stimulatory responses after TOF stimulation are suppressed to the same extent. Therefore, after succinylcholine, the ratio of the fourth and first twitch (TOF ratio) always equals 1, regardless of the extent of muscle relaxation. That makes the TOF ratio ill-suited for evaluating neuromuscular recovery after succinylcholine. Additionally, no »post-tetanic potentiation- occurs after a succinylcholine-induced depolarization block, which is why the »post-tetanic count- cannot be used either.

16

o


No fading is observed after succinylcholine. As a result, all four stimulatory responses are suppressed to the same extent afterTOF stimu lation and the TOF ratio always equals 1. regardless of the extent of muscle relaxat ion. After DBS. there is no reducti on in the second stimulato ry response either.

Phase II block

Continuous and/or repeated administration of succinylcholine can lead to what is called a phase II block, characterized by fading after repeated stimulation (e.g. TOF). Post-tetanic potentiation can additionally occur. Hence, a phase II block is similar to a non -depolarizing block. Key points - - - - - - - - - - - - - - - - - - - - - - - , The fact that a depolarization block exhibits no fading renders it inap propriate for monitoring recovery. -

The action of depolarizing neuromuscular blocking agents like succinyl choline cannot be reversed with cholinesterase inhibitors.

-

Proliferation of immature acetylcholine receptors in the peri - and extra junctional membrane of the motor end plate can cause life -threatening hyperkalemia after administration of succinylcholine.

1.2.3 Cholinesterase inhibitors

Mechanism of action

The action of non-depolarizing neuromuscular blocking agents can be reversed with cholinesterase inhibitors , although the term »antagonist« is not entirely correct in the pharmacological sense. Rather, cholinesterase inhibitors cause acetylcholine to force non-depolarizing neuromuscular blocking agents away from the receptor. Inhibition of their breakdown causes the concentration of acetylcholine to rise at the motor endplate. Due to the competitive mechanism of action of these reversal agents, the increase in acetylcholine concentration forces non-depolarizing neuromuscular blocking agents to release their bond to the postsynaptic nicotinic receptor and thereby diminishes their action or even cancels it entirely. This mechanism of action has direct and clinically relevant implications: Cholinesterase inhibitors require a certain amount of spontaneous recovery

17

1


before they can be used to reverse a non-depolarizing block. Moreover, they do not act specifically at the motor endplate, but rather show muscarinic side effects. Their indirect action is another weak point of this class of drugs.

Spontaneous recovery As a result of their competitive mechanism of action, cholinesterase inhibitors cannot adequately reverse deep neuromuscular blockade. At the receptor, the concentration of the non -depolarizing neuromuscular blocking agent is so much higher in this situation that an elevation in the acetylcholine concentration induced by cholinesterase inhibitors is not sufficient enough to force the NMBAs away from the nicotinic receptors and thereby cancel their action. Before intermediate-acting NMBAs can be successfully reversed with cholinesterase inhibitors, a spontaneous recovery equivalent to one to two twitches after TOF stimulation is said to be required. By contrast , more than two stimulatory responses must be elicited after TOF stimulation before cholinesterase inhibitors can be used if long-acting drugs like pancuronium have been administered.

Muscarinic sideeffects Acetylcholine is not only important for neuromuscular transmission at the nicotinic receptors of the motor endplate, but is also an important neurotransmitter at the muscarinic receptors of the autonomic nervous system. For that reason, cholinesterase inhibitors do not act at all selectively at the motor endplate. Indeed, their administration is associated with typical muscarinic side effects like bradycardia, bronchoconstriction , contraction of the urinary bladder, partially very painful abdominal spasms, miosis, salivation, nausea and vomiting etc. Cholinesterase inhibitors must always be administered together with a parasympatholytic drug like atropine or glycopyrrolate to prevent or minimize these side effects. These, in turn, can cause new hemodynamic side effects, particular consisting of tachycardia [6].

Indirect action Antagonism with cholinesterase inhibitors does not actually lower the concentration of non-depolarizing neuromuscular blocking agents at the mo-

18


tor endplate, rather, inhibition of acetylcholine metabolism only causes the concentration of their competitors at the nicotinic receptor to rise. If, for whatever reason, the concentration of acetylcholine drops again, clinically relevant recurarization can be the result.

Representative compounds Clinically common cholinesterase inhibitors include neostigmine along with pyridostigmine and edrophonium. None of these three quaternary ammonium compounds can pass the blood -brain barrier. They exert their action exclusively at peripheral cholinergic synapses. Neostigmine is most frequently used to reverse the action of non -depolarizing neuromuscular blocking agents. The duration of action of neostigmine is approx. 20-30 min. This feature leaves at least the intermediate-acting NMBAs enough time for spontaneous recovery to take place concurrently and is the reason why recurarization is not expected after the action of these compounds has elapsed. In patients with impaired renal function , the plasma clearance of neostigmine is reduced and a corresponding prolongation of its elimination half-life can be expected. Pyridostigmine has structural similarities with neostigmine; however both its onset and duration of action are significantly longer. In particular, its very slow onset of action is one of the main reasons why pyridostigmine is of little clinical relevance in anesthesia. Edrophonium is around 10 times less potent than neostigmine and moreover has the shortest duration of action « 10 min) of the three cholinesterase inhibitors . Appropriately, edrophonium is only suitable to reverse short-acting NMBAs like mivacurium or to reverse weak residual blockades when spontaneous recovery is already well advanced. Key points - - - - - - - - --

-

-

-

-

-

-

-

-

-

-

-

---,

Cholinesterase inhibi tors elevat e the concentration of acetylcholin e at the motor end plate and thereby force non -depolarizing neuromuscular block ing agents from the ir bond at the nicot inic receptor. Under no circumstances, however, do they reduce the concentration of muscle relaxant at the motor end plate .

-

Due to the ir competit ive mechan ism of action, cho linesterase inhibi tors

-

cannot reverse deep neuromuscular blockades. The administration of cholinesterase inhibitors also activates autonomic ganglia w ith the associated muscarinic side effects.

19

1

1.2 . Pharmacolog ical principles

1.2.4

Selective relaxant binding agents drugs

Terminology In the foreseeable future, two different drug classes with completely different mechanisms of action will become available for treating residual neuro muscular blockades induced by non-depolarizing neuromuscular blocking agents. The group of reversal agents known for decades, which include the various representatives of the cholinesterase inhibitors, the new group of selective relaxant binding agents. Sugammadex belongs to the latter group (a Fig. 1.4).

Mechanism of action Sugammadex, a modified y-cyclodextrin from the group of cyclic oligosaccharides, is currently proving to be an innovative and very promising approach to reversing the effects of the non-depolarizing steroidal NMBAs rocuronium and vecuronium. Consistent with its physical properties, sugammadex exclusively encapsulates steroidal neuromuscular blocking agents (NMBA). The term selective relaxant binding agents aptly describes the underlying mechanism of action of this new drug class (a Fig. 1.5). Cyclodextrins belong to the class of cyclical oligosaccharides that are held together by a-l,4-glycoside-linked glucose molecules. They form ringlike structures with a hole in the middle. The number of sugar molecules dictates the Greek letter prefixing the name. For example, a -cyclodextrin has 6 monosaccharides, p-cyclodextrin 7 and y-cyclodextrin 8. Thanks to the hydrophobic cavity in their interior and their hydrophilic outer core,

Muscle relaxant reversal agents

Antagonists

Selective relaxant bindingagents

- Neostigmine - Pyridostigmlne

- Sugammadex

a Fig. 1.4.Classification of reversal agents

20

Chapter 1 • Principles of neuromuscu lar transmission

Rocuronium

Sugammadex

Sugammadex-Rocuronlum·Complex

a Fig. 1.5. Sugammadex-Rocuronium-Complex

cyclodextrins are able to form solid, water-soluble inclusion complexes with apolar, organic compounds. By modifying the electrically charged side chains, the drug was engineered to specificallybind rocuronium. The sugammadex/rocuronium complex is very stable. Once encapsulated within this doughnut-like complex, the NMBA can no longer exert its neuromuscular blocking effects [7]. Because it is highly water soluble, the sugammadex/rocuronium complex undergoes renal elimination.Compared to the action of cholinesterase inhibitors, the interaction between rocuronium and sugammadex takes place directly in the plasma and not indirectly at the motor endplate. After i.v, injection, sugammadex very rapidly encapsulates the rocuronium molecules in the plasma, thereby preventing them acting at their receptors. As a result, the free concentration of the rocuronium in the plasma is decreased. In turn, this drop in concentration causes rocuronium to diffuse away from the motor endplate and back into the plasma. This lowers the concentration of the muscle relaxant at the nicotinic receptors of the motor endplate, thereby cancelling the muscle-blocking action of rocuronium directly at the site of action. A major advantage of this novel mechanism of action is that it does not rely on a minimum of spontaneous recovery being present before the neu-

1

21 1.2 . Pharmacological principles

25

21 20 15

C

g 10 41

E

i=

5 0 Placebo

0.5

1

2

3

4

I_

Dose (mg/ kg)

a

Fig. 1.6. Sugammadex was given at reappearance of the second TOF response (T2) . Data presented in minutes to recovery of the TOFratio to 0.9 [8]

romuscular blockade can be reversed. With this drug, reversal is possible at any time point during anesthesia, even immediately after the injection of rocuronium. Following sugammadex administration, complete neuromuscular recovery is accomplished dose-dependently within an extremely short time (1-2 min) ( Fig. 1.6). This approach opens up new options for the perioperative contr~ of neuromuscular blockade. Relaxation may be cancelled, say because of intubation difficulties, within a flash. During laparoscopic procedures, for example, a deep neuromuscular blockade can be maintained literally down to the last suture and, the patient can still be reversed and extubated rapidly thereafter. Moreover, sugammadex does not influence the activity of cholinesterase nor does it act on any nicotinic or muscarinic cholinoreceptors . Any otherwise-associated autonomic side effects have not been observed so far. Since sugammadex does not need to be administered together with a parasympatholytic agent, none of the associated cardiovascular side effects are to be anticipated either. Based on the current evidence, it can thus be assumed that sugammadex will offer a very efficient and safe therapeutic addition to the agents available for the reversal of steroidal NMBAs, in particular rocuronium.

22


Key points - - - - - - - - - - - - - - - - --

-

-

-

-

---,

Sugammadex is a modified y -cyclodextrin belonging to the group of oligosaccharides. -

Because o f it s physical p ropert ies. sugammadex exclusively encapsulates ste roi dal NM BA, in pa rt icular ro cu ro niu m .

-

A minimum of spontaneous recovery d o es not need to be present befo re sugammadex can be administered. Even t he most d eep neuromuscular blockade can be reversed rapidly within 1-2 min. Tha nks to its mechanism o f action, fewer autonomic side effects are to be anticipa te d with sugammadex.

References

2 3

4

5

6 7 8

Lefkowitz RJ, Hoffman BB, Taylor P (1998) Neuronale Obertragung (Neurotransmission): Das autonome und somatomotorische Nervensystem. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Goodman Gilman A (Ed.) Pharmakologische Grundlagen der Arzneimitteltherapie. McGraw-Hili Internat ional (UK)Ltd. Maidenhead, Berkshire, p. 113-148 Alberts B, Bray D, Lewis J, Raff M, Roberts K, and Watson, JD (1994) Molecular Biology of the Cell,3rd Edition. New York.Garland Publishing, lnc, p. 538 ff., 847 ff. Taylor P (1998) Substanzen, die an der neurornuskularen Endplatte und autonomen Ganglien wirken. In: Hardman JG, Limb ird LE, Molinoff PB, Ruddon RW, Goodman Gilman A (Ed.) Pharmakologische Grundlagen der Arzneimitteltherapie. McGraw-Hili International (UK) Ltd. Maidenhead, Berkshire, S 187-206 Schreiber JU, Fuchs-Buder T (2006) Neuromuskulare Blockade: Substanzen, Oberwachung, Antagonisation . [Neuromuscular blockades. Agents, monitoring and antagonism] . Anastheslst 55:1225-1236 Schreiber JU, Lysakowski C, Fuchs-BuderT,TrarnerMR (2005) Prevention of succinylcholine-induced fasciculation and myalgia: a meta-analysis of randomized trials. Anesthesiology 103: 877-884 Kleinschmidt S, Ziegeler S, Bauer C (2005) Cholinesterasehemmer: Stellenwert in Anasthesle, Intensivmedizin, Notfallmedizin und Schmerztheraphie. Anastheslst 54:791-799 Meistelman C, Fuchs-Buder T (2007) Les medicaments de l'anesthesie: Sugammadex. MAPAR 13-23 Sorgenfrei IF, Norrild K, Larsen PB, Stensballe J, Ostergaard D, Prins ME, Viby-Mogensen J (2006) Reversal of rocuronium- induced neuromuscular block by the selective relaxant binding agent sugammadex: A dose-finding and safety study. Anesthesiology 104: 667674

