Neuromuscular Monitoring in Clinical Practice and Research

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

Physiological principles

1.1.1

Anatomical principles

- 2

1.1.2

Action potential

1.1.3

Acetylcholine

1.1.4

Postsynaptic nicotinic acetylcholine receptors

1.1.5

Presynaptic nicotinic acetylcholine receptors

1.1.6

Striated muscles

- 2

- 4 - 5 - 7 - 9

- 10

1.2

Pharmacological principles

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

Physiological principles

1.1.1

Anatomical principles

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

Chapter 1 . Principles of neuromuscular transmission

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

Chapter 1 . Principles of neuromuscular transmission

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

Chapter 1 . Principles of neuromuscular transmission

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

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

Pharmacological principles

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

Chapter 1 . Principles of neuromuscular transmission

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

Chapter 1 . Principles of neuromuscular transmission

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 . Pharmacological principles

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

Chapter 1 . Principles of neuromuscular transmission

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

1.2 . Pharmacological principles

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

Chapter 1 . Principles of neuromuscular transmission

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

Chapter 1 . Principles of neuromuscular transmission

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

Double-burst stimulation

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

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

'\

, "" "" ' , ,, .

. ....

"

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

'" . . .

...

"

",

"",

"

........•

'

...... _

'<,

"

~-

.. __ .. _ ...

................... _

-..~~

,

_-,'

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

!

,.. ~: ' , , .': ,. ,

,'

",

" "

,

/

./ ./

~/

l

.. / /'

."

I

r

Nerve

/

/

//

a Fig. 2.3. The distance between the two stimulation electrodes determ ines the penetration depth of the stimulation current

Stimulation electrodes have meanwhile been developed especially for neuromuscular monitoring (a Fig. 2.4). On these electrodes, the distance and size of the contact area are selected according to the above-mentioned specification, which also facilitates their handling.

Polarity There is evidence in the literature that the polarity of the electrodes can similarly influence nerve stimulation [4]. According to these data, the best results are achieved by connecting the negative electrode cable to the distal electrode (a Fig. 2.4 and 2.5).

Direct muscle stimulation Regardless of which stimulation electrodes have been chosen, it is important to make sure that they are positioned so as to ensure that the target motor nerve is actually stimulated, while avoiding any direct stimulation of the muscle. One way direct muscle stimulation can be identified is by the weak contractions of the muscle that occur without the fading commonly observed following administration of non-depolarizing NMBA. Additionally, these weak contractions also continue to be detectable during deep neuromuscular

29

2

2.2 . Stimulation electrodes

a Fig. 2.4. Special neuromuscular monitoring electrodes. The stimulation cable is connected properly, i.e., the negative cable clasp (black) is fastened to the distalelectrode.

a Fig. 2.5. This is not the recommended wayto connect the stimulation cable. Here, the negativecableclasp(black) is fastenedto the proximal electrode.

30

Chapter 2 • Principles of neuromuscular mon itor ing

blockade. There is always a risk of direct muscle stimulation whenever the stimulation electrodes are attached directly over the muscle to be assessed. To prevent this, it is recommended that the nerve-muscle unit be chosen so that the nerve stimulation and the subsequent twitch are unmistakably topographically separate from each other. One way to ensure this topographic separation is to stimulate the ulnar nerve and assess the twitch at the adductor pollicis muscle. Key points - - - - - - - - - - - - - - - - - - - - - - - - , -

The stimulation electrodes should not take up a contact area larger

-

The stimulation electrodes should be posit ioned 2.5-4 cm apart from

than 7-11 mm. each other, along the course of the nerve to be stimulated. It is recom mended to place the negative electrode to the distal. -

To prevent direct muscle stimulation, the nerve -muscle unit should be chosen so that the site of stimulation is unmistakably separated from that of the muscle twitch.

-

A direct stimulation of the muscle is identified by weak muscle con tractions in the direct vicinity of the stimulation electrodes . The fading common after non -depolarizing relaxants is not observed . Additionally, these weak contractions continue to be detectable even during deep neuromuscular blockade.

2.3

Stimulation site/test muscle

An ideal stimulation site is one that is easily accessible during surgery and where the corresponding neuromuscular response can be identified clearly and unmistakably. Furthermore, it is a general rule that any direct muscle stimulation should be avoided and a nerve-muscle unit should be selected that best allows the twitch to be recorded. In clinical practice, the ulnar nerve/adductor pollicis muscle, the posterior tibial nervelflexor hallucis brevis muscle and the facial nerve/orbicularis occuli muscle and/or the facial nerve/corrugator supercilii muscle are the respective nerve-muscle units used for neuromuscular monitoring. These four nerve-muscle units meet the requirements profiled above to varying degrees.

31

2.3 . Stimulation site/test muscle

2.3.1

Ulnar nerve/adductorpollicis muscle

The ulnar nerve and the adductor pollicis muscle combine to form the nerve-muscle unit most frequently used for neuromuscular monitoring. One reason for this is that neuromuscular mon itoring of this nerve-muscle unit will normally not affect the surgical conditions. Another reason is that this nerve-muscle unit is easily accessible intraoperatively, at least when the arm is placed in an outstretched position . Moreover, the stimulatory response can be evaluated by tactile, visual and objective means concurrently. Yet another advantage is that the adductor pollicis muscle is located on the lateral side of the arm, while the ulnar nerve runs along the median side. Therefore, the risk of any direct muscle stimulation can essentially be ruled out. Together with the median nerve and the brachial artery, the ulnar nerve runs along the inner side of the upper arm and passes subcutaneously behind the medial epicondyle of humerus, sometimes referred to as the »crazy bone« or »funny bone «. There, it is easily palpable through the skin. From here, accompanied by arteries and veins, the ulnar nerve runs down the anterior compartment of the forearm to the hand . In the distal portion of the ulna, the nerve courses radial to the head of the ulna before it emerges through the ulnar tunnel into the palm of the hand . Here, the ulnar nerve runs very close to the surface and, because of its direct proximity to the ulnar artery and the head of ulna, it is easy to localize. For that reason, this is site where the ulnar nerve is typically stimulated during neuromuscular monitoring. For stimulation, the distal electrode is attached at the ulnar head directly over the groove for ulnar nerve (sulcus nervi ulnaris), the second stimulation electrode is positioned along the course of the nerve, around 2.5-4 em proximal to this groove, as shown in a Fig.2.4. Alternatively, the ulnar nerve can also be stimulated directly at the funny bone. However, if this stimulation site is chosen, attention must be paid that the arm does not lie directly on the electrode as this could easily cause compression of the nerve. The ulnar nerve is responsible for the motor supply to all interosseous muscles, the two lumbrical muscles on the ulnar side, all muscles in the hypothenar compartment and to the portions of the thenar eminence (ball of the thumb), including the deep head of flexor pollicis brevis and the adductor pollicis muscle. Corresponding to its innervations area, stimulation of

2

32

Chapter 2 • Principles of neuromuscular monitoring

the ulnar nerve triggers flexion of the metacarpal heads and also leads to adduction of the thumb and the little finger, although adduction of the thumb is usually the only sign considered for neuromuscular monitoring. Assessment of the thumb's motor response is more effective when the other four fingers are restrained .

2.3.2 Posterior tibial nervelflexor hallucis brevis muscle

Like the nerve-muscle unit of the upper extremity comprising the ulnar nerve and the adductor pollicis muscle, the nerve-muscle unit consist ing of the posterior tibial nerve - a branch of the sciatic nerve - and the flexor hallucis brevis muscle can analogously be used for neuromuscular monitoring on the lower extremity. For this purpose, the posterior tibial nerve is stimulated in the region of the medial malleolus ( a Fig. 2.6) and the degree of neuromuscular blockade is assessed by noting flexion of the

a Fig. 2.6. Electrode position for stimulating the posterior tibial nerve. The negative end of the stimulation cable is attached at the distal electrode as recommended

33

2.3 . Stimulation site/test muscle

big toe. The time profile of the neuromuscular blockade of the flexor hallucis brevis muscle is mainly consistent with that of the adductor pollicis muscle. The nerve-muscle unit consisting of the posterior tibial nerve and the flexor hallucis brevis muscle is always a good choice for neuromuscular monitoring, whenever the arms have to be immobilized on the body during surgery or access to them is encumbered. However, it is important to note that both the stimulation site and the stimulatory response - manifest as adduction of the big toe - are localized on the medial side of the foot. This anatomical situation slightly increases the risk of direct muscle stimulation compared to the ulnar nerve/adductor pollicis muscle unit. Moreover, moni toring adduction of the big toe is technically not as easy as monitoring adduction of the thumb, which is why the posterior tibial nerve/flexor hallucis brevis muscle nerve-muscle unit is less suited for objective neuromuscular monitoring than that unit consisting of ulnar nerve/adductor pollicis muscle described at the beginning of this chapter. 2.3.3

Facial nerve/orbicularis occuli muscle or facial nerve/ corrugator supercllll muscle

Alongside the, extremity muscles, i.e. adductor pollicis and flexor hallucis brevis, some portions of the mimic muscles are equally suitable for neuromuscular monitoring [5]. These muscles are mainly supplied by the facial nerve. The facial nerve is the 7th cranial nerve (facial nerve). It is made up of sensitive, sensory, parasympathetic and motor fibers and innervates broad regions of the head. After exiting the stylomastoid foramen, the facial nerve passes anteriorly through the parotid gland to resurface in the petrous portion of the temporal bone where it combines with the parotid plexus to form a fine neural network. This parotid plexus gives rise to several branches which innervate the mimic muscles in particular. Alongside the temporal and zygomatic branches supplying the entire zygomatic arch and the eye, this region is supplied by the buccal and the marginal mandibular branches that innervate the mimic muscles of the mouth and cheek, as well as by the cervical, most inferior, branch of the facial nerve. In principle, two muscles innervated by this neural network are suited for neuromuscular monitoring: the orbicularis occuli muscle and the corrugator