2 Principles of neuromuscular monitoring 2.1

Nerve stimulation

- 24

2.2

Stimulation electrodes

- 26

2.3

Stimulation site/test muscle

2.3.1

Ulnar nerve/adductor pollicis muscle

2.3.2

Posterior tibial nerve/flexor hallucis brevis muscle

2.3.3

- 30 - 31 - 32

Facial nerve/orbicularis occuli muscle or facial nerve/corruga tor supercilii muscle

- 33

2.4

Anesthesia-relevant muscle groups

2.4.1

Diaphragm

2.4.2

Laryngeal muscles

2.4.3

Abdominal muscles

2.4.4

Extrinsic muscles of the tongue and floor of mouth

2.4.5

Pharyngeal muscles

2.5

Stimulation patterns

- 38

2.5.1

Single twitch

- 42

2.5.2

Train-of-four

- 43

- 39 - 39 - 40 - 41

2.5.3


2.5.4

Tetanic stimulation

2.5.5

Post-tetanic count

- 49

- 51 - 53

2.6

Assessment of stimulatory response

2.6.1

Simple nerve stimulators

2.6.2

Quantitative nerve stimulators References

- 37

- 70

- 56 - 59

- 56

- 40

24

Chapter 2 . Principles or neuromuscular monitoring

2.1

Nerve stimulation

Neuromuscular monitoring is a method used to assess a muscle's response to electrical stimulation of its corresponding motor nerve. When a single muscle fiber reacts to this stimulation, it followsthe »all or nothing principle«, By contrast, the number of muscle fibers activated in total determine s the extent to which the muscle twitches. The muscle's strength progressively increases with increasing electrical current. The affected muscle develops its maximum possible strength, as soon as the stimulation current is sufficiently high to stimulate all its muscle fibers. Once this plateau has been reached, no matter how much higher the current is raised, it will not induce any further increase in muscle strength (D Fig. 2.1). This threshold is termed the peak current and can differ slightly among the various nerves. Empirical data has shown that this threshold is approx. 40-50 mA for the ulnar nerve, a nerve frequently used for neuromuscular monitoring.

Supramaximal current To enable the comparison of differing stimulatory responses intraoperatively - and thereby to assess the extent of a neuromuscular blockade - a comparable number of muscle fibers belonging to the corresponding muscle must be stimulated during every nerve stimulation. In clinical practice, this concordance is achieved by ensuring that the electrical stimulation activates as many muscle fibers of the target muscle as possible and thereby triggers the maximum possible muscle response. After administration of a NMBA, the muscle's stimulatory response is diminished as a function of the number of muscle fibers blocked. If the stimulation of the motor nerve is maintained at a consistent level, the reduction in stimulatory response by the muscle directly reflects the extent of neuromuscular blockade. However, a general rule to note is that, during surgery, many different factors can affect the intensity of the electrical stimulation and thereby directly influence the ensuing muscle response. For example, anesthetic drug-induced changes in vessel tone as well as changes in skin temperature can alter the skin's resistance . Moreover, the distance between electrode and nerve to be stimulated can shift when the arm being measured is moved. To guarantee that all muscle fibers are reliably activated during surgery despite these potential confounding factors,

2

2S 2.1 . Nerve stimula tion

Plateau

900

~

825 750

•

C

675

5upramaximal stimulation (30mA)

~

600

e-o

525

\

ClJ

o

~

m

:; .~ Vi

450 375 300 225 150 75 10

20

30

40

50

60

Current (rnA)

a Fig. 2.1. Neuromuscular response increases with increasing current. Here, 30 mA marks the threshold to supramaximal stimulation.

the muscle is stimulated with a current that is above the peak threshold of 40-50 m.A, This is the only way to ensure that, despite any potential changes in skin resistance, the maximal possible neuromuscular response is actually triggered each time [1]. Typically, the supramaximal current is deduced by adding 10-20 % to the maximum current. There are a few nerve stimulators, including the acceleromyographs of the TOF-Watch" series, which automatically calculate the current necessary for supramaximal stimulation during their calibration routines . However, most of the nerve stimulators employed nowadays require that the desired current be set manually. Usually, a current of 50-60 mA is selected. Since supramaximal nerve stimulation can be painful, this technique should only be performed on the anesthetized patient.

26

Chapter 2 • Principles of neuromuscular monitoring

Submaximal current Compared to the above, stimulation with a lower current (i.e., between 10 rnA and 30 rnA = submaximal stimulation, depending on the stimulated nerve) is much less painful and therefore better tolerated by the awake patient. To be able to assess neuromuscular recovery using neuromuscular monitoring techniques, even in the awake patient in the recovery room, several authors have examined the merits of submaximal stimulation. It was found that the accuracy of the measurement fell, while, at the same time, the results were spread over an ever-wider range. These results were independent of whether the muscle contraction was assessed subjectively by tactile or by visual means, or was quantified objectively [1-3]. Submaximal stimulation thus proved to be irrelevant for clinical practice and it appears that there is still no satisfactory solution for objective assessment of neuromuscular recovery in awake patients in the recovery room. Intraoperatively, however, great care should be taken that the stimulation of the target motor nerve is always performed at supramaximal current, as this is the only way that clinically conclusive results can be obtained . Key points - - - - - - - - - - - - - - - - - - - - - - - - - , The muscle twitch is determined by the number of activated muscle fibers. At constan t stimulation of the motor nerve, the reduction in the muscle's stimu latory response d irect ly reflects the extent of neuromuscular blockade. -

The application of a supramaximal curren t ensures constant stimulation of all muscle fibers of a muscle despite the potential for intraoperative alterations in skin resistance.

-

Submaxlmal nerve stimulation can falsify measurements and should not be used in routine clinical practice.

2.2


Stimulation electrodes conduct the current selected on the nerve stimulator against the skin resistance to the underlying tissue structures. These electrodes playa major role in ensuring that the target motor nerve is actually stimulated with the selected current and are thus crucially important for the

27 2.2 · Stimulation electrodes

2

a Fig.2.2. Positioning the stimulation electrodes overthe ulnar nerve

quality of neuromuscular monitoring. To guarantee optimum conduction of the stimulation current, it is recommended that the area of the skin where the electrodes are to be attached is cleaned or degreased with an alcoholic solution. Moreover, any strong hair growth covering this area should be shaved off. Stimulation electrode type and positioning are other important factors to be considered for proper stimulation of the respective motor nerve [3]. In principle, the Ag/Agel electrodes used perioperatively as ECG leads can also serve as stimulation electrodes for neuromuscular monitoring. However, it is important to make sure that the adhesive electrodes have contact with the smallest possible area. This is the only way to ensure that the selected (supramaximal) stimulation current is conducted at full strength against the skin's resistance and is actually delivered for stimulation of the target motor nerve. Typically, the contact area of the stimulation electrodes should not exceed a diameter of 7-11 mm. Furthermore, the electrodes should be positioned as shown in a Fig. 2.2, i.e. 2.5-4 em apart on either side of the presumed course of the nerve. Any significantly larger or smaller distance between the two stimulation electrodes should be avoided as this might alter the penetration depth of the stimulation current, thus potentially preventing optimal stimulation of the target nerve (aFig.2.3) .

28

Chapter 2 . Principles of neuromuscular monitoring

'- -- -

,

......

--.. .... .... __ .. " .." ",,",,,," : .:" : ~

.......... x:'-. -', '\" "" ,".... \

TIssue

'\

, "" "" ' , ,, .

. ....

"

- - _ - " ...' , ' . .". ........ ~-....... ~

'" . . .

...

"

",

"",

"

........•

'

...... _

'0 a TOFby visual/tactile assessment b TOFobjectively measured

dividual components of the respective stimulation pattern. Common to all stimulation patterns are the form and duration of the individual stimulus, i.e., a square wave of 200 fls duration and the fact that they were developed for supramaximal stimulation. The following section describes the individual stimulation patterns, evaluates the power of their findings and delineates their clinical applications ( DTab.2.2).

2.5.1

Single twitch

Single-twitch monitoring is the simplest form of nerve stimulation and, for many years, also offered the only mechanical means of monitoring neuromuscular blockade. Stimulation pattern. In the single-twitch mode, a single supramaximal electrical stimulus is applied to the target motor nerve and the motor response

43

2.5 . Stimulation patterns

to this single stimulus is evaluated. Depending on the nerve stimulator, the frequency with which the single stimuli are applied varies between 1 Hz (i.e., one stimulus per second) and 0.1 Hz (equivalent to one stimulation every 10 s). It is important to note that the twitch can fade after high-frequency stimulation. As soon as a stimulation frequency of 0.15 Hz is exceeded, fade (i.e., fatigue of the muscle response) can be observed. The higher the stimulation frequency, the more pronounced the fade becomes [10]. As a result, the degree of neuromuscular blockade may be overestimated. This phenomenon can be avoided by applying a stimulation frequency of less than 0.15 Hz. That is the reason why most devices apply a frequency of 0.1 Hz in the single twitch mode. Some devices still use the I-Hz stimulation frequency, but only for automatically measuring the supramaximal current. Strength of findings. The extent of the muscular response to a single-twitch

stimulation can only be assessed in comparison with a reference value recorded prior to the administration of the NMBA. Without this comparator, the strength of findings of a single-twitch stimulation is rather limited. Applications. As a stand-alone stimulation pattern, single-twitch stimulation is no longer of any clinical relevance. In clinical practice, it is only ever used as a component of TOF or PTC. However, in conjunction with a monitoring device, this stimulation mode still continues to be employed in scientific trials specifically to study the onset time. Although, to prevent the stimulation frequency from affecting the measurements, the stimulation frequency is normally kept at 0.1 Hz.

2.5.2 Train-of-four In the early 1970s, a Liverpool-based working group under C. Gray developed the train-of-four (TOF) stimulation mode and introduced it into clinical practice [11]. Prior to that point in time, only the single twitch stimulation was available for clinical use, and, without a monitoring device, its findings had limited power. When used in combination with monitoring devices like those based on mechanomyography or electromyography, single-twitch stimulation clearly produces stronger results: The extent of each individual muscle contraction can be measured objectively and compared

2

44


with the previously measured baseline value. Nonetheless, neuromuscular monitoring by this means is time-consuming, complicated and prone to malfunction. In other words, the method was not viable for routine clinical use. Not surprisingly, neuromuscular monitoring was poorly accepted in clinical practice back then. Stimulation pattern . Therefore, the aim was to develop a stimulation pattern that could deliver sound results even with a simple nerve stimulator and without the need for complicated objective monitoring, and, at best, throughout all relevant phases of neuromuscular blockade, i.e., at the onset of action, during surgical blockade and neuromuscular recovery. This goal was achieved for the first time with the TOF stimulation. This mode involved four individual stimuli that stimulated the target motor nerve every 0.5 seconds. The stimulation frequency here is thus 2/s, or the equivalent of2 Hz (D Fig.2.9). Like all stimulation patterns that work at a frequency higher than 0.15 Hz, repeated TOF stimulation can also lead to a fade of the stimulatory response even though a muscle block may not necessarily exist. After TOF stimulation in the unrelaxed patient, all four stimulatory responses are detected individually and with the same intensity. However, when several TOF stimuli are applied in direct succession, progressive fade of the motor response may indeed be observed. To prevent this phenomenon from appearing and falsifying the interpretation of the neuromuscular blockade, a sufficiently large interval must be allowed between two TOF series to let the neuromuscular endplate regenerate. If a minimum interval of 10 seconds is maintained between two successive TOF series, this »iatrogenic« fading can be ruled out with certainty. Modern quantitative nerve stimulators like the TOF-WatchOacceleromyography device (see below) are therefore preconfigured with the appropriate time interval of 10-20 seconds between two TOF stimulations. As a result, these devices never allow this interval to be undershot and thereby prevent falsification of the measurements. However, if »simple« qualitative nerve stimulators are used, the doctor himself must make sure to maintain this minimum interval. Applications. TOF stimulation is the mode with the broadest application

profile and is especially suited for monitoring non-depolarizing NMBAs. Non-depolarizing block. As the action of a non-depolarizing NMBA takes

effect, all four stimulatory responses will demonstrate fatigue or fade, start-

2

45 2.5 . Stimulation pa tterns

Stlrnulation

0.5 s

10 s

H

I------i

ml Jill[]Wl ml

Twitch

L T1 Onset of action

T4

T1 Intraoperative monitoring

T,

T4

Recovery

Injection of

NMBA

a Fig. 2.9. Train-of-four (TOF) stimulation ing with the fourth twitch (T 4) -before they ultimately disappear completely. This makes it easy to set the appropriate time for intubation. Depending on the NMBA's time -action profile, the duration of the ensuing phase without detectable response after TOF stimulation may vary in length before any muscle contractions reappear. As the process unfolds, the individual stimulatory responses reappear in the reverse order of their disappearance, i.e., the first response in the series of four returns at the earliest , before the second, third and finally the fourth response can be re-detected one after another. Intraoperatively, the degree of neuromuscular blockade can thus be assessed by counting the muscular responses detectable after TOF stimulation: We call this the TOF count. If one to two of the four possible responses are still

Chapter 2 . Principles of neuromuscular monitoring

detectable, then the degree of relaxation will be sufficient for the majority of surgical procedures . The occurrence of the second twitch correlates with a 10-15% recovery ofT I . The occurrence of the fourth twitch of the TOF correlates very well with a 25% recovery of T, and thus signals the end of surgically practicable relaxation. Depend ing on desired depth of the neuromuscular block, reappearance of the respective TOF response can be used to judge the time point for NMBA reinjection. Moreover, the TOF count lets one establish whether the spontaneous recovery from the neuromuscular block is already sufficient to reverse the residual blockade with a cholinesterase inhibitor. Due to the competitive mechanisms of action of intermediate-acting NMBAs like atracurium or rocuronium, at least one to two of the four TOF responses should be present after their administration at the time of reversal; while more than two TOF responses should be present after pancuronium, before reversal, say with neostigmine can be given. Neuromuscular recovery starts as soon as all four stimulatory responses have become discernable again. During this phase, progressive fade occurs within a TOF series. In such a situation, the relatively high stimulation frequency of 2 Hz will promote fade. While the first of the four contractions will be most perceptible, the intensity of the three subsequent muscular responses will diminish incrementally. Accordingly, the fourth twitch is the least discernable. The extent of fade serves as a basis for assessing the degree of neuromuscular recovery. This involves comparing the fourth response within a TOF series with the first (TiT)). The value obtained is termed the TOF ratio. The intensity of the second and third response is not included in the assessment of neuromuscular recovery. Depolarization block. Fade is the most important TOF criterion to be

considered when assessing neuromuscular blockade, whether it is used as a TOF ratio for assessing neuromuscular recovery or intraoperatively as a TOP count. After repeated, high-frequency stimulation, the fade phenomenon is characteristic of non -depolarizing blocks. Among other things, this is attributed to the fact that non-depolarizing NMBAs inhibit presynaptic acetylcholine release. After administration of the depolarizing NMBA succinylcholine, there is no fade in response to the individual TOF stimulation , all four stimulatory responses are reduced in equal measure. Consequently, the TOF ratio is always 1.0 and thus not suitable as a criterion for assessing

47

2

2.5 . Stimulation patterns

a depolarization block (also referred to as a phase I block). Additionally, all four TOF responses disappear at the same time. That means, the TOF count is either »four« or »zero« and thus just as ill-suited for describing a depolarization block.

o

A succinylcholine-induced depolarization block alwaysproducesa TOF ratio of 1.0.

A phase II block (dual block) can occur in patients with atypical plasma cholinesterase and/or after administration of high succinylcholine doses, for example after repeated bolus injections or long-term infusion. Compared to the typical depolarization block, a phase II block exhibits similar behavior as a non -depolarizing block where fade can again be observed. Accordingly, TOF stimulation can provide clinically useful information for monitoring phase II blocks in these situations. Strength of findings. The train-of-four stimulation (TOF) is the most commonly employed stimulation mode. Its introduction into clinical practice in the early 1970s made it possible for the first time to obtain essential information about the onset of action, surgical relaxation and neuromuscular recovery, in particular after administration of non-depolarizing relaxants - and all that without complicated monitoring procedures. Thus, with TOF stimulation, anesthesiologists were able, for the first time, to acquire clinically relevant information about all phases of neuromuscular blockade using compact, portable devices. This was an essential prerequisite for propagating the concept of neuromuscular monitoring in the years to come. One limitation, however, applies: TOF stimulation is not suitable for monitoring deep neuromuscular blockade. Moreover, the strength of its findings for subjectively assessing the quality of neuromuscular recovery (whether by tactile or visual means) is also very limited. Deep neuromuscular blockades. After the usual intubation dose (twice the ED9s) of a non-depolarizing NMBA, and depending on the drug administered, it takes between 20-40 min before the first TOF response is discernable again. During this period, however, no additional information about the depth of the neuromuscular blockade can be obtained by the TOF mode. Because the diaphragm is much more resistant to non-depolarizing neuromuscular blocking agents, this means that surgical conditions, especially in

48


epigastric procedures, may already be impaired by the patient coughing or bucking during this phase. For the anesthesiologist to be able to reinject the NMBA in a controlled manner and thereby prevent overdosing and cumulative effects, neuromuscular monitoring must be able to provide information about deep blocks; but this is where the TOF mode is pushed to the limit. In such situations, the post-tetanic count alone can deliver clinically relevant information about the block depth . The second weakness of the TOF »universal stimulation mode« is its inaccuracy in predicting the patient's response when neuromuscular recovery is assessed subjectively (by tactile and/or visual means). While objective measurement of the TOF ratio, e.g. with a TOF-Watch" neuromuscular transmission monitor, allows accurate assessment of neuromuscular recovery, the TOF ratio is far less reliable after subjective assessment. Fade is the basis for subjective evaluation of neuromuscular recovery by TOF stimulation. As soon as a fade is no longer discernable, the neuromuscular recovery can no longer be assessed either. In this context, J. Viby-Mogensen et al. demonstrated back in 1985 that even the most experienced investigator in neuromuscular monitoring is not able to reliably detect a TOF ratio above 0.5. In 80% of the cases studied, no fade of the stimulatory responses above this value could be detected after TOF stimulation. Above a TOF ratio as low as 0.4, less experienced investigators rated all four TOF stimulatory responses with the same intensity [12]. Hence, the tactile and visual evaluation of the TOF ratio markedly overestimates the extent of actual neuromuscular recovery and is thus not suitable for detecting residual blockades reliably. A study conducted in 1990 by the same working group also confirmed this result [13]. The authors compared the frequency of undetected residual blockades in the recovery room: Intraoperatively, anesthetists assessed the degree of neuromuscular recovery either by manual evaluation of the response to TOF nerve stimulation or by clinical criteria. In the group evaluated solely by clinical criteria, postoperative residual neuromuscular blockade went undetected in 20% of the patients, and was still as high as 15% in the group monitored by TOF nerve stimulation. The study set a TOF ratio of just 0.7 as adequate for neuromuscular recovery. However, if that value had been set at a TOF ratio of 0.9, the incidence of undetected residual blockades would even have been much higher in the two groups. Such findings limit the accuracy of TOF in assessing neuromuscular recovery and exemplify the need for a simple stimulation

49

2

2.5 . Stimulat ion patterns

pattern that proves superior to the TOF in the tactile or visual assessment of neuromuscular recovery. 2.5.3


A few years later, Viby-Mogensen and colleagues developed the double-burst stimulation (DBS) mode which they presented for the first time in 1989 [14]. Their aim was to establish a stimulation pattern that was more sensitive than the TOF in the manual or visual assessment of residual blockade. Stimulation pattern. DBS consists of two short-lasting, 50-Hz bursts separated by a 750-ms interval. The duration of each individual impulse within a burst is 0.2 ms, equivalent to a stimulation frequency of 50 Hz, each of the individual tetanic stimuli are 20 ms apart (a Fig.2.10). In the DBS3,3 mode,

Stimulation

/

Response

D Fig. 2.1O. Double-burststimulation (DBS)

1

50

Chapter 2 . Principles of neuromuscular moni toring

there were three impulses in each of the two bursts; in the DBS3,2 mode, only the first burst had three impulses with the second only consisting of two individual impulses. Due to the high stimulation frequency of 50 Hz, the individual twitches elicited by one burst blend together and are detected as one muscle contraction, which is why fade is easier to detect after DBS than after TOF stimulation. Applications. While DBS was originally developed to improve the tactile and/or visual assessment of residual neuromuscular blockades, investigators were quick to also test whether the DBS mode was equally suitable to monitor the onset profile of non-depolarizing NMBAs and/or their intraoperative time course [15]. These studies showed that the DBS mode can also be used to establish the intubation time. Nonetheless, the subjective (tactile or visual) assessment of neuromuscular recovery remains the main indication for the DBS, which meanwhile has essentially replaced TOF in this respect. Beyond this, however, the DBS mode offers no advantages over the TOF stimulation for monitoring depolarization blocks after succinylcholine; both stimulation patterns are equally ill suited for this indication. Strength of findings. The fade in response after DBS is far more pronounced than after TOF stimulation. Hence, the DBS mode can also reliably detect residual blockades corresponding to a TOF ratio of 0.6-0.7 by tactile or visual evaluation . However, residual blockades beyond this threshold are no longer discernable , even by DBS. In light of new evidence on the pathophysiological implications of incomplete neuromuscular recovery, a neuromuscular recovery corresponding to a TOF ratio of 0.9 and/or even 1.0 is now being required to reliably prevent residual blockade . This subject will be dealt with in greater detail in ~ Chapter3. The author and colleagues conducted their own studies that were the first to test whether the power of the DBS mode is sufficient to detect residual blockades reliably within the new limits [16]. The following variables were investigated (DTab. 2.3): - Sensitivity: The probability that the respective test will detect fade when a residual blockade is in fact present. - Specificity: The probability that the respective test will not detect fade when residual blockade is in fact not present.

2

Sl

2.S . Stimulation patterns

a Tab. 2.3. Reliability of DB5 and tetanus in assessing neuromuscular recovery SensitIVity ['lb]

SpecifiCity ['Ill)

NPV [ )

PPV [%)

DB5

29 (13-45)

100( 100)

29 (13-45)

100 (100)

Tetanu s

74 (59-89)

SS (23- 88)

38 (12-64)

85 (72-99)

Data are expressed in percent with 95% confidence int erval

-

Positive predictive value (PPV): The probability that a patient in whom the respective test detects fade in fact has a residual blockade. Negative predictive value (NPV): The probability that a patient in whom the respective test does not detect fade in fact does not have any residual blockade.

From the clinician's viewpoint, the NPV and sensitivity are clinically relevant. Both of them were only 29%; i.e. although no more fade was detectable after DBS, two of three patients still had a residual blockade - defined as a TOF ratio 0.8 15 minutes after neostigmine/glycopyrrolate. Another 15 minutes later all patients except for two and five patients, in the groups respectively, had

116

Chapter 3 • Clinical application

attained a TOF ratio >0.9 (D Ta b. 3.7). At no point in time were any significant differences observed between the two NMBAs. The authors cautiously concluded that the incidence of critical residual blockade in the recovery room could be expected to be lower with routine reversal and routine monitoring with a simple nerve stimulator. One caveat: qualitative monitoring does not allow the outcome of reversal to be mon itored. The same authors reported on one patient whose inadequate recovery from a residual neuromuscular block was not detected by tactile assessment of TOF [54]. At the time of reversal with neostigmine/atropine, two of the four TOF stimulatory responses were detectable. Once all four stimulatory responses were then detectable with the same intensity, these researchers assumed that the neuromuscular recovery was adequate . At this time point, however, the TOF ratio measured by acceleromyography had just reached 0.4. In other words, a deep residual block still persisted. Adequate neuromuscular recovery was not attained until another dose of neostigmine was given, thus allowing the patient to be extubated safely.

a Tab. 3.7. Neuromuscular recovery of cisatracurium and rocuronium (mod ified after [52]) Clsatracurlum (n 30)

Rocuronium In 30)

P

TOFratio at 5 min

0.49±O.11

0.61±O.14

100%, the monitor will only ever display a value of 100%. Thanks to these modifications, the two devices no longer produce excessive TOF responses . However, this begs the question as to whether these changes limit the assessment of neuromuscular recovery. In an initial study, Kopman and Kopman [9] explored this concern. Their results showed that the newly modified T4/T2 algorithm did not change the accuracy of the TOF ratio for assessing neuromuscular recovery. While the change in TOF algorithm considerably simplified clinical application of the devices, it still did not adversely affect their results. The two models, TOF-Watch· and TOF-Watch· S, are therefore especially suited for clinical use, but should not be used for research studies where original, unaltered data are desired. It should also be noted that the TOP-Guard model is not equipped with this modified algorithm so that

---------- ----------- -----------

-----

---------- ----------_. -----------

-----

a Fig. 4.4. TOF-Watch· ponse [9]

algorithm: Marked difference between the first and second TOF res-

133 4.3 . TOF-Watch- models

4

it continues to produce TOF values markedly above the 1.0 level. Hence, caution is advised when using these older-generation acceleromyographic nerve stimulators for interpreting recovery data. The TOF-Watch" SX model was designed primarily for research studies and therefore does not work according to this new TiT 2 algorithm either. Before the actual measurement on this device can start, the anesthesiologist must wait until both the T I response and the TOF ratio have stabilized to constant readings. Once the TOFWatch" SX is calibrated and the baseline reading taken, the nerve stimulator is operational.

o

The TOF-Watch- and TOF-Watch- 5 are equipped with an algorithm that prevents the TOF ratio from exceeding 100%. This facilitates handling of the devices without limiting their clinical accuracy in assessing neuromuscular recovery.