2

34

Chapter 2 . Principles of neuromuscular mon itoring

supercilii muscle. The orbicularis occuli muscle encircles the orbital opening. Stimulation through the zygomatic branches of the facial nerve causes the eyelids to close. By contrast, the corrugator supercilii muscle is innervated by the temporal branch and draws the medial end of the eyebrow downward, producing the typical wrinkling of the brow. The main argument favoring the use of the facial nerve as a stimulation site for neuromuscular monitoring is that it normally gives the anesthesiologist good and unimpaired intraoperative access to the regions of the head. However, because this neural plexus is in direct proximity to the intrinsic mimic muscles, the risk of direct muscle stimulation at this stimulation site is very large. Therefore, great care must be taken that the correct stimulatory response is assessed (eyelid closure or wrinkling at the superciliar y arch) and not to falsely interpret any other twitching muscle in the direct proximity of the stimulation electrode as an effect of neuromuscular blockade. Moreover, it is important to know that, compared to the ulnar nerve, supramaximal stimulation of the facial nerve can be accomplished with significantly lower currents. Experience has shown that as little as 25-30 mA are often sufficient to elicit a response [5]. Using higher currents for stimulation runs the risk of direct muscle stimulation due to the nerve's proximity to the mimic muscles. Additional note should be taken that both the orbicularis occuli and the corrugator supercilii muscles vary in their responses to NMBAs. While the neuromuscular blockade at the orbicularis occuli muscle is similar to that of the adductor pollicis muscle, the corrugator supercilii muscle is much more resistant to NMBAs and hence its blockade is more consistent with that observed on the laryngeal adductor muscles or the diaphragm (arab. 2.1). Therefore, it is best to selectivelystimulate either the zygomatic branches to elicit the response from the orbicularis occuli muscle or to stimulate the temporal branches of the facial nerve and produce the typical eyebrow wrinkles from the corrugator supercilii muscle. If the response of the corrugator supercilii muscle has been selected for monitoring, the acceleration transducer should be secured above the eyebrow in the median half of the face (a Fig. 2.7a) . If, on the other hand, the anesthesiologist decides to take the acceleromyographic measurement at the orbicularis occuli muscle, the transducer has to be placed laterally above the eyelid (aFig. 2.7b) . In general, however, stimulation of these two muscles is technically difficult and the outcome is frequently unsatisfactory in clinical practice.

3S 2.3 . Stimulation site/test muscle

a Fig.2.7a,b. Monitoring the stimulatory response of the corrugator supercilii muscle (a):The acceleration transduceris attachedabovethe eyebrow in the medial half of the face. Monitoring the stimulatory response of the orbicularisocculi muscle(b):Theacceleration transduceris attached in the lateral region between eyeand eyebrow

2

36

Chapter 2 . Principles of neuromuscular mon itoring

a r ab. 2.1. TImeprofile of neuromuscular blockadeafter 0.5 mglkg rocuronium measured at the adductorpollicis muscle(AP), orbicularisocculi muscle(00) and corrugator supercilii muscle (CP). (Modified after [5]). DU~m1nl

TOfulmlnl

100(1)

25 (4)

43 (6)

218 (78)'

93(8)

24 (10)

49(7)

194 (59)'

80 (20)°

Onsettime [sl

MaxImal effect

AP

83(28)

00

CP

1"1

The data are presented as mean (5D). Onset time: interval between injection of NMBA and maximalblockade; maximal effect: maximalreduction in height ofT l ; DUR 2S: interval between injection and recovery ofT, to 25%of baseline;TOFo.9 : interval between injection and recovery of the TOF ratio to 0.9. a P <0.05 versus AP; b P <0.05 versus 00.

Key points - - - - - - - - - - - - - - - - - - - - - - - - , Typically, the ulnar nerve is stimulated for neuromuscular monitoring and adduction of the thumb is assessed as the stimulatory response . -

The ulnar nerve can be easily located at the d istal ulna .

-

With this nerve -muscle unit, any risk of direct muscle stimulation is excluded. Analogous to the nerve-muscle un it comprising ulnar nerve/adductor pollicis muscle, the unit comprising the posterior tibial nervelf1exor hallucis brevis muscle can be used for neuromuscular monitoring at the lower extremity where flexion of the big toe is assessed. A neuromuscular blockade at the adductor pollicis muscle runs a comparable time course as that at the flexor hallucis brevis muscle. An additional option for neuromuscular monitoring is to stimulate the facial nerve and then to assess the response triggered at the orbicularis occuli muscle (typical muscle response : eyelid closes) or at the corrugator supercilli muscle (typical muscle response : brow wrinkles).

-

The orbicularis occuli muscle and the corrugator superc ilii muscle react

-

When the facial nerve is selected as the stimulation site, there is a risk

to NMBAs with varying sensitivities. that direct stimulation of the mimic muscles may occur inadvert entl y.

37

2

2.4 . Anesthesia-relevant muscle groups

2.4

Anesthesia-relevant muscle groups

As early as 200 years ago, a surgeon named Brodie described the breathing patterns of a pig after applying curare into a fresh wound: 10 min after administration, the pig was incapable of walking although it continued to breathe normally. Several minutes later, the scientist observed that , although the pig lay motionless before him, its respiration was functioning, albeit perceptibly weakly [6]. Indeed, this observation can be regarded as one of the first pieces of evidence proving that NMBAs exert a more potent action on peripheral muscles than on respiratory muscles [7]. Over 150 years later, Gal and Smith described this phenomenon as a »respiratory sparing effect« [8]. These authors investigated the effects of a partial neuromuscular blockade on respiration and on the strength of the hand muscles in humans . After administration of low doses of d-tubocurarine, the subjects' grip strength was reduced down to a mere 6% of the control value, although their respiration continued unimpaired [8]. Subsequent studies were able to establish more precisely that the diaphragm in particular is one structure that exhibits a specific resistance capacity to the effects of NMBAs blockade. These studies illustrate clearly how intraoperative monitoring of relaxation on a certain muscle can only be used as a spot check and the finding is not directly transferrable to other muscle groups. Reasons for this phenomenon have been attributed, among others , to differences in muscle circulation, muscle composition, i.e., to the proportion of slow-twitch (type 1) and fast-twitch (type 2) muscle fibers. Differences in receptor composition and density and temperature fluctuations have also been provided as explanations . The consequences of this for clinical practice are that neuromuscular blockades measured at the adductor pollicis muscle and/or other test muscles do not reflect the muscle relaxation of other muscles, such as those that influence intubation or surgical conditions or that are responsible for respiration or keeping the upper airways free. Our currently available means of neuromuscular monitoring do not allow direct monitoring of these anesthesiarelevant muscle groups. In order to be able to interpret the findings obtained on test muscles correctly, anesthesiologists should be aware of the not insignificant differences in action that NMBAshave on the various muscle groups (a Fig. 2.8). For this reason, the neuromuscular characteristics of each of the

38

Chapter 2 • Principles of neuromuscular monitoring

- Pharyngeal muscles - Masseter muscle - Genioglossus muscles

- Adductor pollicis muscle Abdominal muscles - Orbicularis occuli muscle - Vocal cord muscles - Corrugator supercilii muscle - Diaphragm

a Fig. 2.8. NMBA-specific sensitivity

of various muscle groups. The diaphragm exhibits the lowest and the pharyngeal musclesthe highest sensitivity.

anesthesia-relevant muscle groups will be presented below and compared with the gold standard for neuromuscular monitoring, namely the adductor pollicis muscle.

2.4.1

Diaphragm

The musculomembranous partition separating the abdominal and thoracic cavities is known as the diaphragm. In anesthesia, the diaphragm plays an important role for several key reasons. Firstly, it counts as the major muscle of the respiratory tract, performing approximately 60-80% of the work involved in inspiratory respiration. The diaphragm itself generates a large portion of the functional vital capacity (up to 60%). Secondly, functions that the diaphragm controls, like coughing and bucking, not only critically affect intubation but also have an impact on surgical conditions in general. Espe-

39

2

2.4 . Anesthesia-relevant muscle groups

cially during epigastric procedures, a complete blockade of the diaphragm is an essential prerequisite for creating good surgical conditions. The diaphragm shows the lowest sensitivity to NMBAs (both depolarizing and non-depolarizing NMBAs). Compared with the adductor pollicis muscle, 1.5 to 2 times the NMBA dose is required to achieve complete neuromuscular blockade of the diaphragm. At the same time, because of the relatively high proportion of diaphragmatic circulation on total cardiac output, the NMBA'sonset of action at the diaphragm takes place approx . 60 s earlier than at the adductor pollicis muscle. By contrast, the duration of action and the neuromuscular recovery are up to 20-30% shorter than at the reference muscle.

2.4.2 Laryngeal muscles The muscles of the larynx are made up of the cricothyroid muscle and vocalis muscle, which adjust the tension of the vocal folds, and of the posterior cricoarytenoid, the lateral cricoarytenoid, the thyroarytenoid, the transverse arytenoid and the oblique arytenoid muscles, which open and close the rima glottidis among other functions. A sufficiently deep neuromuscular blockade of the laryngeal muscles is imperative for atraumatic intubation. Moreover and importantly, the laryngeal muscles work together with the pharyngeal muscles and the extrinsic muscles of the tongue and the floor of the mouth to coordinate swallowing. Therefore, sufficient recovery of the laryngeal muscles is essential for ensuring that no postoperative pulmonary aspiration occurs . Similar to the diaphragm, the laryngeal muscles are also more resistant to the effects ofNMBAs than the adductor pollicis muscle. Also, the onset of action here takes place earlier and the duration of action is accordingly shorter than at the reference muscle . 2.4.3 Abdominal muscles In terms of their sensitivity to depolarizing and non-depolarizing NMBAs, the muscles of the abdomen do not differ from those of the extremities. Furthermore, the time profile of neuromuscular blockade is comparable between the two muscle groups.