4.3.2 Calibration modes

»Simple- nerve stimulators are only useful for assessing the stimulatory response subjectively - be it tactilely or visually. Their high ease of operation is contrasted by their limited accuracy. As their name implies, quant itative nerve stimulators, on the other hand, measure the objective response and are accordingly more accurate. To reliably perform quantitative measurements, however, several technical requirements must be met before the NMBA can be injected and the neuromuscular block actually monitored. In this regard, it makes no fundamental difference whether the respective device is used for neuromuscular monitoring in clinical practice or in research. In general, the following requirements deserve mention: - The stimulatory response must be stabilized - The stimulation current must be sufficient for supramaximal stimulation - The nerve stimulator must be calibrated. As described above, the TOF-Watch" and TOF-Watch" S models feature a special algorithm that obviates any time-consuming stabilization phase for the TOF ratio, whereas with the TOF-Watch" SX model, there is a wait before stabilization.

134

Chapter 4 . Acceleromyography

But, afterwards, the anesthesiologist just needs to ensure that an adequate stimulation current is applied throughout the entire surgical procedure and that the nerve stimulator has been calibrated. Both functions take place at the same time during the actual calibration. During this process, the twitch after a single stimulus (T 1) is measured and, if necessary, automatically amplified by an internal gain until it finally equals 100%. Particularly in small children, but also when monitoring muscles in the ocular region, the twitch signal is often rather weak and needs to be amplified accordingly to achieve a baseline value of 100%. When T 1 responses >100% are elicited , the calibration function likewise ensures that the control value is optimized to 100%, meaning that the T 1 response is reduced. It is imperative that this take place prior to NMBA injection. The gain determined during calibration is then stored for the entire measurement. Since the same gain factor is used for all of the patient's measured data, the interrelationship of the individual T 1 responses to each other and the TOF ratios does not change. Indeed, this calibration is more like a metrological procedure that keeps amplifying the response signal until a pre-set baseline value is reached. That makes the measurement more stable and more reliable. This fact was ultimately confirmed by the results of a recent study of Baillard et al. [10] in which the authors observed considerable discordances in the individual, directly successive TOF ratios when calibration of the acceleromyographs was omitted. The various TOP-Watch· models differ in terms of their calibration functions: two different programs are available .

CAL 1. With the more simple calibration function (CAL 1), the T 1 response is set to 100% after just a few single twitches. Unless the corresponding setting is changed in the set-up menu, the stimulation is carried out automatically at the pre-set default current of 50 rnA. In total, this calibration procedure takes less than 10 s! CAL 2. The second calibration function (CAL 2) detects both the supramaximal stimulation current and the control twitch height. Both measurements are carried out automatically in just around 30 seconds! Stimulation is initiated at a current of 60 rnA and the T 1 response set to 100% after a few single twitches . Next, the stimulation current is reduced in increments of 5 rnA for as long as it takes the T I response to drop to below 90% of the baseline value

4

135

4.3 . rOF-Watch- models

(e.g. 35 rnA). The last stimulation current before the reduction in T 1 response drops to values below 90% counts as the maximum current (here: 35 mA+5 mA=40 rnA). The supramaximal current is defined as 10% above this peak value (and thus equals 44% in the example cited). Then, this supramaximal current (i.e., 44%) is used for stimulation and the response is finally set to 100% (D Fig. 4.5). With this, the calibration procedure is concluded. The two stimulation programs are easy to use and can be carried out during anesthesia induction with little extra effort of time. The TOF-Watch· is only equipped with the first, more simple stimulation mode. On this model, the supramaximal current is not measured, but rather stimulation takes place at the pre-set current; the default setting is 50 rnA. With the TOF-Watch" Sand TOF-Watch" SX models , the user can choose between the two calibration procedures. Pre-programmed functions on the models allow the second calibration function to be activated by pressing the calibration button, i.e. initiating automatic measurement of the supramaximal stimulation current as well as the control twitch height. This calibration function is indicated in the display as »CAL 2«. In the setup menu, the user can also optionally set these two models to run the first, simple calibration mode or »CAL 1«. When activated, CAL 1 is indicated in the display. Although all TOF-Watch" nerve stimulators can essentially be used without pre-calibration, their accuracy is not only diminished in detecting a single twitch but also in the important TOF mode if not pre-calibrated.

Stability testing

Gain setting

n n nu

I

.1 0 %

--:;;------:i\-----:J\----~- ::; StimulatO 1 s) of this button is required to switch the unit on and/or off.

Short activation « 1 s) toggles the ongoing stimulation to off and clears the last twitch while the device continues to remain operational. For example, if the stimulation was performed in th e TOF mode, the TOF stimulation will be toggled off and the last TOF value cleared from the monitor. If the nerve stimulator is used again at a later point in time, all the anesthesiologist has to do to activate the desired function is press the button with the corresponding stimulation pattern. The original calibration parameters remain stored in the memory. This function is especially relevant if the nerve stimulator is not intended to be used intraoperatively for a longer period of time. As recommended, the TOF-Watch" can be calibrated at the onset of anesthesia and subsequently switched to the stand-by mode by briefly pressing the on-off button. As the end of the surgery intervention nears, the neuro muscular recovery can be assessed based on the initial calibration parameters. Here, it should be noted that the device automatically switches itself off after 2 h of non-use.

o

Press the on -off button for < 1 s (short activation) to switch the device to stand-by.

4.4 . rOF-Watch-

143

4

Y Calibration button On this model, the calibration routine takes 10 seconds at the most and is not at all comparable with the calibration of a measuring instrument used for research purposes. Here, the transducer gain in the response to a single 1-Hz stimulation is simply adjusted to 100%; this value then serves as the reference value for the further quantitative measurements, i.e., single twitch and TOE To calibrate, this button must be pressed for at least 1 second . Calibration of the nerve stimulator is successful when the corresponding symbol is indicated on the monitor. Now, the device is operational and the NMBA can be injected.

o

The calibration procedure with the rOF·Watch - takes no more than lO s.

The nerve stimulator can also be used without pre-calibration. In that case, however, the results after single twitch and after TOF stimulation in particular, are less accurate. Operation without previous calibration is indicated by the flashing symbol

Up and down rnA (lJC) buttons This button is used to set the stimulation current. On the TOF-Watch- S and TOF-Watch" SX models, the supramaximal current is measured and set automatically during the calibration routine, whereas on the TOF-Watch" a stimulation current of 50 rnA is factory-set in the set-up menu. If a different stimulation current is required , it must be manually set by the user; here a range of 0-60 rnA is available. Functionally, this button features an up and down option for manually adjusting the strength of the stimulation. The current is continuously stepped up or down depending on which part of the button is pressed. After short activation of this button « 1 s), the display indicates the stimulation current. Pressing again increases or decreases the current. long activation of this button (> 1 s) continuously steps up and/or decreases the stimulation current; the current keeps increasing or decreasing for as long as the up or down part of the button is pressed.

o

On th is rOF -Watch- model, the default stimulation current is SO mAo Any settings other than this must be made manually.

144

Chapter 4 · Acceleromyography

Selecting the stimulation mode The other four buttons on the TOF-Watch" are used for selecting the stimulation mode; without exception, all of them have a double function . With the three stimulation buttons, a total of six stimulation modes can be selected. The respective double function of the button is activated by pressing the secondary function button. The twitch after TOF stimulation and/or after single twitch (1 Hz or 0.1 Hz) can be objectively measured and the result subsequently indicated in the display. The other three stimulation modes featured are DBS, PTe and tetanic stimulation . None of these three stimulation patterns is suitable for objective monitoring. Therefore, they should be assessed subjectively, i.e., either tactilely or visually, with the TOF-Watch" nerve stimulator. Secondary function button The three stimulation buttons on the TOF-Watch" have the double functions as listed below: TOF stimulation and DBS button PTe and tetanic stimulation button I-Hz single twitch and/or O.I-Hz-single twitch button. The secondary function of these buttons is activated by first pressing the »secondary function button« for less than 1 s and then activating the corresponding stimulation button . Along with the selected stimulation mode, the symbol for the secondary funct ion . appears in the display. If none of the three double function stimulation buttons is selected within 5 s, the device automatically toggles to the stimulation mode that was previously activated.

o

The secondary function of a stimu lation button is selected by pressing the secondary funct ion button for < 1 s and then pressing the corresponding stimulation button.

Pressing the secondar y function button for > 1 s (long activation), switches the acoustic stimulation sig!,lalon/off and the corresponding symbol is indicated in the display for 1 s 18 If the acoustic stimulation signal is switched on, a short beep can be heard each time the nerve stimulator TOF-Watch" performs a stimulation . Therefore, when the device is used in clinical practice,

145 4.4 . rOF-Watch"

4

the recommended setting is to have the acoustic stimulation signal switched off. If the signal is not switched off, the corresponding setting can be made in the set-up menu.

rOF or DBS button This is one of the three buttons with a double function. The TOF is the primary and the DBSthe secondary function. Short activation starts a single TOF stimulation. Pressing the button for longer than 1 s, starts a repetitive TOF stimulation that occurs in IS-second cycles. Once all 4 TOF responses are detected, the display indicates the TOF ratio in percent (%). When less than four TOF responses are detected or if the first twitch is less than 20%, only the number of responses is displayed (without the % symbol). The following should be noted : - Stimulatory responses below the threshold of 3% control twitch height are not counted as independent TOF responses. - The use of DBS and TOF is automatically excluded for 12 s after the last TOE

o

Short activation « 1 s) ofTOF button starts a single rOF stimulation ; long activation (> 1 s) of th e button starts a repetitive rOF stimulation.

DBS mode. To start a DBS, first press the secondary function button for < 1 s and then the corresponding stimulation button. The twitch is assessed by visual or tactile evaluation. Alongside the selected stimulation mode, the display only shows the selected current. Compared to the TOF mode, the DBS cannot be used as a continuous stimulation mode, but only on-demand as a single stimulation . Another DBS or a TOF stimulation cannot be started until 20 s after the last DBS stimulation. The TOF-Watch" is equipped with the two DBS modes, i.e. DBS 3.2 or DBS 3.3. The corresponding setting can be made in the set-up menu. The default is pre-set to the DBS 3.2 mode.

o

In the DBS mode. the response can only be assessed by tactile or visual evalu ation. The display shows the stimulation strength in m illiamperes (mA) on ly.

146


Post-tetanic count (PTe) or tetanic stimulation button

This button also has a double function. PTC is the primar y function and tetanic stimulation is the secondary function. PTe mode. In this stimulation mode, the TOF-Watch" device starts by performing 15 single stimulations at a frequency of 1 Hz. Since the PTC can only be used during deep blockade, the device automatic ally stops the PTC stimul ation and switches to the TOF-mode if after the first 15 single stimulations the patient responds to more than five consecutive stimulations. Only if fewer than 5 of the original 15 stimulatory responses are detected, i.e. an appropriately deep neuromuscular block has been attained, will a 5-second long tetanic stimulation of 50 Hz follow. After a pause of 3 seconds, the next 15 single stimulations will follow; the number of detected responses is indicated as PTC on the display. After 12 seconds, the display clears and the TOF-Watch" automati cally enters the continuous TOF stimulation mode. The next PTC cannot be started until after another 2 minutes! The PTC mode can only be used in deep neuromuscular blockade; If the block is not sufficiently deep, the unit automatically switches back to TOF stimulation. Tetanic stimulation. Activation of the secondary function starts a tetanic stimulation of 50 Hz or 100 Hz that lasts 5 seconds. The desired stimulation frequency can be programmed in the set-up menu (see below). The default setting is a 100-Hz stimulation. The response after tetanic stimulation has to be evaluated visually or tactilely, the display only shows the selected stimulation frequency of 50 Hz or 100 Hz. Like the PTC mode, the TOF-Watch" excludes the use of another tetanic stimulation for 2 min. 1 Hz I 0.1 Hz stimulation button This button also features a double function that can be used to trigger a single twitch. A I-Hz stimulation is the primary function and a D.I-Hz stimulation the secondary function. Short activation « 1 s) starts a single stimulation; long activation (> 1 s) starts repetitive single stimulations. The display shows the twitch height of the last response calculated from a control value and indicated in percent. To use this function, the nerve stimulator must be calibrated before the NMBA is injected and the corresponding control value must have been measured. Without initial calibration, the

147

4

4.4 . rOF-Watch "

TOF-Watch " compares the response with an internal reference control. The response is also indicated in percent. In this case, the calibration symbol in the display flashes to indicate that no calibration was performed. In this stimulation mode, too, the accuracy of findings of an uncalibrated measurement is markedly limited.

Alarms In this context, there is a difference between information about the current nerve stimulator functions and error signals. The former includes the previou sly presented symbols for: - Secondary function - Calibration - Switch on - Stimulation beep symbol Therefore, we will now only discuss the error signals along with the re maining display for timer function, stimulation signal and stimulation current.

.,.

.: ~ :. Optical stimulation signal and timer

When the center dot in the timer symbol is flashing, the TOF-Watch" is currently performing a stimulation. This signal appears during all six stimulation patterns. During repetitive stimulation, the timer symbol indicates the time to next stimulation.

1 s) of this button is required to switch the unit on and/or off.

Short activation « 1 s) toggles the ongoing stimulation to off and clears the last twitch while the device continues to remain operational. For example, if the stimulation was performed in the TOF mode, the TOF stimulation will

155 4.5 . TOF -Watche 5

4

be toggled off and the last TOF value will be cleared. If the nerve stimulator is used again at a later point in time, all the anesthesiologist has to do to activate the desired function is press the button with the corresponding stimulation pattern. The original calibration parameters remain stored in the memory. This function is especially relevant if the nerve stimulator is not intended to be used intraoperatively for a longer period of time. As recommended, the TOF-Watch" S can be calibrated at the onset of anesthesia, and subsequently switched to the stand -by mode by briefly pressing the on-off button. As the end of the surgery intervention nears, the neuromuscular recovery can be assessed based on the initial calibration parameters. Here, it should be noted that the device automatically switches itself off after 2 h of non -use.

o

Pressthe on -off button for < 1 s (short act ivat ion ) to swi tch the dev ice to stand -by.

Calibration button

On this model, the calibration routine takes a maximum of 30 seconds at the most. In the pre-set default CAL 2 function, the TOF-Watch· S automatically determines the supramaximal current and simultaneously calibrates the device. Alternatively, the CAL 1 calibration function can be selected in the set-up menu. In this case, calibration only lasts 10 seconds, but, in return , the supramaximal current is no longer measured, instead stimulation is carried out at a preset current of 50 rnA. To calibrate, this button must be pressed for at least 1 second. Calibration of the nerve stimulator is successful when the corresponding symbol is indicated on the monitor. Now, the device is operation al and the NMBA can be injected. The nerve stimulator can also be used without pre-calibration . In that case, however, the results after single twitch and after TOF stimulation in particular, are less accurate. Operation without previous calibration is indicated by the flashing symbol. The secondary function on this button can be used to display the sensitivity of the acceleration transducer and change it as needed . This function will be explained in more detail in the »Settings« section.

o

On the TOF-Watch e 5, the calibration procedure (CAL 2) takes approx. 30 s, the supramaximal current is measured automatically.

156


Up and down rnA

(~C)

buttons

These buttons are used to manually set the stimulation current. On the TOF-Watch· Sand 'I'Ol--Watch" SX models, the supramaximal current is measured and set automatically during the calibration routine. Whereas, if a different stimulation current is required, it must be manually set by the user; here a range of 0-60 rnA is available. Functionally, this button features an up and down option for manually adjusting the strength of the stimulation. The current is continuously stepped up or down depending on which part of the button is pressed. After short activation of this button « 1 s), the display indicates the stimulation current. Pressing again increases or decreases the current. Long activation of the button continuously steps up and/or decreases the stimulation current; the current keeps increasing or decreasing for as long as the up or down part of the button is pressed.

o

On this rOF-Watch- model, the stimulation current is pre -selected. Any set tings other than this must be made manually

Selecting the stimulation mode The other four buttons on the TOF-Watch" S are used for selecting the stimulation mode ; without exception, all of them have a double function . With the three stimulation buttons, a total of six stimulation modes can be selected. The respective double function is activated by pressing the secondary function button. The twitch after TOF stimulation and/or after single twitch (l Hz or 0.1 Hz) is measured objectively and the result indicated in the display. The other stimulation modes featured are PTC, DBS and tetanic stimulation . None of these stimulation patterns are suitable for objective monitoring. Therefore, they should be assessed subjectively, i.e., either tactilely or visually, with the 'I'Ol'-Watch" S nerve stimulator. Secondary function button

The three stimulation buttons on the TOF-Watch" S have the double functions as listed below:

157 4.5 . TOF-Watche S

4

TOF stimulation and TOFs button PTC and DBS I-Hz single twitch andlor a.l -Hz-single twitch button. The secondary function of these buttons is activated by first pressing the »secondary function button « for < 1 s and then activating the corresponding stimulation button. Along with the selected stimulation mode, the symbol for the secondary funct ion . appears in the display. If none of the three double function stimulation buttons is selected within S seconds, the device automatically toggles to the stimulation mode that was previously activated. The secondary function button also features a double function that can be used to change the impulse duration . This function will be explained in more detail in the »Settings« section.

o

The secondary function of a stimulation button is selected by pressing the secondary function button for < 1 s and then pressing the corresponding stimulation button.

Pressing the secondary function button for > 1 s (long activation), switches the acoustic stimulation signal onloff and the corresponding symbol is indicated in the display for 1 s. If the acoustic stimulation signal is switched on, a short beep can be heard each time the nerve stimulator TOF-Watch" performs a stimulation . Therefore, when the device is used in clinical practice, the recommended setting is to have the acoustic stimulation signal switched off. If the signal is not switched off, the corresponding setting can be made in the set-up menu . TOFor TOFs button This is one of the three buttons with a double function. The TOF is the primary and the slow-train-of-four (TOFs) the secondary function . TOF mode. Short activation starts a single TOF stimulation. Pressing the button for longer than 1 s, starts a repetitive TOF stimulation that occurs in IS-second cycles. Once all four TOF responses are detected, the display indicates the TOF ratio in percent (%). When less than four TOF responses are

158


detected or if the first twitch is less than 20%, only the number of responses is displayed (without the % symbol). The following should be noted : - Stimulatory responses below the threshold of 3% control twitch height are not counted as independent TOF responses. - The use of DBS and TOF is automatically excluded for 12 s after the last TOE

o

Short activation « 1 s) ofTOF button starts a single TOF stimulation; long activation (> 1 s) of the button starts a repetitive TOF stimulation.

TOFs mode. To switch to the TOFs mode, first press the secondary function button for < 1 s and then the corresponding stimulation button. The time between two TOF stimulations can now be set to within an interval of 1-60 minutes. The pre-set default is an interval of 3 minutes. The set-up menu can be used to change other settings. PTe or DBS This button also has a double function . PTC is the primary function and DBS the secondar y function . PTe mode. When the PTC mode is activated, the TOF-Watch" S starts by performing 15 single stimul ations at a frequency of 1 Hz. Since the PTC can only be used during deep blockade, the device automatically stops the PTC stimulation and switches to the TOF mode if after the first 15 single stimulations the patient responds to more than five consecutive stimulations. Only if fewer than 5 of the original 15 stimulatory responses are detected , i.e. an appropriately deep neuromuscular block has been attained, will a 5-second long tetanic stimulation of 50 Hz follow. After a pause of 3 seconds, the next 15 single stimulations will follow; the number of detected responses is indicated as PTC on the display. After 12 second s, the display clears and the TOF-Watch" S automatically enters the continuous TOF stimulation mode . The next PTC cannot be started until after another 2 minutes.

o

The PTe mode can only be used in deep neuromuscular blockade. If the block is not sufficiently deep, the unit automatically switches back to rOF stimulation.

159 4.5 . TOF-Watche 5

4

DBS mode. To start a DBS, first press the secondary function button for < 1 s and then the corresponding stimulation button. The twitch is assessed by visual or tactile evaluation . The display only shows the selected current. Compared with the TOF mode , the DBS cannot be used as a continuous stimulation mode , but only on -demand as a single stimulation. Another DBS or a TOF stimulation cannot be started until 20 s after the last DBS stimulation. The TOF-Watch" S is equipped with the two DBS modes, i.e, DBS 3.2 or DBS 3.3. The corresponding settings can be made in the set-up menu . The default is pre-set to the DBS 3.2 mode.

o

In the DBSmode. the response can only be assessedby tactile or visual evalu ation. The display shows the stimulation strength in rnA only.

, Hz / 0.' Hz stimulation button This button also features a double function that can be used to trigger a single twitch. A I-Hz stimulation is the primary function and a OJ-Hz stimulation the secondary function . Short activation « 1 s) starts a single stimulation; long activation (> 1 s) starts repetitive single stimulations. The display shows the twitch height of the last response calculated from a control value and indicated in percent. To use this function, the nerve stimulator must be calibrated before the NMBA is injected and the corresponding control value must have been measured. Without initial calibration, the TOF-Watch" compares the response with an internal reference control. The response is also indicated in percent. In this case, the calibration symbol in the display flashes to indicate that no calibration was performed. In this stimulation mode, too, the accuracy of findings of an uncalibrated measurement is markedly limited.

Alarms In this context, there is a difference between information about the current nerve stimulator functions and error signals. The former includes the preinstalled symbols for the secondary function, calibration, the power button und the stimulation beep symbol. Therefore, we will now only discuss the remaining display for timer function, stimulation signal and the display for the stimulation current.

160


.,.

.: ~:. Optical stimulation signaland timer When the center dot in the timer symbol is flashing, the TOF-Watch· is currently performing a stimulation. This signal appears during all six stimula tion patterns. C. During repetitive stimulation, the symbol indicates the time to the next stimulation. Stimulation units The TOF-Watch" can show the strength of the electrical stimulation in both milliamperes [rrtA] and microcoulomb [Ile]. For routine monitoring, the stimulation strength is indicated in milliamperes. The pre-installed default current is therefore set to a milliampere display. Occasionally, for use in regional anesthesia, the electric charge is indicated in 1lC. IJC Microcoulomb is the unit of electric charge and measures the quantity of electricity. rnA Milliampere is the unit for current. Errorsignals Whenever an error is detected, the stimulation is suspended. The flashing symbol alerts the user to the error. Attention beeps will sound unless the acoustic stimulation signal has been switched off in the set-up menu . The 'I'Oli-Watch" S features the following error alerts:

EI

Battery status symbol: Th is symbol only appears on the display, if the battery is low liil or empty 13. This mean s the battery should be replaced.

1

Internal errorsymbol: This symbol is displayed whenever a technical problem is detected. When this symbol is displayed, the device should be taken to th e technical services department or the responsible service company.

......-=t

Acceleration transducer symbol When this symbol is flashing, either no acceleration tran sducer is present or the signal is too weak. As the case may be, the acceleration transducer should be attached either at the test muscle (normally thumb) or its positionlfixation checked. Moreover, this error signal can also be triggered if the stimulation current is too weak.

161

4

4.5 . TOF·Watch- S

Three different error signals alert the user to problems with the stimulation electrodes and/or any of the cables:

-1f-E) A flashing surface electrode symbol indicates a missing or bad electrode connection.

-E> This flashing symbol means that the skin resistance is too high. Clean the skin where the stimulation electrodes are attached and shave away any excessive hair growth. Poor quality of the stimulation electrodes may be another cause.

-E> 7

If these two symbols are flashing simultaneously, check the connection between the stimulation cables and the two electrodes. Usually, a cable is not connected. This symbol also indicates that the resistance is too high.

Settings This fourth and last section deals with the repeatedly mentioned set-up menu. In the set-up menu, the basic settings of the TOF-Watch- S nerve stimulator can be pre-programmed and remain stored in memor y even when the battery is removed. This menu is used to customize some of the parameters and to permanently store the settings. It is recommended to define standard settings for these parameters and only make changes as agreed. Otherwise, use of the nerve stimulator could easily lead to malfunctions , misunderstandings or misinterpretations. In addition , the following settings are stored as secondar y function of the calibration button and the secondar y function button : The secondary function on this button can be used to display acceleration tran sducer sensitivity for 5 s. During this period, sensitivity can be increased/d ecreased by pressing »mA(flC)« up or down. This function can be used to optimize twitch height percentage manually. This can make sense when the calibration function did not produce a 100% contro l response. Sensitivity can be adjusted between 1 and 512, where 512 represents the most sensitive setting. The sensitivity setting 157 is the default sensitivity.