40

Chapter 2 . Principles of neuromuscular monitoring

2.4.4 Extrinsic muscles of the tongue and floor of mouth

Together with the styloglossus and the hyoglossus muscle, the genioglossus muscles that run from the chin to tongue belong to the extrinsic muscles of the tongue. These muscles attach the hyoid bone to the adjacent osseous structures. Accordingly, their function is to protrude the tongue and the epiglottis. These muscle groups are critical for keeping the upper airways open and for the act of swallowing. Additionally, these muscles also play an important role in the pathogenesis of obstructive sleep apnea. The floor of the mouth muscles include the mylohyoid, geniohyoid and the digastric muscles; this muscle group tautens the floor of the mouth during deglutition and thereby also works to coordinate swallowing. Compared with the adductor pollicis muscle, these two muscle groups the extrinsic muscles of the tongue and the floor of the mouth muscles - react much more sensitivelyto both depolarizing as well as to non-depolarizing NMBAs. Accordingly, the neuromuscular recovery of these muscles lags behind that of the reference muscle.

2.4.5 Pharyngeal muscles

The musculofascial half-cylinder attached above to the base of the skull is called the pharynx, also referred to as the throat or gullet. Muscle forms the outermost and mucosa the innermost layer. Functionally, the pharynx is divided into the superior, middle and inferior constrictor muscles and the longitudinal muscles, e.g. the stylopharyngeus) . At the level of the cricoid cartilage, the pharynx attaches with the top of the esophagus. This is where the respiratory and digestive tract meet, crossing each other in the region called the laryngopharynx, also known as the hypopharynx. When the function of the pharyngeal muscles is impaired, the act of swallowing is also restricted and this state can easily lead to pulmonary aspiration. Like the extrinsic muscles of the tongue and floor of mouth, the pharyngeal muscles react far more sensitively to NMBAs than the adductor pollicis muscle.

2

41

2.5 . Stimulation patterns

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

-

-

-

-

-

-,

The various muscle groups differ in the ir sensitivity to the effect of NMBAs. Therefore, neuromuscular mon itoring on one muscle has the nature of a spot check and is not directly transferrab le to other muscle groups.

-

In part icular, the diaphragm and laryngeal muscles are far more resistant to the action of NMBAs than the adductor po llicis, our reference muscle. Due to the ir good blood circulation, the onset of neuromuscular blockade is earlier in muscles of the extremities.

-

By contrast, the majority of muscle groups involved in the act of swallowi ng react more sensit ively to NMBAs; accord ingly, the ir neuromuscular recovery lags beh ind that of the adductor pollicis muscle. Relevant impairment of the muscles involved in swallowing can occur even though the adductor pollicis muscle shows complete recovery. Insufficient recovery of the extrinsic tongue muscles can lead to inspiratory obstruction of the upper airways. This is also one muscle group that is far more sensitive to non -depolarizing NMBAs than the adductor pollicis muscle.

2.5

Stimulation patterns

The earliest nerve stimulator especially developed to monitor the action of muscle relaxants was presented for the first time in 1958 and was called the »St. Thomas's Hospital Nerve Stimulator « [9). Whereas, back then , the device could only deliver a single twitch, most modern nerve stimulators offer a selection of different stimulation patterns. This feature permits anesthesiologists to monitor each of the clinically relevant phases of neuromuscular blockade, such as onset of action, surgical relaxation, neuromus cular recovery, and to differentiate between depolarization block and non-depolarization blocks. An additional benefit is that the patient's state of relaxation can continue to be monitored on the leu. In this context, the most important stimulation patterns are the single twitch, TOF stimulation, DBS, tetanic stimulation, and what is called the post-tetanic count (PTC). Apart from the single twitch, these stimulation pattern s also occur in combination. The different stimulation modes mainly differ in their stimulation frequencies and in the interval between the in-

42

Chapter 2 • Principles of neuromuscular monitoring

D r ab. 2.2. Recommended application and suitability for assessmentof the different stimulation patterns Stimulation form

Onset of action

Deepneu romuscular blockade

Moderate blockade

Neuromuscular recovery

TOF

Suitable

Unsuitab le

Suitable

Condi· tionally suitab le'

DBS

Conditionally suitable

Suitable

Unsuitable

Conditionally suitable

PTC

Conditionally suitable

Geeignet

Unsuitable

Unsuitable

Tetanus

Ungeeignet

Unsuitable

Unsuitable

Conditionally suitable

Suitable b

(SO/100 Hz)

Deep neuromuscular blockade: TOFcount=O Moderate block : TOFcount >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

Chapter 2 • Principles of neuromuscular monitoring

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

Chapter 2 • Principles of neuromuscular monitoring

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

Double-burst stimulation

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 <0.9 (NPV) - and although the patients showed residual neuromuscular blockade, no more DBS fade was discernable (sensitivity) [16]. Although its predictive power is greater than that of the TOF mode, DBS also apparently tends to overestimate the extent of neuromuscular recovery. Against this backdrop, it is not surprising that more recent studies have confirmed that both the DBS mode and TOF stimulation (at least when fade was assessed by visual or tactile means) are inadequate to exclude residual blockade [17]. 2.5.4

Tetanic stimulation

The concept of using high-frequency tetanic stimuli to reveal incomplete neuromuscular recovery emerged back in the 1970s [18]. Because the findings obtained with DBS and TOF are of limited predictive value - at least when the response is assessed subjectively - the tetanic stimulation mode was proposed several years ago as a possible new way to predict residual blockades.

52

Chapter 2 . Principles of neuromuscular monitoring

Stimulation pattern. Tetanic stimulation is accomplished by applying a high frequency impulse (50-200 Hz), commonly for a duration of 5 seconds. Because the individual stimulatory responses blend together, the investigator only detects one strong, continuous muscle contraction. If the recovery from a non-depolarizing blockade is incomplete, an increase in muscle force is noted initially, followed by marked fade. The higher the frequency of tetanic stimulation, the more pronounced is the fade (D Fig. 2.11). This way, tetanic stimulation should be able to make even low-grade residual blockades discernable. Applications. Tetanus can be used for evaluating neuromuscular recovery. This stimulation pattern is less suitable for monitoring the onset and/or intraoperative time profile of neuromuscular blockade. Tetanic stimulation is painful, and the higher the stimulation frequency is, the more this test hurts the patient. For that reason, this stimulation mode may only be employed on anesthetized patients. At the very most, stimulation frequencies above 100 Hz are reserved for research studies , while 100 Hz is the upper limit under clinical conditions. For current applications, tetanic stimulation is of no major clinical relevance as a stand-alone stimulation pattern, but is only used as a component in the post-tetanic count.

Tetanus (100Hz)

Stimulation (tetanic impulse)

Response (moderate non depolarizing blockade ) D Fig. 2.11. Tetanic stimulation

S3

2

2.S . Stimulation patterns

Strength of findings. The merits of tetanic stimulation have been examined recently in several clinical studies [16, 17, 19]. While the 50-Hz tetanus is no more reliable than the visual or tactile assessment of a TOF, the strength of this stimulation pattern's findings increases at higher stimulation frequencies [17, 19]. For example, its sensitivity after 100-Hz tetanus can reach as high as 74%. The main problem with this stimulation frequency, however, is its low specificity (arab. 2.3). After a 100-Hz tetanus, as few as half of all patients really show no more fade even after complete neuromuscular recovery [16]. Particularly after volatile anesthetics, a pronounced fade can often be observed despite adequate neuromuscular recovery and/or even without prior administration of an NMBA. Regardless of the NMBA's action, the fade observed here is attributable to the effect that volatile anesthetics have on the neuromuscular endplate. Hence, this test has limited accuracy for assessing neuromuscular recovery. Another reaction occurring after tetanic stimulation is called post tetanic facilitation, i.e. a transient exaggerated release of acetylcholine at the endplate. How prominent this presynaptic phenomenon is depends on the duration and intensity of tetanic stimulation. For example, posttetanic facilitation lasts about 3-5 minutes after a 5-second stimulation at 50 Hz. Monitoring should not be undertaken during this period because it would lead to an overestimation of the extent of neuromuscular recovery. Tetanic stimulation is thus not suitable for continuous monitoring of neuromuscular recovery, but only as a spot-check at the end of the surgical procedure.

2.5.5 Post-tetanic count Once again, it was the working group around Iorgen Viby-Mogensen in Copenhagen who advanced this stimulation pattern [20]. Here, the aim was to find a more powerful alternative to TOF for monitoring deep neuromuscular blockades. The post-tetanic count (PTC) stimulation pattern is based on a phenomenon called »post-tetanic potentiation«: Tetanic stimulation induces a transient exaggerated release of acetylcholine which briefly shifts the ratio of acetylcholine and NMBA at the motor endplate in favor of acetylcholine. Even if no twitch had been discern able beforehand, noticeable muscle contractions will occur briefly after tetanic stimulation.

54

Chapter 2 . Principles of neuromuscular mon itoring

Stimulation pattern. The PTC combines a 50-Hz tetanus applied for 5 seconds with 10 to 20 single stimuli of 1 Hz each. The number of single stimuli required depends on the nerve stimulator. The single stimuli start 3 seconds after the end of tetanus (D Fig. 2.12). Two PTC stimulations must be separated by an interval of at least 3 min. Otherwise, the response to the subsequent PTC stimulation may be affected and neuromuscular recovery will be overestimated [21]. A monitoring device is not necessary for measuring PTC; instead only the number of manually or visually detectable single twitches is assessed. In this stimulation mode, the 50-Hz tetanus is not included in the assessment of response, but is only used as a trigger for post-tetanic potentiation. Applications. The PTC is used to monitor deep neuromuscular blockades after administration of non-depolarizing NMBAs. This stimulation pattern is attributed with clinical relevance particularly when it is important to reliably prevent reactions in the resistant diaphragm and/or laryngeal muscles. Epigastric procedures are typical instances where PTC is indicated and where coughing and bucking can easily impair surgical conditions, although a twitch of the adductor pollicis muscle can no longer be detected after TOF stimulation. Consequently, the TOF mode does not allow for titration of the

Tetanus 50Hz

+1-1 3s

Post·tetanic count(PTC)

Response

3

a Fig.2.12. Post-tetanic count (PTC)

SS 2.S . Stimulat ion patterns

2

NMBA to be reinjected, while PTC does permit controlled post-relaxation under such conditions. Overdosage and cumulative effects can thus be avoided. The fact that 12 to 15 responses can be detected after PTC heralds the immediate return of the first TOF response. According to several studies, the PTC mode can also be used to establish the intubation time point and is thus especially suited for use in situations where every reaction on the part of the diaphragmatic or laryngeal muscles to intubation should be avoided [22] Conversely, the phenomenon of post-tetanic potentiation does not occur after the administration of depolarizing NMBAs, which means that the physiological basis for the PTC mode is lacking. Hence, similar to TOF stimulation and DBS, this stimulation pattern is ill suited for monitoring depolarization blocks after succinylcholine. Strength of findings. The PTC is clearly superior to the other stimulation patterns for monitoring deep neuromuscular blockades after administration of non-depolarizing NMBAs. Key points - - - - - - - - - - - - - - - - - - - - - - - - , Nowadays, the single stimuli are only ever used as a component of combined stimulation modes and /or in research studies and have no more clinical relevance as stand -alone stimulation patterns.