162

Ch pter 4 . Accele romyogr phy

After successful calibration, do not change the sensitivity as this will invalidate any previous calibration of the device. By contrast, any change made at this point will not affect the default setting selected in set-up menu. The secondary function on this button can be used to toggle stimulation pulse width between 200 and 300 ps. This makes sense if, previously, 200 fls at 60 rnA was not sufficient to produce supramaximal stimulation. In this case too, any previous calibration will be invalidated. By contrast, any change made at this point will not affect the default setting selected in set-up menu. The set-up mode can only be accessed when the TOF-WatchO S is switched on. The set-up menu is operated by pressing one of the two rnA (flC) up and down buttons and the calibration button. To enter the set-up menu, press both rnA (flC) up and down buttons Simultaneously. To modify the setting of the displayed parameter, now press either the mA{flC) up or down button. To store the modified setting, again press both rnA (flC) up and down buttons simultaneously. Within the activated set-up menu , press the calibration (CAL) button to activate the individual parameters (a Fig.4.9).

o

To enter the set-up menu, press both mA (~C) up and down buttons simultaneously. Press the calibration button to select the individual parameters.

4

163

4.5 . TOF-WatchOS

S -up 0 sp

ra: s nlJ51Jing (TOF S te

l ion Ii e) TOF S repetitlon time n be djusted between 1 nd 60 minu .

3I:

o

rode + sti ation nlJ51Jing (stitraJlatitln IItIits) Surfac:e eledrodestI ulJtIon sttength In m loa peres. Surfac:e eledrode mu tIon sttength In miaoalulomb. 0

SutfDQI ectrode .. stitraJlation nlJ51Jing (plJs. 200 liS: De u surf ~ stImulJ on pulse

h) han be selected

to2ooor3~

SutfDQI

50

~c: rnA:

1:

arode + stifrIJation noshing (stitraJlatitln size) Oef ult surfl~ electTod stimulatlon strength an be adjusted between0 nd 60 rnA (0 nd 1 2118~ .

I. oM + stimulation flashing(stimtJation urits) Needle stlmu Ionstrength shown In mlcro I s) starts repetitive single stimulations. The display shows the twitch height of the last response calculated from a control value and indicated in percent. To use this function , the nerve stimulator must be calibrated before the NMBA is injected and the corresponding control value must have been measured. Without initial calibration, the TOF-Watch" compares the response with an internal reference control. The response is also indicated in percent. In this case, the calibration symbol in the display flashes to indicate that no calibration was performed. In this stimulation mode, too, the accuracy of findings of an uncalibrated measurement is markedly limited.

Alarms In this context, there is a difference between information about the current nerve stimulator functions and error signals. The former includes the pre-in stalled symbols for the secondary function, calibration, the power button und the stimulation beep symbol. So now, the TOF alarm function, the temperature button, the remaining displays for timer function and for the stimulation signal as well as the display for the stimulation current.

TOF alarm function

The secondary function on this button can be used to silence or activate the TOF alarm function . As soon as the number of TOF responses drops below the number of responses previously set in the set-up menu, an acoustic alarm signal beeps. On the display, the loudspeaker symbol and the transducer symbol are flashing. By default, this function is not activated.

175

4.6 . rOF-Watch- SX

Temperature button When pressed, the surface temperature measured by the temperature sensor is shown. If the temperature drops below 32°C (measured on the surface of the extremities!), an attention beep will sound and the temperature display (0C) flashes. Pressing the temperature button causes the flashing to stop. The temperature display will flash in a similar fashion if the temperature sensor becomes disconnected .

:~: Optical stimulation signal and timer When the center dot in the timer symbol is flashing, the TOF-Watch" is currently performing a stimulation. This signal appears during all six stimulation patterns. During repetitive stimulation , the symbol .". indicates the time to next stimulation. Stimulation units The TOF-Watch" can show the strength of the electrical stimulation in both milliamperes [rnA) and microcoulomb [fiC)o For routine monitoring, the stimulation strength is indicated in milliamperes. The pre-installed default current is therefore set to a milliampere display. Occasionally, for use in regional anesthesia, the electric charge is indicated in fie. IJC Microcoulomb is the unit of electric charge and measures the quantity of electricity. rnA Milliampere is the unit for current. Error signals Whenever an error is detected, the stimulation is suspended . The flashing symbol alerts the user to the error. Attention beeps will sound unless the acoustic stimulation signal has been switched off in the set-up menu. The TOF-Watch" features the following error alerts:

EI

Battery status symbol : This symbol only appears on the display, if the battery is low ~ and/or empty 13. This means the battery should be replaced.

1

Internal error symbol : This symbol is displayed whenever a technical problem is detected. When this symbol is displayed, the device should be taken to the technical services department or the responsible service company.

4

176


Acceleration transducer symbol When this symbol is flashing, either no acceleration transducer is present or the signal is too weak. As the case may be, the acceleration transducer should be attached either at the test muscle (normally thumb) or its position/fixation checked. Moreover, this error signal can also be due to a too weak stimulation current. Three different error signals alert the user to problems with the stimulation electrodes and/or any of the cables. -+€) A flashing surface electrode symbol indicates a missing or bad electrode connection. -€) This flashing symbol means that the skin resistance is too high. Clean the skin where the stimulation electrodes are attached and shave away any excessive hair growth. Poor quality of the stimulation electrodes may be another cause. -€)..., If these two symbols are flashing simultaneously, check the connection between the stimulation cables and the two electrodes. Usually, a cable is not connected. Resistance too high symbol. ;....-c::::::I

Settings This fourth and last section deals with the repeatedly mentioned set-up menu . In the set-up menu, the basic settings of the TOF-Watch" nerve stimulator can be pre-programmed and remain stored in memory even when the battery is removed. This menu is used to customize some of the parameters and to permanently store the settings. It is recommended to define standard settings for these parameters and only make changes as agreed. Otherwise, use of the nerve stimulator could easily lead to malfunctions, misunderstandings or misinterpretations. In addition, the following two settings are stored as a secondary function of the calibration button and of secondary function button: The secondary function on this button can be used to display acceleration transducer sensitivity for 5 s. During this period, sensitivity can be increased/decreased by pressing »mA (flC)« up or down. This func tion can be used to optimize twitch height percentage manually. This can make sense when the calibration function did not produce a 100% control response.

177

4

4.6 . TOF-Watch- SX

The sensitivity can be adjusted between 1 and 512, where 512 represents the most sensitive setting. Sensitivity setting 157 is the default sensitivity. After successful calibration, do not change sensitivity because this will invalidate any previous calibration of the device. By contrast, any changes made at this point would not affect the default setting selected in set-up menu. The secondary function on this button can be used to toggle stimulation pulse width between 200 and 300 fls. This makes sense if, previously, 200 fls at 60 rnA was not sufficient to produce supramaximal stimulation. In this case too, any previous calibration will be invalidated. By contrast, any changes made at this point would not affect the default setting selected in set-up menu . The set-up mode can only be accessed when the TOF-Watch" SX is switched on. The set-up menu is operated by pressing one of the two rnA (flC) up and down button and the calibration button . To enter the set-up menu, press both rnA (flC) up and down buttons simultaneously. To modify the setting of the displayed parameter, now press either the mA(flC) up or down button . To store the modified setting, again press both rnA (flC) up and down buttons simultaneously. Within the activated set-up menu, press the calibration (CAL) button to activate the individual parameters (D Fig. 4.11).

o

To enter the set-up menu, press both mA (!leI up and down buttons simultaneously. Pressthe calibration button to select the individual parameters.

178


Set.up param tt>r.

ra: 5 n0511ing (fOF5 rtpf1ition time) TOFS repetition time n be adjusted belW~n I nd 60 minutes.

3I:

Surfaa tltarode + 51ilTlJfotionnoshing(51itrXJlotion unia) rnA: Surfaaelectrodestil1lulation st~ngth in l1IiUi-ampertS.

IJC:

Surfaa electrodestil1lU lion st~ngth in lIiclO-COUloI'Ib.

SurfrJa earod«+ 51itrXJlotion n05hing (pUlf . 11) 200 uS: Default sulfa« stil1lulatlon pulsewidth can be selected t0 200or 3~

SurfrJa SOmA:

NtMft ~C:

rnA:

aroa« + 51ilTlJlotionnOll1ing (j/ itrXJlotion lizt) Oet ult sulf ceelectrodestlmulation stlength can be adjusted btlW~n 0 and 60 mA (0 nd 121 18llC).

tarodt + 5limulotion f105hing (5rimrJoo'on uBa ) Needle stimu ionstltngth shownIn l1Iicro0.9

No fade

No fade

0.06

2

0.16

3

0.18

4

0.20

S

0.24

6

0.2B

7

0.39

B

0.44

9

0.47

10

0.48

11

0.50

12

0.52

13

0.57

14

0.60

15

0.60

16

0.63

17

0.66

18

0.67

19

0.72

20

0.73

21

0.76

22

0.76

~

I

188

Chapter 4 • Acceleromyography

a Tab. 4.3. Conrinued Patient

MMGTOF ratio

23

0.79

24

0.79

2S

0.80

26

0.81

27

0.82

28

0.84

29

0.85

30

0.86

31

0.87

32

0.90

33

0.90

34

0.91

3S

0.91

36

0.92

37

0.93

38

0.94

39

0.94

40

1.00

AMGTOFratio >0.9

1OO-Hz tetanus, No fade

DBS No fade

Neuromuscular recovery was measured by mechanomyography (MMG) in 40 patients. At the end of the intervention, neuromuscular recovery were assessedon the contralateral arm by a double-burst stimulation (DBS), a single acceleromyographic (AMG) TOF stimulation and a 1OO-Hz tetanus; the results of this study were subsequently compared with the reference value obtained by MMG. The MMG values of the 40 patients are listed in ascending order. Dark blue :Test revealed residual blockade; Light blue :Test showed complete neuromuscular recovery.

189

4

4 .7 · FAQS

o

When initially calibrated. rOF -Watch- nerve stimulators can rule out even low-grade residual blockade reliably. This way, patients who no longer need to be reversed can be detected with certainty.

One thing to be noted, however, is that all this evidence about the accuracy of TOF-Watch" nerve stimulators is based on the assumption that the acceleration transducer is actually connected and the nerve stimulator is truly measuring by acceleromyography. In contrast, if, as seen occasionally, the TOF-Watch" nerve stimulator is used without the acceleration transducer, i.e. the corresponding nerve is stimulated and the subsequent twitch assessed by tactile or visual evaluation only, then the device produces an accuracy comparable to that of a »simple« nerve stimulator. Concurrent with the discussion about the probability with which neuromuscular mon itoring is capable of detecting the limits of neuromuscular recovery, one should not forget that continuous monitoring of the neuromuscular blockade can provide even further clinically relevant information . Indeed , more knowledge is gained about the pharmacology of the NMBA used; an aspect that is especially pertinent for doctors training for further specialization. Likewise, each individual patient's reaction to the respective drug can be analyzed - evidence that is certainly valuable, even for the experienced specialist, and enables judicious and safe administration ofNMBAs. Such information cannot be gathered without quantitative neuromuscular monitoring that is continuous. Even if the benefits of continuous monitoring are very difficult to document in randomized, controlled and prospective studies (if at all), this type of information nevertheless goes into the decision-making as to whether a patient has already recovered from their neuromuscular block sufficiently enough to be extubated safely or if reversal should be administered before extubating. Such evidence is consequently of clinical relevance. Hence, continuous neuromuscular monitoring conveys substantially more information than just drawing an arbitrary »line in the sand« for sufficient neuromuscular recovery.

190


4.7 .S Can neuromuscular monitoring with the TOF-Watch 8 nerve stimulator prevent residual blockade?