TOF stimulation allows the anesthesiologist to assess the onset of action, Intraoperative course and neuromuscular recovery after non depolarizing NMBAs. The basis for this assessment is the TOF count, l.e., the number of detectable stimulatory responses and /or the TOF ratio , l.e.• the ratio of the fourth to the first twitch (TiT1)' Visual and /or tactile evaluation of the TOF ratio overestimates the extent of neuromuscular recovery . Above a TOF ratio of just 0.4. even very experienced investigators assessedall four muscle contractions after

TOF stimulation as similarly intense. DBSIs more suitable than TOF for tactile and/or visual assessment of neuromuscular recovery. However. above a TOF ratio of 0.6-0.7, no fade is discernable with DBSany more either. There is no fade phenomenon after succinylcholine. Thus, neither TOF stimulation nor the DBSmodes are suitable for evaluating depolariza~

tion blocks.

56

Chapter 2 . Principles of neuromuscular mon itor ing

The 50-Hz tetanus is no more reliable in predicting neuromuscular recovery than TOF. Conversely, the essential weakness of the 100-Hz tetanus is its low specificity. -

PTC can be used to monitor deep neuromuscular blockade even in situations where no more response can be detected by TOF. This property has clinical relevance whenever it is paramount to reliably avoid reactions of the resistant diaphragm and/or laryngeal muscles.

2.6

Assessment of stimulatory response

Depending on the type of response assessment, nerve stimulators are classified into two types: »simple nerve stimulators« which only allow a subjective estimation of the muscular response, and »quantitative nerve stimulators- and/or devices that objectively measure the extent of neuromuscular blockade.

2.6.1

Simple nerve stimulators

The se types of neuromuscular transmission monitors can be used to stimulate the target nerve only. Conversely, the ensu ing muscle twitch is exclusively assessed subjectively by the investigato r's senses, whether tactile or visual. Objective measurement is not possible with these nerve stimulators. Therefore, these devices do not need to be equ ipped with a screen; they also feature a more simple design overall and are easier to operate CDFig.2.13). Indeed, they attribute their popularity to the fact that no baseline value needs to be logged prior to administration of the NMBA. Therefore, the se devices can be employed at any point in time during surgery, for example , whenever there is doubt about neuromuscular recovery. The clinical strength of the findings obtained with these simple devices is comparable with the information acquired by quantitative nerve stim ulators, at least in terms of onset of action and intraoperative management of neuromuscular blockade: The complete disappearance of all four stimulatory responses after TOF stimulation can be regarded as the right time for intubation. This time point

57

2

2.6 . Assessment of stimulatory response

a Fig.2.13.A »slmple«, i.e.,qualitativenervestimulator

can also be reliably established without a monitoring device, simply by counting the TOF responses. Deep neuromuscular blockades are usually monitored in the PTC mode until the first TOF response reemerges, while the assessment is based on the number of visually detectable stimulatory responses. Again, no recording device is required, but simple counting of the PTC responses is enough under these conditions . Subsequently, the extent of the non -depolarizing blockade can be described by simply counting the stimulatory responses that are still discernable after TOF stimulation. At the earliest, the effects of intermediate-acting NMBA can be reversed with cholinesterase inhibitors as soon as two of the four TOF responses are detected; after pancuronium, the anesthesiologist must wait for the fourth TOF response before antagonizing. The reappearance of the fourth TOF response counts as the offset of surgical relaxation and is a suitable time for NMBA reinjection. Furthermore, a highly predictable relationship exists between the occurrence of the individual TOF responses and the first objectively measured

58

Chapter 2 . Principles of neuromuscular monitoring

twitch (T 1) . According to the rule formulated by Lee in 1975, the occurrence of the second twitch (T2) corresponds to a 10 to 15% recovery of T I and the occurrence of the TOF fourth twitch (T4 ) a 25% recovery of T, [23]. Krombach et al. confirmed this rule and additionally showed that these values are mostly dose-independent and stay within a narrowly defined 95% confidence interval. The authors reported that the T2 and T4 reappeared at 11±2% and 24±6% recovery of TI' respectively. In their study, the time difference between the first occurrence of T4 and the attainment of a 25% recovery of T I was - 1±2 min [24]. Not only the TOF count, but also the cornerstone information provided by Lee [23] and Krombach et al. [24] allows the anesthesiologist to establish the most feasible time point for NMBA reinjection and/or possible reversal with cholinesterase inhibitors and do so with sufficient accuracy in most routine clinical settings, even using simple nerve stimulators. However, it is in the assessment of neuromuscular recovery that neuro muscular monitoring gains key significance. Whereas our so-called »sirnplenerve stimulators still provide relevant information about the onset of action and/ or the intraoperative duration of the non-depolarizing block, these devices meet their limits, when the task is to reliably detect residual blockades. The performance of simple nerve stimulators in detecting residual neuro muscular blockades was systematically investigated for the first time in 1985 [25). The auth ors found that althou gh the TOF fade was more effectively detected by tactile than visual assessment , even experienced investigators were not able to feel any fade after TOF stimulation above a TOF ratio of 0.5. Thus, a simple nerve stimulator used in the TOF mode did not enable tactile or visual detection of a TOF ratio of 0.7 at the then valid th reshold for sufficient neuromuscular recovery. Since then , the requirements for neuromuscular recovery have indeed risen markedly. At present, a TOF ratio of at least 0.9, measured at the adductor pollicis muscle, is required to exclude the residual effects ofNMBAs, particularly at the more sensitive pharyngeal muscles. Although the DBS mode can better detect a fade in muscular response than TOF, and was sufficient for detecting the threshold of 0.7 in the past, the mere tactile assessment of the DBS responses is much too inadequate to fulfill the current requirement for a threshold of 0.9 [26). Tetanus, the last stimulation mode available for assessing neuromuscular recovery, is similarly ill suited to reliably predict residual blockades. Whereas a 50-Hz tetanus does not yield more powerful results than the tactile assess-

2

S9

2 .6 . Assessment of stimulatory response

ment ofTOF [17], poor specificity is the limiting factor for a 100-Hz tetanus. For example, Capron et al. reported that in 21 of the 32 patients a 100-Hz tetanus could not be maintained for 5 seconds without fade, even after complete neuromuscular recovery [17). This confirms the data of the author's own working group [16). The strength of the TOF stimulation mode is its universal applicability in all phases of a non-depolarizing block. This stimulation mode, with TOF count, is especially suitable for establishing the time to reinject NMBAs and/ or to test whether reversal with cholinesterase inhibitors can already be given. The PTC mode is particularly suited for monitoring deep neuromuscular blockade that can no longer be detected by TOF assessment. This feature has especially great clinical relevance in epigastric procedures. Although superior to the TOF in the subjective assessment of neuromuscular recovery, the DBS mode cannot reliably exclude residual blockades either. In order to achieve optimum monitoring of neuromuscular blockades in the many different clinical situations, an anesthesiologist should be able to apply the following stimulation patterns using a »simple nerve stimulator« (arab. 2.2): - Train -of-four (TOF) stimu lation - Post-tetanic count (PTC) - Double-burst stimulation (DB Key points - - - --

-

-

-

-

-

-

-

-

- - - --

- - ----,

Simple nerve stimulators deliver clinically useful information about the onset of action as well as about the time to reinject NMBAs and /or reversal agents -

Conversely, the stimulation patterns currently available on these de vices do not allow reliable detection of residual blockades by assessing the response using mere tactile or visual means. This fact lim its the ben efits of simple nerve stimulators.

2.6.2 Quantitative nerve stimulators Originally, quantitative nerve stimulators were developed for scientific purposes. Meanwhile, compact , battery-powered, user-friendly devices have become available that are especially designed for clinical applications. Compared

60

Chapter 2 . Principles of neuromuscular monitoring

to the simple models discussed above, the new quantitative nerve stimulators permit the anesthesiologist to objectively measure i.e., to »quantify« the stimulatory response. As a result, the strength of the findings is markedly improved, particularly when it comes to assessing neuromuscular recovery with the TOF mode . Whereas the anesthesiologist is unable to subjectively assess fade starting from a TOF ratio of 0.5 and therefore will markedly overestimate neuromuscular recovery, when used properly, quantitat ive nerve stimulators allow accurate determination of the degree of neuromuscular recovery. Various methods can be employed to objectively measure the depth of neuromuscular blockade. The major ones of note include mechanomyography, electromyography, acceleromyography and kinemyography. Another novel method for quantifying neuromuscular blockade that is currently in the development pipeline is phonomyography.

Mechanomyography Principles. Mechanomyography (MMG) is the only method that directly measures muscle force. Conventionally, the isometri c contractile force of the adductor pollicis muscle is measured after supramaximal stimulation of the ulnar nerve. With the hand supinated, the thumb is abducted at a preload of 2-3 N and restrained in this position. The force transducer is attached in such a way that the force development of the thumb is located exactly along the transducer's axis. The preload and abduction are critical to the accuracy of the measurement. Just the slightest change in the hand's position can significantly alter the preload and/or the degree of abduction. This, in turn, has a disproportionately large effect on the force development. Moreover, the stimulatory response can be potentiated within the first 15 min of supramaximal stimulation. It is not until this point has been reached that the measurement stabilizes. To avoid falsification of the measurement, an appropriately long stabilization phase is therefore recommended prior to administration of the NMBA. This phase can be shortened by tetanic stimulations (50-Hz tetanus for 5 s). After the stabilization phase, the device is recalibrated and the reference value determined. Now, and not before, the NMBA can be injected and the actual measurement started. Applications. The reliability of mechanomyographic measurements is subject to certain technical prerequisites that often cannot be achieved under

61

2

2.6 . Assessment of stimulatory response

clinical conditions. Besides, this measuring method is very time-consuming and prone to malfunction. Neuromuscular monitoring devices based on the principle of mechanomyography are not suited as measuring instruments for routine clinical use, but instead are intended for purely scientific purposes. That is why mechanomyography is normally used to acquire the pharmacodynamic reference data for the respective NMBAs. Furthermore, mechanomyographically acquired data supply the comparators for validating the nerve stimulators intended for clinical use. International research practice guidelines for pharmacodynamic studies of neuromuscular blocking agents, last updated in 2007, provide a detailed description of how mechanomyography should be applied in research studies [3]. Special aspects. This measuring method is only suitable for certain muscle groups, namely, the flexor hallucis brevis and the adductor pollicis muscles. Other muscle groups, like the orbicularis occuli muscle, diaphragm or laryngeal muscles, which may play important roles intraoperatively, cannot be monitored by mechanomyography. Furthermore, this method is limited by the fact that no mechanomyographs have been marketed commercially since production of the »Myograph 2000« biometer was stopped several years ago. And, therefore the use of this method is becoming increasingly rare, even in research studies.

Electromyography Principles. The electrical activity of a muscle is proportional to its force development. As an alternative to the direct measurement of muscle force, electromyography (EMG) can be used to record the electrical activity of the muscle and thus to indirectly quantify neuromuscular blockades. This technique records the compound action potentials produced by stimulation of individual muscles and/or muscle groups in the supply area of a nerve. In addition to the two stimulation electrodes, this method requires another three surface electrodes applied over the insertion and/or the belly of the test muscle to record the action potentials. After stimulation of the associated motor nerve, the evoked electrical response of the individual muscle fibers can be derived and recorded as the integral of the compound action potentials. Typically, electromyographical stimulation is applied in the TOF mode. Here too, the anesthesiologist must wait until the stimulatory response

62

Chapter 2 . Principles of neuromuscular monitoring

has stabilized. Next, the device has to be recalibrated, the baseline value obtained and presented in a graph prior to administration of the blocking agent. With the integration method , the EMG measurement can be output on a recorder that produces an image of each individual TOF response. However, here it should be noted that the integrated EMG signal is not identical to the original EMG signal, but rather represents the result of complex electronic data processing. Accordingly, electromyography is susceptible to electrical artifacts. Overall, however, for assessing the neuromuscular blockade, data captured by electromyography show very good agreement with those obtained by mechanomyographic methods . Applications. Compared to mechanomyography, electromyography does not require complete immobilization or a constant preload of the selected test muscle. This yields direct advantages for practical application. For example, the investigator is not restricted in his choice of test muscle to the adductor pollicis. Indeed, the EMG signals at the abductor digiti minimi muscle can be amplified after stimulation of the ulnar nerve. Neither is it necessary for the hand to be supinated. Basically, electromyographic measurements can be taken with the hand in any position . This feature makes it easier to adapt to the clinical circumstances. In addition to the muscle groups of the hand, an evoked electromyogram can also be recorded on muscles, like the diaphragm, that are not monitorable by mechanomyog raphy. Alongside mechanomyography, electromyography is recognized as a suitable measuring method for research studies. A detailed description of the application of electromyography in research studies can be found in ~ Chapter 4. Overall, electromyography is far less complicated to perform than mechanomyography. Besides promoting use in research studies, this property permits electromyography to also be employed for quantitative neuromuscular monitoring under clinical conditions. Special aspects. The principle of electromyography is based on the direct connection between electrical activity of the muscle and its force development. Consequently, the findings of this method are of limited power as soon as any changes occur in the muscle that affect electromechanical coupling. And, this fact can certainly have clinical implications. For example,

63

2

2.6 . Assessment of stimulatory response

inhibition of the calcium-mediated activation of actin and myosin after administration of dantrolene leads to a dose-dependent electromechanical decoupling, and, as a consequence, the muscle force measured by direct mechanomyography is diminished. However, the depolarization mechanisms at the endplate remain unaffected by the drug's mechanism of action. As a result, the muscle action potential is also unaffected and, therefore, indirect measurement by evoked electromyography will not demonstrate any changes. Thus, mechanomyography and electromyography produce different results under the same clinical conditions. Moreover, if the investigated muscle group gets too cold, this will markedly enhance the response and thereby falsify the measurement. Therefore, it is best to keep the temperature of the investigated muscle group as constant as possible.

Acceleromyography Principles. Acceleromyography (AMG) is based on the piezoelectric effect. This involves generating an electrical current by applying a mechanical force. The piezoelectric effect derives from the phenomenon that electrical charges can be present on the surface of certain materials (mostly crystals). Their electrical current can be measured and provide information about the force. Notably, the piezoelectric effect is utilized for two methods of neuromuscular monitoring, namely acceleromyography and kinemyography. In kinemyography, the electrical current is generated by deformation of a mechanosensor integrated in the piezoelectric element (a Fig.2.14). In acceleromyography, by contrast, the current is induced by acceleration of the piezoelectric element, also called the acceleration transducer (a Fig.2.15). According to Newton's second law, force equals mass times acceleration (F=Mxa) . Given a constant, freely moving mass, the measured acceleration and the evoked potentials can be used to make deductions about the force of the stimulated muscle. Hence, acceleromyography can be performed on muscles whose movement after stimulation is easily measured. Usually, the ulnar nerve is stimulated and the acceleration is subsequently measured with a piezo electrode fixed to the thumb. This allows assessment of the force development of the adductor pollicis muscle. As an alternative, acceleromyography can be applied to the nerve-muscle unit consisting of the posterior tibial nerve

64

Chapter 2 . Principles of neuromuscular monitoring

a Fig. 2.14. Piezoelectricacceleration transducer in kinemyography

a Fig. 2.15.TOF-Watch" hand adapter

6S

2

2.6 . Assessment of stimulatory response

and the flexor hallucis brevis muscle on the foot or the unit consisting of the facial nerve and the orbicularis occuli muscle and/or the facial nerve and the corrugator supercilii muscle in the face. In addition to the force generated in the stimulated muscle, acceleration is similarly affected by the direction of movement against gravity, the initial position and the elastic components of the test muscle investigated. For reliable measurements, the hand must be restrained in a supinated position. Moreover, the thumb may only move in a strictly horizontal direction in order to keep the effects of gravity constant. It was originally required that the thumb move freely. Meanwhile, the recommendation is to measure with a preload, at least in research studies. The reason for this is based on observations that the first twitch after TOF stimulation on the acceleromyograph prior to administration of the NMBA was occasionally much smaller than the subsequent responses and the TOF ratio was thus greater than I! The explanation given for this phenomenon was that the thumb did not return exactly to its starting position during a TOF sequence and, as a result, its resting extension changed before the next TOF stimulation. It took a certain stabilization phase for the elastic components of the nerve-muscle unit to readjust before this phenomenon disappeared again. The advantage of this preload lies in the fact that the thumb always returns back to its exact starting position. As a result, the measurement is less prone to error and a TOF ratio above 1 is no longer observed. Since intraoperative repositioning of patients is not uncommon in clinical practice, e.g. lowering their head or turning them on their side, and the starting position of the thumb can also shift in relation to the patient's position, the use of a preload outside of research studies as well indeed makes sense. This recommendation is particularly apt ever since an accessory part, the TOF-Watch" hand adapter, especially developed for these purposes has become available (a Fig. 2.1 5).

Applications. Acceleromyography was the first measuring method especially developed for quantitative neuromuscular monitoring under clinical conditions [27]. AMG is much easier to use than the previously described quantitative measuring methods (i.e., MMG and EMG). At the same time, it is more precise than qualitative nerve stimulators that only allow subjective assessment of the twitch. In 1994, the TOF Guard was introduced into clinical practice, the first portable, battery-operated device based on the principle

66

Chapter 2 . Principles of neuromuscular monitoring

of acceleromyography. Now, it had become possible to perform objective monitoring routinely in clinical settings. As early as 1997, the TOF-WatchO series was launched as a completely updated and optimized version of these acceleromyography-based nerve stimulators. According to surveys, acceleromyographs are the most frequently employed neuromuscular monitoring devices in Germany. As recent studies have proven, the strength of the findings obtained by acceleromyography is critically dependent on the nature of their application. Certain demands must be placed on the equipment in order to be able to also reliably exclude »minimal« residual blockades and thereby pinpoint with certainty at the end of a surgical intervention the patients in whom reversal of neuromuscular blockade is not necessary. One requirement is calibration of the nerve stimulator - a step that has to be carried out before the NMBA is injected. On the current AMG models, calibration only takes a few seconds, while the reliability of measurement is markedly increased [28]. This means that monitoring should start right at the onset of the neuromuscular blockade and not only for spot checking at the end of the intervention. Finally, as already mentioned, the use of a hand adapter also improves the quality of the results, since this accessory ensures that the thumb returns to its original position after each measurement. Thereby, intraoperative repositioning of the patient no longer affects the starting position of the thumb or the measurement. Special aspects. All current TOF-WatchOneuromuscular transmission monitors can also be used to localize nerves for regional anesthesia procedures. As soon as the designated stimulation cable is connected, the TOF-WatchO nerve stimulators automatically switch to the regional anesthesia program and reconfigure the stimulation parameters to fit the new indication.

Phonomyography Principles. Phonomyography (PMG) records the sounds emitted by a muscle contraction through a condenser microphone applied to the skin's surface. These low-frequency acoustic signals are measured peak to peak between 4 and 6 Hz, where 90% of the frequency spectrum lies between 0 and 50 Hz. The contraction sounds of the muscle are proportional to the force developed. These sounds are amplified, filtered and analyzed algorithmically and plotted on graphs.