Residual blockades corresponding to a TOF ratio of 0.5-0.9 can lead to a reduction in vital capacity, upper airway obstruction, pharyngeal dysfunction and impairment of the hypoxic respiratory response, among other immediate sequelae. It has moreover been proven that residual blockade is an independent risk factor for postoperative pulmonary complications [20]. Although residual blockade poses a potential risk for patients in the immediate postoperative phase, anesthesiologists cannot rule them out reliably by their mere senses nor with the aid of »sirnple« nerve stimulators. Even under clinical conditions, acceleromyography can objectively measure neuromuscular recovery and reliably detect minimal partial neuromuscular blockade. Whether this method is actually able to lower the incidence of residual blockade, however, not only depends on the functionality of neuromuscular monitoring, but also on other determinants like whether the method is even employed at all and what therapeutic measures follow on the diagnosis of »incomplete neuromuscular recovery«. That said, successful management of neuromuscular blockade is ultimately reliant on a well thought-through overall strategy. Citing examples from their own hospital, Baillard et al. [21] showed how appropriate management lowered the incidence of residual blockade down to 3% from formerly 62%. Within a quality assurance project, the authors surveyed the incidence of residual neuromuscular blockade in their postanesthesia care units (PACU). To this aim, a total of 435 patients were studied over a 3-month period. The large majority underwent abdominal surgery. The sobering result is well known: 62% of them did not meet the criteria of adequate neuromuscular recovery, i.e., a TOF ratio >0.9! The same internal survey additionally examined how frequently neuromuscular monitoring was used intraoperatively and finally how frequently patients were reversed. A mere 2% of the 435 patients received neuromuscular monitoring and just 6% of the cases were reversed. This was in the year 1995. The authors established a causal relationship between the high incidence of incomplete neuromuscular recovery and the rather reticent use of monitoring and reversal strategies. As a response to the findings from this first survey, they implemented the following measures:

4

191

4.7 · FAQS

All operating rooms were equipped with objective neuromuscular monitoring devices (TOF-Guard, and later TOF-Watch"), with one nerve stimulator per workplace Anesthesiologists and anesthesiology nurses were educated about the causes and sequelae of residual blockade Anesthesiologists and anesthesiology nurses were educated on the subject of neuromuscular monitoring and the pharmacology ofNMBA and their antagonists Anesthesiologists and anesthesiology nurses were instructed in the operation of the newly purchased nerve stimulators The effectivenessof this quality assurance project was reviewed by means of regular surveys over the ensuing years

-

The effects of the measures introduced are summarized in a Fig.4.14. The incidence of residual blockade declined continuously from a former high of 62% in the year 1995 to just 3% by 2004! At the same time, the number of patients whose neuromuscular blockade was monitored intraoperatively rose from an original 2% to 60% by 2004. In parallel to the increase in the

100 80 VI

C 60

.!!!

~

~

40

20 0

_ 1995

2000

2002

2004

n=435

n=130

n=101

n=218

a Fig. 4.14. Blacksquares: Incidence of residual neuromuscular blockade. Blue bars: Number of patients (%) receiving intraoperative monitoring and/or reversal (adapted from [21])

192

Chapter 4 • Acceleromyography

frequency of neuromuscular monitoring, the number of patients who were reversed went up to 42% from an initial 6%. Neuromuscular monitoring exposed residual blockade that were subsequently treated with antagonists. Based on the data gathered, the authors identified the following independent predictors for the occurrence of incomplete neuromuscular recovery : _ Omitting the use of neuromu scular monitoring was identified as the most important independent predictor for postoperative residual blockade. - Absence of reversal also markedly elevated the risk of a residual block. - The duration of surgery was a similarly important determinant in this context. The shorter the duration of surgery, the greater was the probability that the patient did not completely recover from the neuromu scular block at the end of the operation . Another aspect this survey looked at were the factors influencing the individual anesthesiologist's actual decision to reverse the neuromuscular blockade at the end of surgery. The intraoperative use of neuromuscular monitoring and the time interval between the last NMBA injection and the end of surgery indeed impacted decision-making on reversal: - The use of neuromuscular monitoring had a crucial impact on the anesthesiologist's willingness to reverse. When neuromuscular blockade was mon itored intraoperatively, the probability that the patient was reversed at the end of the surgical procedure was also markedly greater. Nevertheless, even neuromuscular monitoring often did not prevent the occurrence of residual blockade. This finding may be primarily due to the patient cohort. A large portion of the patients were undergoing abdominal surgery, which meant that deep neuromuscular blockade frequently had to be maintained until the peritoneum was closed. The incidence of residual blockade was accordingly high. Most of the time, however, the anesthesiologists only discovered these residual blockade thanks to

-

neuromuscular monitoring, but were therefore that much more willing to administer reversal agents. The time between the last NMBA injection and the end of surgery similarly influenced their decision to reverse: The shorter this period , the greater was the probability that an anesthesiologist would decide to reverse their patient.

193

4

4.8 · Acceleromyography in research

One by-product of the availability of neuromuscular monitoring: The amount of NMBAs used for reinjection dropped by around 35% in each of the operating rooms. It was perfectly clear that the intraoperative use of neuromuscular monitoring enabled a more targeted use of NMBA reinjection. The result was that a reduction in NMBA consumption was observed over the entire 9-year period. The long-term savings gained by the reduced consumption of NMBAs certainly offset the investment costs spent on purchasing the neuromuscular transmission monitors instead.

o

The survey of Baillard et al. clearly illustrates that neuromuscular mon itoring and on -demand reversal can in fact prevent postoperative residual blockad e. This finding not only applies within the scope of pre-designed study protocols. but also in rout ine clinical operations.

4.8

Acceleromyography in research

With the objective of improve the quality of research studies and facilitate the comparability of research results, a group of international experts convened for the first time in 1996 to define research standards for pharmacodynamic studies on NMBAs. Within this framework, the experts unified pharmacodynamic end points, among others, and presented the »Copenhagen Score" - a system for assessing intubating conditions. Moreover, these guidelines established which monitoring methods are suited for research studies on neuromuscular blockade and how these measuring methods are used properly [22). These recommendations were broadly accepted and have significantly impacted research in this field. Back then, the method of acceleromyography had not been considered for research , since it was originally developed for clinical monitoring of neuromuscular blockade. As the first research guidelines in this sector were finalized in 1996, few studies were available that had compared this new method with established ones like mechanomyography and electromyography. Consequently, back then, it would have been premature to also recommend acceleromyography for research . In the meantime, innumerable comparative studies have been published on acceleromyography. Indeed, mechanomyographs and electromyographs are hardly commercially marketed anymore, a development which has promoted the use of accelero-

194


myographs in research studies . Therefore, these research guidelines , newly revised and updated in the year 2007, reassessed the merits of this monitoring method. The new research guidelines accepted acceleromyography in principle for pharmacodynam ic studies and defined how it is to be used in research [8]. The following section will recount the particular aspects to be observed when using acceleromyography for research purposes. However, before any researcher starts planning a scientific study on the action of NMBAs, they should studiously read the »Good Clinical Research Practice Guidelines«. The recommendations contained therein will help prevent serious method ological errors , likely improve the quality of the acquired data and certainly up the probability that the paper will get published.

4.8.1

Neuromuscular monitoring for scientific purposes: What should anesthesiologists generally look out for?

When neuromuscular monitoring is intended for scientific purposes, this list of standard recommendations should be observed - irrespective of the monitoring method employed.


To ensure optimal cond uction of the stim ulation current, it is recommended to meticulously clean and degrease as well as slightly roughe n and, if appropriate, shave the area of the skin where the stimulation electro des are to be attached . Additionally, the stimu lation electrodes should have a contact area of 7- 11 mm in diameter and be positioned 2.5-4 cm apart ( . Chapter 2.2).

Stimulation patterns

Among others determinants, the stimulatory response depends on the stimulation frequency. It has been shown that supposedly comparable stimulation patterns, such as a 0.1-Hz single twitch stimulation every 10 seconds and a 2-Hz TOF stimulation every 12 seconds lead to different pharmacodynamic outcomes. Furthermore, the time to stability of baseline values influences

195

4

4.8 . Acceleromyography in research

both the neuromuscular blockade's duration of onset and its duration of action . Increasing the stimulation frequency should thus lead to a shortening of the onset time and extend the duration of action. In order to avoid repetitive nerve stimulations and/or direct muscle stimulation , the individual stimulation pulse should last 300 fis at most. The pre-defined default current is usually set at 200 fis. The response to PTC stimulation varies depending on the duration and frequency of the tetanic stimulation as well as on the interval between tetanus and the onset of a single twitch. These variables should therefore be kept constant and be adequately described in the methods section of the publication.

Temperature

Just as body temperature influences the pharmacodynamics and pharmacokinetics of NMBAs, fluctuations in skin temperature occurring around the target nerve-muscle unit can affect the stimulatory response. Therefore, body temperature and skin temperature at the stimulation site should be monitored and maintained at > 35°C for the body and> 32°C on the skin.

Supramaximal stimulation

Always ensure that each patient is stimulated with a supramaximal current. The respective stimulation strength and the way it is to be determined should be described in the methods section ( ~ Chapter 2.1).

Calibration

The nerve stimulator used should be calibrated before injecting the NMBA in order to ensure that reliable and reproducible data are produced. Calibration involves setting the transducer gain so that the twitch after single stimulation and/or the T1 response to TOF stimulation equals 100%. This shifts the acceleration signal into the optimal measuring range and reduces background noise to a minimum. Later, this baseline value serves as a reference value throughout the entire measurement. The calibration procedure differs from nerve stimulator to nerve stimulator and should also be detailed in the paper's methods section.

196


For example, on the TOF-WatchOSX,·the »CAL 2« mode determines the supramaximal stimu lation strength while it is performing the calibration ( . Chapter 4.3.2).

Signal stabilization Lastly, a stable baseline value should be obtained before the NMBA is injected and the actual monitoring started. To this end, the stimulatory response obtained over a period of several minutes should not deviate from the baseline value by more than S%. The stimulation frequency influences the time needed to maintain a stable baseline value. The higher the stimulation frequency, the faster the stimulatory response will stabilize. The following procedure is recommended to coordinate calibration, supramaximal stimulation and signal stabilization when starting the measure ment (D Fig. 4.15): _ After switching on the nerve stimulator, first apply a couple of stimulations (single twitch stimulations of TOF) Next, a SO-Hztetanus for S s Calibrate the stimulatory response Determine the supramaximal stimulation strength Onset of stimulation using the stimulation mode and stimulation frequenc y to be applied during the study (typically TOF, every 12 s) - When the twitch remains stable for 2-S min «S% deviation), the NMBA can be injected and the actual measurement started; otherwise recalibrate.

Immobilization All neuromuscular monitoring methods react sensitively to movement. For that reason, the target extremity should be immobilized to prevent motion artifacts.

Intu bation conditions Since they can be influenced by the depth of anesthesia, intubating conditions should be assessed separately, i.e. independently of the examinations on the time-action profile of the neuromuscular blockade under investigation. This is the sole way to ensure that intubation is performed under real-life conditions.

197

4

4.8 . Acceleromyography in research

50 Hz Tetanus for 5 s (only for use with Ml\I G and

r - - - - - - - --

MG )

Ca libration

Supramaximal stimulation ( 1.0 Hz )

Recalibratio n (if needed )

Stable response 1:1 "ting 2-5 min '! ' - - - - - Nil

~

Yes

1

lnject I MBA

a Fig. 4.15. Flow chart for determining supramaximal stimulation strength, calibration and signal stabilization (modified after [8]).

4.8.2

Particulars of performing acceleromyography

Unlike its use in clinical practice, the procedure for performing acceleromyography differs in several ways when used for research purposes.

Choice of materials

Not all commercially available acceleromyographs are suited for research studies. For example, the latest TOF-Watch" and TOF-Watch" S models are equipped with a special TOF ratio algorithm ( ~Chapter 4.3.1). This algorithm always ensures that whenever the second TOF response (T2) turns out to be greater than the first (Tl), the TOF ratio is not calculated from the ratio of T4/Ti' but from the ratio T 4/T2• Moreover, no TOF ratios >1 are indicated on either of the two models. Even though these two modifications presumably have no vital clinical implications, nerve stimulators equipped with them should still not be used in scientific studies. Currently, neither the TOF-Guard nor the TOF-Watch" SX are implemented with these modifications; as a result, the prevailing opinion is that these two models may be used for research purposes.

198


Preload

Originally, it was demanded that the thumb be allowed to move freely as prerequisite for acceleromyographic measurement of neuromuscular blockade at the adductor pollicis muscle. Meanwhile, evidence is gathering that the use of an appropriate preload markedly reduces the variability of the stimulatory response and the susceptibility of the method to motion artifacts. Therefore, it is recommended to use a preload of 75-150 g in research studies. The TOF-Watch" hand adapter is suited for this purpose. Of course, any other method can be used that ensures a constant preload. Whichever method is employed, it should be described and the preload given in grams (g) or newton (N).

Normalization

Now, in the meantime, acceleromyography has been satisfactorily compared with mechanomyography and electromyography, i.e., the two reference methods . Evidence has shown that acceleromyography frequently produces slightly higher recovery values than its comparators. Therefore, AMG values cannot be directly equated with the comparators' measurements. For this reason, some authors have proposed to »normalize- the neuromuscular recovery values measured by acceleromyography, i.e. by first comparing them with the baseline value, and not to assume adequate neuromuscular recovery until this normalized value equals a TOF ratio of at least 0.9 (j- Chaptera.s.f ). Nevertheless, further study is pending before this method can truly be recommended. Given the above, studies should always indicate the time to achieving an uncorrected, i.e., non-normalized, TOF ratio of 0.9. It is also advisable to indicate the time it took acceleromyography to measure an uncorrected TOF ratio of 1.0.