67

2

2.6 . Assessment of stimulatory response

Applications. According to reports, phonomyography is straightforward and easy to install and can additionally be used to monitor the different muscle groups. That means that it is possible to simultaneously monitor different muscle groups in one and the same person. Therefore, this method is especially interesting for research studies. While the first studies on this measuring method proved very promising (DTab.2 .4), phonomyography needs further evaluation before any final conclusions can be made about its suitability for monitoring neuromuscular blockade in clinical practice and whether it can be used as a future measuring method within the context of research studies [29,30]. Special aspects. One limitation that should certainly be taken into consideration is that the majority of currently published studies all derive from the same working group and were conducted on a prototype. Demonstration of the method's reproducibility by other investigators is still pending. Similarly, we will also have to wait and see if industry is willing to develop the appropriate devices.

a Tab. 2.4. Comparison of phonomyography versus mechanomyography for measu· ring neuromuscular blockade after mivacurium 0.2 mg/kg. The two measuring me thod s were applied simultaneously in each ofthe 14 patients (3 1).Data are presented as mean (5D) n-14

Phonomyography

Mechanomyography

Onset t ime lsl

217 (66)

216 (70)

Maxima l effect ['l&)

97 (3)

96 (4)

TOFo2s [mi n)

28 (6)

29 (7)

TOFo.s [m in )

31 (9)

32 (8)

TOFo.7S(min]

40 (12)

376 (11)

TOFo.9 [min )

51 (14)

53 (14)

Onset t ime : Interval between injection of NMBA and maximum blockade. Maximal effect: maximal T1 blockade; TOFo.2S : Interval between injection and a 0.25 TOF rat io recovery; TOFo.s: interval between injection and a 0.5 TOF ratio recovery;TOF o.7S: interval between injection and a 0.75 TOF ratio recovery ; TOFo.9 : interval between injection and a 0.9TOF rat io recovery.

68

Chapter 2 . Principles of neuromuscular monitoring

Kinemyography Principles. Like acceleromyography, kinemyography is also based upon the piezoelectric effect (for more details, see »Principles« under Acceleromyography). As discussed above, the piezoelectric principles are utilized by both monitoring methods. Unlike acceleromyography, where the electrical current is generated by acceleration, in kinemyography, the electrical current is generated by deformation of a mechanosensor that contains an integrated piezoelectric element (D Fig. 2.14). Kinemyography measures the electrical current generated after deformation of the mechanosensor. Hence, acceleromyography and kinemyography are two different measuring methods that are both based on the same physical principle. Nonetheless, the data captured by these two methods are not directly comparable. The mechanosensor consists of a molded plastic device that is placed into the groove of the thumb and index finger; no additional restraint of the hand is necessary. Stimulation of the ulnar nerve triggers adduction of the thumb which in turn causes deformation of the mechanosensor. A neuromuscular transmission (NMT) module measures the electrical current generated during this process. Essentially, the hand can be placed in any position as long as it does not impair movement of the thumb or subsequent deformation of the mechanosensor. In contrast to the other methods , strict supination of the hand is not necessary. Applications. The NMT module marketed by GE Healthcare is based on the principle of kinemyography. This method of neuromuscular monitoring is available for routine clinical application. Given that fact, it is surprising that information about the measuring accuracy of this method is so sparse. Dahaba et aI. compared the NMT module using the Relaxometer" mechanomyograph as reference method [31]. In a total of20 patients, the neuromuscular block after a standard dose of rocuron ium (0.6 mg/kg equivalent to twice the ED95) was monitored by kinemyography on one of the patients' hands and by mechanomyography on the other hand . The two devices were synchronized to make the time intervals directly comparable. Although the data on neuromuscular recovery produced in this study were comparable for the two measuring methods, the clinical duration of action was significantly different (Drab.2.5). More recent data published by Trager et al., albeit on just 14 patients, confirm the good agreement of the two methods for assessing neuromuscular recovery [32]. Additional comparative studies would be

69 2.6 . Assessment of stimu latory respo nse

a Tab. 2.5. Comparison of kine myography versus mechanomyography in neuromuscular blockade after rocuronium 0.6 mg/kg; the two monitoring methods were applied simultaneously on each of the 20 study patients [31]. Data are presented as mean (SO)

n 20

K1nemyography

Mechanomyog

Onset time ls]

90 (18)

108 (36)

OUR,o[m in]

21.8 (6.7)

15.9 (5.2)"

DUfn [min ]

25.6 (8)

20.2 (6.3)"

Interval n _7S [min]

10.8 (8.4)

9.5 (3.7)

Interval '0-90 [m in]

20.4 (18.2)

17.6 (7.2)

Int erval,s..:>.. [m in]

23.1 (15.1)

30.3 (19)

TOFo.a[m in)

49.4 (8.1)

50.9 (9.9)

Onset t ime : interval between NMBA inject ion and maximal blockade ; DURlO: interval between injection and recovery of T, to 10% of baseline; DUR25: interval between injection and recovery ofT, to 25% of baseline; interval,s _75: Interval between 25% and 75% recovery ofT,; interval lO_90 : interval between 10% and 90% recovery ofT,; interval,~.8: interval between 25% recovery ofT, and a TOF ratio of 0.8;rOF 0.8: interval between injection and a recovery of the rOF ratio to 0.8;

*: P <0.05.

useful for better assessing the strength of findings obtained by kinemyographic methods in terms of the time-profile of neuromuscular blockade. According to the manufacturer, a special size is available for neonates and infants (PediSensor) in addition to the one-size-fits-all mechanosensor for adults. This begs the question whether the mechanosensor is truly made to fit every patient properly. And, the only muscle that can be monitored intraoperatively by current devices is the adductor pollicis muscle. Therefore, it should be noted that this method is not suited for procedures where the arms have to be immobilized on the body, because the patient's hand will not be freely accessible. Special aspects. The NMT module is one of the few devices that permits neuromuscular blocks to be monitored as part of an »integrated solution «. The kinemyograph is not a stand-alone unit, but is integrated into a monitor-

2

70

Chapter 2 • Principles of neuromuscular mon itoring

ing system. The data on the neuromuscular blockade are displayed on the actual patient's monitor together with the other intraoperatively monitored parameters. In addition, alarm limits can be defined, e.g. which signal secondary relaxation as soon as two of the four TOF responses are detectable. The NMT module additionally features a selection of stimulation modes: TOF, single twitch, DBS and PTe. Key points - - - - - - - - - --

-

-

-

-

-

-

-

-

-

-

---,

Quantitative nerve stimulators can be used to objectively measure the stimulatory response and , in particular, improve the reliability ofTOF stimulation for assessing neuromuscular recovery. -

Mechanomyography is the gold standard for objective neuromuscular monitoring. However, this measuring method is reserved for scientific purposes.

-

Besides its use in research studies, electromyography can also be used for neuromuscular monitoring under clinical conditions with some caveats.

-

Acceleromyography was specifically developed for routine clinical quantitative neuromuscular monitoring. It is easy to use and delivers reliable results .

-

Both kinemyography and acceleromyography are based on the piezoelectric effect. To date, only a limited number of comparative studies have been conducted on kinemyography. Phonomyography measures the contraction sounds a muscle emits and thereby delivers information about the muscle's force. It remains to be seen whether this experimental approach can be turned into marketable products.

References Helbo-Hansen HS, Bang U, Kirkegaard Nielsen H, Skovgaard LT (1992) The accuracy of train-of-four monitoring at varying stimulating currents. Anesthesiology 76:199-203 2 BaillardC, Bourdiau5, LeToumelinPet al (2004) Assessing residual neuromuscularblockade can be deceptive in postoperativeawakepatients. AnesthAnalg 98: 854-857 3 Fuchs-Buder T,Claudius C, Skovgaard LT, Eriksson L1, Mirakhur RK, Viby-Mogensen J (2007) Good clinical research practice in pharmacodynamic studies of neuromuscularblocking agents II: the Stockholmrevision. Acta Anaesthesiol Scand 51: 789-808

71 References

4

Brull SJ, Silverman DG (1995) Pulse Width, Stimulus Intensity, Electrode Placement , and Polarity dur ing assessment of neuromuscular block . Anesthesiology 83: 702-709

5 Plaud B, Debaenne B, Donat i F (2001) The corrugator supercilii, not the orbicularis occuli , reflects rocuron ium neuromuscular blockade at the laryngeal adductor muscles. Anesthesio logy 95: 96-101 6

Brodie BC (1811) Experiments and observations on the different modes in which death is produced by certain vegetable poisons . Philos Trans R Soc 101: 194-195

7 Fuchs-Buder

T.

Eikermann M (2006) Neurornuskulare Restblockaden : Klinische Konse-

quenzen, Haufiqkeit und Vermeidungsstrategien. Anaesthesist 55: 7-16 8 Gal TJ,Smith Te (1976) Partial paralysis with d-tubocurarine and the ventilatory response to C02: an example of respiratory sparing? Anesthesiology 45: 22-28 9 Christ ie TH, Churchill-Davidson HC (1958) The St. Thomas's Hospital nerve stimulator in the diagnosis of prolonged apnoea . Lancet 12: 776-780 10 Eikermann M, PetersJ (2004) Nerve stimulation at 0.15 Hz when compared to 0.1 Hz speeds the onset of action of cisatracurium and rocuronium. Acta Anaesthesiol Scand 44: 170-174 11 Ali HH, Utting JE, Gray C (1970) Stimu lus frequency in the detection of neuromuscular block in humans . Br J Anaesth 42: 967-978 12 Viby-Mogensen J, Jensen NH, Engbaeck J, Ording H, Skovgaard LT, Chraernmer -Jerqensen B (1985) Tactile and visual evaluation of the response to train-of-four nerve stimulation. Anesthesiology 63: 440-443 13 Pedersen,T,Viby-Mogensen J, Bang U, Olsen NV, Jensen E, Engboek J (1990) Does perioperative tactile evaluation of the train-of-four response influence the frequency of postoperat ive residual neuromuscular blockade? Anesthesiology 73: 835-839 14 Engbaek J, Ostergaard D, Viby-Mogensen J (1989) Double-burst stimu lation (DBS): a new pattern of nerve stimulation to identify neuromuscular block . Br J Anaesth 62: 274-278 15 Jain AK, Sharma PK,Bhattacharya A (1995) Double-burst stimulation for mon itoring neuromuscular blockade for tracheal int ubati on. Anaesthesia so: 23-25 16 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 17 Capron F, Fortier Lp' Racine 5, Donati F (2006) Tactile fade detection with hand or wrist stimulation using train-of-four, double-burst stimulation, SO-Hertz tetanus, 100-Hertz tetanus, and acceleromyography. Anesth Analg 102: 1578-1584 18 Tassonyi E (1975) A new concept in the measurement of neuromuscular transmission and block . Anaesthesist 24: 374-377 19 Baurain M, Hennart SINCE, Godschalx A, Huybrechts I, Nasrallah G, d'Holiander AA, Cantraine F (1998) Visual evaluation of residual curarisation in anesthetized pat ients using one hundred-hertz, five-second tetanic stimulation at the adductor pollicis muscle. Anesth Analg 87: 185-189 20 Viby-Mogensen J, Howardy-Hansen

p.

Chraemmer-Jorgensen B, Ording H, Engbaek J,

Nielsen A (1981) Post-tetanic count (PTe): a new method of evaluat ing an intense nondepolarizing neuromuscular blockade. Anesthesiology 55: 458-461 21 Motamed C, Kirov K, Combes X, Duvaldest in P (2005) Does repetition of post-tetanic count every 3 min du ring profound relaxation affect accelerographic recovery of atracurium blockade? Acta Anaesthesiol Scand 49: 811-814

2

72

Chapter 2 • Principles of neuromuscular monitoring

22 Ueda N, Muteki T,Tsuda H, Masuda Y,Ohishi K, Tobata H (1993) Determining the optimal time for endotracheal intubation during onset of neuromuscular blockade. Eur J Anaesthesiol 10: 3-8 23 Lee CM (1975) Train-of-four quantitat ion of competitive neuromuscular block . Anesth Analg 56: 649-653 24 Krombach J, Krieg N, Diefenbach C (1999) Zuverlassiqkeit and Dosisabhanqiqke it des Train-of-Four Count [Accuracy and do se dependency of the train-of-four countl, Anaesthesist 48: 519-522 25 Viby-Mogensen J, Jensen NH, Engbaek J, Ording H, 5kovgaard LT, Chraernmer-Jerqensen B (1985) Tactile and visual evaluat ion of the response to train-of-four stimulation. Anesthesiology 63: 440-443 26 Drenck NE, Ueda N, Olsen NV,Engbaek J, Jensen E,5kovgaard LT, Viby-Mogensen J (1989) Manual evaluation of residual curarization using double-burst stimulation: A comparison with train-of-four. Anesthesiology 70: 578-581 27 Jensen E, Viby-Mogensen J, Bang U (1988) The accelerograph : a new neuromuscular transmission monitor. Acta Anaesthesiol 5cand 32: 49-52 28 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 29 Bellemare F, Couture J, Donati F, Plaud B (2000) Temporal relation between acoustic and force response at the adductor pollicis during nondepolarizing neuromuscular block. Anesthesiology 93: 646-652 30 Hemmerling TM, Michaud G, Trager G, Deschamps 5 (2004) Phonomyographic measurement of neuromuscular blockade are similar to mechanomyography for hand muscles. Canadian Journal of Anaesthesia 51: 795-800 31 Dahaba AA, of Klobucar F, Rehak HP, List WF (2002) The neuromuscular transmission module versus the relaxometer mechanomyograph for neuromuscular block monitoring. Anesthesia Analgesia 94: 591-596 32 Trager G, Michaud G, Deschamps 5, Hemmerl ing TM (2006) Comparison of phonomyography, kinemyography and mechanomyography for neuromuscular monitoring . Canadian Journal of Anesthesia 53: 130-135

3

Clinical application

3.1

Neuromuscular monitoring during anesthesia induction - 76

3.1.1

Neuromuscular blocking agents for anesthesia induction? - 77

3.1 .2

Test muscles and stimulation patterns

3.1.3

What level of neuromuscular block for intubation?

3.2

Intraoperative application of neuromuscular monitoring - 90

3.2.1

Accumulation of NMBAs

3.2.2

Stimulation patterns and test muscles

- 82

- 91 - 95

3.3

Monitoring neuromuscular recovery

3.3.1

Pathophysiological implications of residual

3.3.2

Frequency of residual neuromuscular blockade

3.3.3

Clinical implications associated with residual

3.3.4

Stimulation patterns and test muscle

3.3.5

Prevention strategies for residual neuromuscular

neuromuscular blockade

neuromuscular blockade

blockade

- 114

References

- 120

- 87

- 97

- 98

- 108 - 110

- 106

74

Chapter 3 • Clinical application

In 1942, Griffith and Johnson introduced the first muscle relaxant into clinical practice. Its chemical name was d-tubocurarine, the active component isolated from curare [1]. D-tubocurarine is a non-depolarizing relaxant with a long duration of action. This drug was still used up until the early 70s, before it was finally replaced by pancuronium. In March 1967, Ronald 1. Katz published the results of his own investigations into the neuromuscular action of d-tubocurarine [2]. He injected 100 patients each with 0.1 mg/kg of d-tubocurarine - 0.5-0.6 mg/kg being the typical intubation dose at that time - and then measured the maximum muscle-blocking effect by mechanomyography. Despite the reduced curare dose, 7 of 100 patients developed a complete neuromuscular blockade, whereas 6 patients showed no measurable neuromuscular effect at all. Between these two extremes, all intermediate stages were observed (DFig.3.1). The same study showed that a dose elevation reduced the variability of the onset profile: in all patients studied, 0.3 mg/kg d-tubocurarine led to a 90 to 100% block. Nevertheless, marked fluctuations in the clinical duration of action were evident. Given the huge variability observed, the action of d-tubocurarine was ultimately not predictable in individual patients! This result has a myriad of consequences for clinical application: - Variability in block onset can influence intubating condition s. _ Different durations of action can lead to an accumulation of NMBA, particularly when the NMBA is reinjected at set time intervals. - Individual differences in neuromuscular recovery are associated with the risk of residual blockade. Marked variability, though , is not restricted to d-tubocurarine. Despite improved control, the pharmacodynamic action of our modern NMBAs is similarly subject to more or less pronounced individual fluctuations and the predictability of these fluctuations in the individual patient tends to be limited as well. This statement applies both to non-depolarizing drugs and to succinylcholine. For example, Levano et ai. reported , among others, on one female patient who was given 1.5 mg/kg succinylcholine for rapid-sequence induction before a cesarean delivery. Due to the reduced enzymatic activity of her plasma cholinesterase, however, it took 5 hours before the first signs of neuromuscular recovery could be detected [3]. Likewise, the effect of mivacurium is directly affected by the activity of plasma cholinesterase. One case to be mentioned here is that of a 52-year-old

3

75 Chapter 3 • Clinical application

0 .1 mg/kg dTC 16 14 12

:s

10

ell .;;

S

'" C IQ

Q.

6 4 2 0 0

1-10 11-20 21-30 31-40 41-50 SHiO 61·70 71·80 81-90 91-99

100

Death of the neuromuscular blockade (%)

a Fig. 3.1. Depth of the neuromuscular block after 0.1 mg/kg d-tubocura rine (dTe) [2]. X-axis: Siock depth in percent (O=no measurable neuromuscular block; 100=complete blockade. Yaxis: Number of patients.

woman who was originally scheduled to undergo an outpatient arthroscopy but had to be postinterventionally ventilated on the leu because of prolonged neuromuscular blockade after mivacurium . Intraoperatively, she had received a total of 18 mg mivacurium; 6 hours later she showed the first signs of neuromuscular recovery; 12 hours later it was possible to extubate her. Afterwards, the laborator y workup revealed that her total plasma cholinesterase activity was 1859 UII (reference range: 2800-7400 U/I) and the dibucaine number was 19 (reference range: 80-100) [4). Following administration of 0.1 mglkg cisatracurium (equivalent to twice the ED9s ) ' it took an average of 4-5 minutes for the onset of action to be complete. Depending on the study, the standard deviation ranged from 60 to

76

Chapter 3 • Clinical application

120 seconds. Individual patients can take up more than 7 minutes to reach complete onset of action after this dose of cisatracurium. Hence, the individual onset profile during anesthesia induction is not truly predictable [5]. According to Debaene et al., the incidence of residual neuromuscular blockade may to be as high as 37% even 2 h after a single intubation dose of an intermediate-acting NMBA and without any intraoperative re-injection of another bolus of the muscle relaxant [6]. This gives us yet another idea about the great interindividual variability that the action ofNMBAs can have. In this study, it did not matter whether vecuronium, rocuronium or atracurium were used as the representative NMBA. The reasons for this great variability were multifactorial. In addition to impaired renal and/or hepatic function, other variables like gender, age, body temperature, concomitant diseases, long-term medication, anesthesia technique and genetic predisposition played a role. Lately, the advent of medical devices for monitoring anesthesia depth has brought to the fore the fact that the action of hypnotics and anesthetics is also subject to great individual variability and shows similar unpredictability in the individual patient. The same applies to innumerable analgesics [7, 8]. Accordingly, most drugs used in anesthesia can indeed be expected to exhibit a more or less pronounced interindividual variability. Unlike hypnotics and analgesics, however, the action of NMBAs is easy to monitor and can be adjusted to meet the individual's need by subsequent injections; any potential re-curarization NMBAs may cause at the end of the intervention can be reversed. This permits the anesthesiologist to manage the pharmacodynamic action of non -depolarizing NMBAs, despite their great variability, and to adapt their effects as needed to the specific situation. For that reason, the action of NMBAs should be monitored as a routine course. This edict is valid even in cases where only a single intubation dose of the relaxant is used and the time interval between intubation and extubation is long. The following section will describe in detail how to apply neuromuscular monitoring during anesthesia induction to manage intraoperative NMBA reinjection and neuromuscular recovery.