4.8.3 Guidelines for measuring onset and time profile of neuromuscular blockade

The stimulation mode influences onset time. Data gathered by a variety stimulation modes will therefore not be directly intercomparable . The O.l-Hz single twitch or the TOF stimulation are typically used, while the minimum

200


Intense or deep neuromuscular block

For a certain amount of time after injection of the NMBA, single twitch stimulations or TOF stimulations will fail to produce a detectable response. The best mode for monitoring this phase is the PTC mode. The block here is defined as intense according to the PTC response, i.e. when even PTC stimulation fails to produce a single detectable response. Deep neuromuscular blockade

Next followsthe phase of the deep neuromuscular blockade. This phase starts with the occurrence of the first PTC response and ends with the reemergence of the first TOF response. Moderate neuromuscular blockade

The phase of moderate neuromuscular blockade is defined as the period from the occurrence of the first TOF response to the reemergence of the fourth TOF response. Neuromuscular recovery

The neuromuscular recovery starts with the occurrence of the fourth TOF response and ends once the TOF ratio baseline value is achieved. Additional time intervals of note include »Duration 25« and »Duration TOF 0.9«. These cover the period from start ofNMBA injection up to a 25% recovery of the T 1 response and/or a recovery of the TOF ratio to 0.9. The first interval indicates the duration of surgical relaxation; the second interval defines the total action time of the investigated drug. Irrespective of the measuring method, the first of three successive measured values above the respective limit of 25% and/or 0.9 should be evaluated.

Concluding remarks

This textbook has presented the anatomical, metabolic and pharmacolog ical principles of neuromuscular monitoring by starting with an explanation of the action of acetylcholine at the synaptic junction and the effects of neuromuscular blocking agents at the neuromuscular endplate. The further detailed description of the underlying concept of neuromuscular monitoring covered the discovery of muscle relaxants and a history of nerve stimulation.

201

4

Concluding remarks

The mechanisms of action of established depolarizing and non-depolarizing neuromuscular blocking agents (NMBAs) have been elucidated and those of a new class of selective relaxant binding agents like sugammadex introduced. The key test muscles stimulation sites and stimulation patterns were analyzed in terms of their relevance for anesthesia. Extensive evidence from innumerable clinical study reports has been cited to support the proposed approach towards neuromuscular monitoring device-guided anesthesia. The reasons why neuromuscular monitoring is so relevant to modern clinical practice have been argued in a logical and structured fashion and underpinned by substantiated data. It could be demonstrated that neuromuscular monitoring is indicated for the timing of anesthesia induction, for intraoperative and postoperative control, for the timing of extubation, in effect, for perioperative monitoring that extends to the patient's recovery on the postanesthesia care unit. The various methods employed to objectively measure the depth of neuromuscular blockade by mechanomyography, electromyography, kinemyography and be acceleromyography in particular were discussed and the data supporting the effectiveness of devices such as the TOF-Watch" series of neuromuscular monitors laid out, always with reference to a body of pertinent literature. The final and extensive chapter on the features and operation of modern neuromuscular monitoring devices serves as a manual in the use of these simple and effective instruments. The reader learns how to place stimulation electrodes, properly select the stimulation mode and interpret the findings obtained with neuromuscular monitors. At the end of each subsection, the key points are summarized succinctly for the reader. The general conclusion of each of these sections and of the entire book is that neuromuscular monitoring is critical for the judicious use of neuromuscular monitoring agents and, in combination with pharmacological reversal, is fundamental to every successful strategy for managing postoperative residual blockade. The near future can be predicted to see the concept of device-supported neuromuscular monitoring becoming an indispensible element of safe and effective anesthesia in both clinical practice and research. This compendium of all the essential information needed to monitor neuromuscular function hopes to prove a useful guide to anesthesiologists in clinical practice and research throughout the world.

202

Chapter 4· Acceleromyography

References Fuchs-Buder T, Hofmockel R, Geldner G, Diefenbach C, Kulm K, Blobner M (2003) Einsatz des neurorn uskularen Mon itorings in Deutschland. Anaesthesist 52: 522-526 2

Jensen E,Viby-Mogensen J, Bang V (1988) The Accelograph: a new neuromuscular transmission monitor. Acta Anaesthesiolo 5cand 32: 49-52

3

Veda N, lnoue S, Muteki T, Shinozaki M, Tsuda H, Nishina H, Jensen E (1988) A new neuromuscular transmission mon itoring system (Accelograph): the rat ionale beh ind the method and its clinical usefulness. Masui 37: 1265-1272

4

Viby-Mogensen J, Jensen E, Werner M, Nielsen HK (1988) Measurement of accelerat ion: a new method of monitoring neuromuscular function . Acta Anaesthes iol Scand 32: 45-48

5

Veda N, Muteki T, Poulsen A, Espensen JL (1989) Clinical Assessment of a new neuromuscular transmission monitoring system (Accelograph)-a comparison w ith the conventional method. J Anaesth 3:90-93

6

Veda N, Masuda Y, Muteki T, Tsuda H, Hiraki T, Harada H, Tobata H (1994) A new neuro muscular transm ission monitor (TOF-Guard): the rationale behind the method and it s clin ical usefulness. Masui 43: 134-139

7

Suzuki T, Fukano N, Kitajima 0 , Saecki S, Ogawa S (2007) Normalization of acceleromyographic train-of four ratio by baseline value for detecting residual neuromuscular block .

8

Br J Anaesth 96: 44-47 Fuchs-Buder T,Claudius C, Skovgaard LT, Eriksson L1, Mirakhur RK, Viby-Mogensen J (2007) Good clin ical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision Acta. Anaesthesiol Scand 51: 789-808

9

Kopman AF,Kopman OJ(2006) An analysis of the TOF-Watch algorithm for modifying the displayed train-of-four ratio Acta. Anaesthesiol Sand 50: 1313-1314

10 Baillard C, Bourdiau S, Le Toumelin P, Ait Kaci F. Riou B, Cupa M, Samama CM (2004) Assessing residual neuromuscular blockade using acceleromyography can be deceptive in postoperative awake patients. Anesth Analg 98: 854-857 11 Aveline C (2006) Choix d'un neurostimulateur pour l'anesthesle locoreqlonale. Annales Francalsesd'Anesthesie et de Reanimation 25 : 96-103 12 Driessen JJ, Robertson EN, Booij LHDJ (2005) Acceleromyography in neonates and small infants : baseline calibration and recovery of the response after neuromuscular blockade with rocuronium. Europ J Anaesth 22: 11-15 13 Nakamura K, Terasawa N, Konishi K, Kino A, Nakanishi I, Sumida H, Yamakawa T, Kitamura R, Tsutsumi K,Toyoda S (2004) Erythemas caused electrodes while monitoring neuromuscular blockade: three cases. J Anaesth 18 : 296-299 14 Amberger M, Stadelmann K, Alischer P, Ponert R, Melber A, Greif R (2007) Mon itoring of neuromuscular blockade at the P6 acupuncture point reduces the incidence of postoperat ive nausea and vomiting. Anesthesiology 107: 903-908 15 Saitoh Y, Nakazawa K,Toyooka H, Amaha K (1995) Opt imal stimulating current for train-offour stimulation in conscious subjects . Can J Anaesth 42: 992-995 16 Brull SJ, Silverman DG (1995) Pulse width, stimulus intensi ty, electrode placement, and po larity during assessment of neuromuscular block . Anesthesiology 83: 702-709

203 References

17 Samet A. Capron F, Alia F,Meistelman C, Fuchs-Buder T (2005) Single accelerometric trainof-four, 100-Hertz tetanus or double-burst stimulation : which test performs better to detect residual paralysis? Anesthesiology 102: 51-56 18 Capron F, Fortier Lp, Racine S, Donati F (2006) Tactile fade detection with hand or wr ist stimulation using train-of-four, double-burst stimulation, 50-Hertz tetanus, 100-hertz tetanus, and acceleromyography. Anesth Analg 102: 1578-1584 19 Capron F, Alia F, Hottier C, Meistelman C, Fuchs-Buder T (2004) Can acceleromyography detect low levels of residual paralysis? A probability approach to detect a mechanomyographic train-of-four ratio of 0.9. Anesthesiology 100: 119-124 20 Fuchs-Buder T, Eikerman M (2006) Neuromuscular residual blocks: Clinical implications, frequency and prevention strategies. Anasthesist 55: 7-16 21 Baillard C, Clec'h C, Catineau J, Salhi F, Gehan G, Cupa M, Samama CM (2005) Postoperative residual neuromuscular block : a survey of management. Br J Anaesth 95: 622-626 22 Viby-Mogensen J, Engbaek J, Eriksson L1, et al. (1996) Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthe siol Scand 40:59-74

4

Subject Index

206

Subject Index

A

0

abdominal muscles 39

decrease in inspiratory airflow 105

acceleromyography 63

depolarization 4

accelograph 127

depolarization block 15,46

accumulation of NMBA 91

depolarizing neuromuscular blocking

acetylcholine 3, 5

agents 15

acetylcholine receptors 7

diaphragm 38,82

acetylcholinesterase 3

difficulties in swallowing 101

acetylcholine synthesis 6

direct muscle stimulation

ACh receptor 6

double-burst stimulation 49,86

28

AChvesicles 6 actin 10 action potential 4 adductor pollicis muscle 31,82 all or nothing principle 8,24 anesthesia induction 76

E edrophonium 18 electromechanicalcoupling electromyography 61 endplate potent ial 10

c

10

Elyexchange 8 extrajunctional 8

Call

134

extrinsic musclesof the tongue and

Cal2 134

floor of mouth 40

calibration 133 calibration funct ion (CAL 1) 134 calibration function (CAL 2) 134 cholinesterase inhibitors

11,16

clinical signs 110 complete neuromuscular recovery 97 cormack grade 80, 81 corrugator supercilii muscle 33, 82 y-cyclodextrin

11,19

F facial nerve 33 fading 12,14 fetal acetylcholine receptor 8 flexor hallucis brevis muscle 32 forced vital capacity 98 frequency of residual neuromuscular blockade 106

-p

207

Subject Index

G genioglossusmuscle 40, 99

M mechanomyography 60 minimal residual neuromuscular blockade 104

H

motor neuron 2 motor unit 2 musclefasciculations 15

head lift test 111

myalgia 15

hypoxia 99

myosin 10

N incidence of residual neuromuscular

negative predictive value (NPV) 51

blockade 76 inspiratory flow 99

neostigmine 18

intubating conditions 78,84,86,87, 88,89 intubation difficulty scale(IDS) 78

K kinemyography 68

L laryngeal muscles 39 low-dose concept 88

nerve stimulators 56 neuromuscular endplate 2 neuromuscular monitoring 24 Newton'ssecond law 63

o orbicularis occuli muscle 33,82

p patient comfort 102 perceived accumulation 91 perijunctional 8 pharyngeal function

101

208

Subject Index

pharyngeal muscles 40

resting potential 4

phase-I block

15

reversal 115

phase-II block

16

phonomyography 66 piezoelectr ic effect

s

63

piezoelectric element

63

polar ity of the electrodes

28

posit ive predictive value (PPV) 51

safety margin

posterior tib ial nerve 32

Selective relaxant binding agents drugs

postoperative hoarseness 78 postsynaptic nicotinic acetylcholine receptor

9

19 sensit ivity

50, 51

simple nerve stimulators

post-tetanic count

56

single twitch 42

53

post-tetanic potentiation

12, 14,53

presynaptic nicotinic acetylcholine receptors 9 pronounced residual neuromuscula r blockade

13, 101, 102

104

skin erythema specificity

180

50

stimulation patterns

41,85

submaximal current

26

succinylcholine

15

pulmonary muscles 98

Sugammadex 19

pyridostigmine 18

supramaximal current

24

swallow ing difficulties

105

Q

T

quantitative nerve stimulators 59 test muscles 82 . tetan ic stimulation

R

51

the accelograph and the rOF-Guard 127 the rOF ratio algorithm

recurarization

101, 102

reduct ion in uppe r airway volumes

rOF count

45

rOF-Guard 128 rOF ratio 46

105 regional anesthesia 136

rOF responses 46

reinjection of NMBA 91,94

rOF stimulation 46

respiratory control

rOF-Watch'" 138

99

130

209 Subject Index

TOF-Watch~

models 130

TOF-W6tch~

5 150 SX 164

TOF-Watch~

tongue depressortest 111

u ulnar nerve 27,31 upper airway dilator muscle 105 upper airway dysfunction 99 upper airway function 105 upper airway obstruction

100

upper airway volume 99 upper esophageal sphincter 101

v vocal cord injuries 78 vocal cord muscles 82

p-z

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