3.1

Neuromuscular monitoring during anesthesia induction

Despite identical intubation doses of NMBAs, pronounced differences in onset time and maximal effect are observed as a result of their interindividual

77

3

3.1 . Neuromuscular mon itoring

variability of action . In such situations, neuromuscular monitoring not only lets the anesthesiologist monitor the individual onset of the NMBA's action, but also provides valuable information for optimally timing intubation. In this context, two questions are of clinical interest: - Can the use of neuromuscular monitoring during induction expedite the intubating time and thereby allow earlier intubation? - Can the use of neuromuscular monitoring during induction reliably prevent adverse reactions to intubation like coughing? Before exploring these two questions in greater depth, we will elucidate the merits of NMBAs in facilitating intubation. 3.1.1

Neuromuscular blocking agents for anesthesia induction?

Whether or not NMBAs are at all necessary for facilitating intubation is occasionally the subject of controversial debate. Adequate anesthesia depth, suppression of pain and reflexes as well as muscle relaxation are all essential prerequisites for atraumatic endotracheal intubation. In order to achieve these conditions fast and reliably,a balanced technique consisting of a shortacting i.v, hypnotic, an opioid and a NMBA are usually administered. When this strategy is applied, the dose of each of the drugs can be reduced and, in turn, their side effects minimized. Since NMBAs were introduced into clinical anesthesia, techniques that claim to create good intubating conditions without NMBAs have been described on a regular basis. Lewis pioneered the first relaxant-free induction technique back in 1948when he published a series of200 elective intubations after injection of thiopental alone, i.e., without any further assistive measures such as inhalat ion anesthet ics or NMBAs. He described the application of this method as safe, reliable and generally applicable [9]. In retrospect, however, his concept did not become established in clinical practice. With every new i.v. hypnotic developed, renewed speculation emerges as to whether it has now become possible to create adequate intubating conditions that obviate the use of NMBAs. At the beginning, several authors even proposed propofol as a mono -drug for intubation [10]. However, it soon became clear that rapid -onset opioids like alfentanil or remifentanil improve intubating conditions after propofol provided that they administered as suf-

78

Chapter 3 . Clinical application

ficiently high doses. Scheller et al. proposed up to 60 fig/kg alfentanil and Grant et al. up to 2 fig/kg remifentanil [11, 12]. It was moreover shown that higher doses of propofol had to be given when administered in conjunction with a relaxant-free induction technique. Baillard et al. determined that 2.7 mg/kg of propofol are needed, setting a 95%-confidence interval of 2.33.3 mg/kg when the drug is administered together with opioids and NMBAs as part of a balanced induction strategy [13]. When, however, the muscle relaxant was spared, much larger doses of propofol were necessary.The mean became 3.6 mg/kg and the 95% confidence interval ranged from 2.9-4 .5 mg/kg [13]. Sparing muscle relaxants meant that both the i.v. hypnotic, typically propofol, and the opioid had to be dosed significantly higher, which, in turn invariably led to an increase in hemodynamic side effects and/or an elevated demand for vasopressors during induction. The authors concluded that, although this dose regimen can often be used to accomplish intubation, intubating conditions will nevertheless be better if the chosen induction sequence concept includes a muscle relaxant [14]. The quality differential in intubating conditions has direct implications for the patient. Data obtained by our own working group proved that the frequency of postoperative hoarseness and vocal cord injuries is directly impacted by intubation quality [15]. The better the intubating conditions, the rarer is the frequency at which these complications are observed . Conversely, insufficient abduction of the vocal cords during intubation and/or coughing as a reaction to the irritation caused by intubation, in particular, significantly elevates the risk for postoperative hoarseness or vocal cord injury. In other words, one out of three patients intubated without relaxants will sustain vocal cord injuries or suffer postoperative hoarseness merely as a result of this induction technique (DTab.3.l) . In individual patients, these two complications can persist for several weeks and are highly sensitive factors adversely affecting postoperative satisfaction of the patients (DFig.3.2). These results have meanwhile been confirmed by other working groups. A recent publication addressed one aspect that has mostly gone unnoticed thus far [16]. The author s of that study investigated whether the use of muscle relaxants facilitated intubation or whether the reverse was true , i.e. that not using a muscle relaxant encumbered intubation (DTab.3.2). The patients' intubation difficulties were rated according to a validated score. The »intubation difficulty scale« (IDS) was based on seven parameters, including the number of intubation attempts, the number of alternative techniques used and the

3

79 3.1 . Neuromuscular monitoring

a Tab. 3.1.Incidence of postoperative hoarsenessand vocalcord injury [151 TIme of assessment

Hoarseness

Vocalcord Injury

MRgroup n=37

Placebo n=36

P

MR9roup n=37

Placebo n=36

RR

6

13

0.1

n.i,

n,l,

24h

0

6

0.01

3

15

48h

0

4

0.05

n.l,

n,l,

72h

0

0.5

>72h

0

0.5

Patients

6

0.02

16

P

0.002

8

0.014

0

2

0.25

3

15

0.002

MRgroup: Patientsintubated using muscle relaxant (MR); Placebo: Patientsintubated without MR. Patients: Numberof patientswith hoarsenessand/or vocalcord injury MR, Muscle relaxant; RR, Recovery room; n.i, not investigated.

a Fig. 3.2. Inj ury to the right vocal fold

SO

Chapter 3 • Clinical application

a

Tab. 3.2. Intubating conditions after anesthesia induction with andlor without muscle relaxant (16) Parameter

Induction technique NMSA-free

Rocuronlum

117

137 11 2

Int ubation attempts 1 Attempt 2 Attempts 3 Attempts 4 Attempts

13 16 4

0

Number of operators 1 operator 2 operators

140

147

10

3

146 4

0

Number of alternative techn iques 0 1

150

Cormack grade I: Vocal cords are visible ; II: Vocals cords are only partly visible III: Only the ep iglottis is seen IV:The epiglottis cannot be see

91 41 17 1

106 5 0

103 47

126 24

41 109

52 98

39

Force applied during laryngoscopy Normal Increased _SURP. No Yes Position of vocal cords Abducted Adducted

117

140

33

10

IDS score > 5

lS /150

11150

81 3.1 . Neuromuscular monitoring

3

Cormack grade [17]. An IDS ~5 was defined as difficult intubation [17] In the relaxant-free group, 20 of the 150 patients required three or four intubation attempts and 18 patients had a Cormack grade ~ III. In the group of 150 patients intubated by the same induct ion technique but this time with the addition of rocuronium, there were two who could not be successfully intubated until the third attempt; none of them required four intubation attempts. Furthermore, five patients in the rocuronium group were classified as Cormack grade III, while none of the patients in this group were Cormack grade IV [16]. In the group of patients intubated without using muscle relaxants, 18 of 150 scored an IDS > 5, whereas only one single patient reached this score in the group with muscle relaxants (p < 0.05)!

o

NMBAs facilitate intubation and improve intubating conditions.

The result was not only statistically significant, but above all, clinically relevant. In other words, individual patients might be classified wrongly as »difficult to intubate «, along with all the implications associated with any future anesthesias they may receive. And all that, merely due to the fact they were once intubated using a relaxant-free induction technique. Indeed, there may be justified cases where intubation without muscle relaxants may indeed pose a judicious alternat ive. Nonetheless, should the results described above be confirmed by further studies, we should start questioning the merits of relaxant-sparing techniques for anesthesia induction even more scrupulously than we have thus far. Key points - - - - - - - - - - - - - - - - - - - - - - - , -

Together with i.v, hypnotics and opioids, NMBAs belong to the standard arsenal of a balanced inducti on strategy . Therefore. muscle relaxants for endotracheal intubation may be omitted only in just ified except ions. If the patient is intu bated without a muscle relaxant. the dosage of op loids and hypnotics must be increased substantially to prevent react ions to the irritati on caused by int ubati on. This regimen directly increases the rate of hemodynamic events. Intubation w ithout relaxant markedly increases laryngeal morbidity. Both the incidence of postoperative hoarseness and direct injury to the vocal cord rises significantly. Moreover, initial. well -founded evidence is gathering that relaxant -free intubation is also associated with a markedly higher incidence of intubation difficulties.

82

Chapter 3 . Clinical applicat ion

3.1.2 Test muscles and stimulation patterns

Test muscles Which muscle is most suitable for monitoring the onset of action of NMBAs? Some authors have proposed the mimic muscles of eye, specificallythe orbicularis oculi and/or the corrugator supercilii muscle. These recommendations are based on evidence that the time course of neuromuscular blockade at these two muscles is similar to that of the diaphragm and vocal cord muscles and they are therefore better suited as test muscles than the adductor pollicis to determine the optimum time for intubation [18]. Studies by Debaene et al. confirmed this observation [19]. His group investigated the intubating conditions after the usual intubation dose (twice the ED9S) of an intermediateacting muscle relaxant in 30 patients. Intubation was performed when either the adductor pollicis muscle (n=15) or the orbicularis oculi (n=15) was completely blocked. Intubating conditions, which were mostly excellent or good, were comparable in the two groups. According to this study, however, complete onset of action of the muscle relaxant was noted at the orbicularis oculi muscle an average of 1.2 minutes earlier than at the adductor pollicis muscle, meaning that the patients in this group could be intubated earlier. One limitation should be mentioned though: the intubating conditions were poor in two patients of each group, despite the use of neuromuscular monitoring. Likewise, Rimaniol et al. [20] reported a faster onset time at the orbicularis oculi muscle compared with the adductor pollicis muscle. For both atracurium and vecuronium, these differences were just 30-40 seconds and thus markedly smaller than in the aforementioned study by Debaene. In contrast, these data have not been confirmed by more recent studies. Larsen et al. [21] even reported an average 30 seconds longer onset time after vecuronium at the orbicularis oculi versus the adductor pollicis. Lastly, Plaud et al. [22] compared the onset of action of 0.5 mg/kg rocuronium at the adductor pollicis, orbicularis oculi and corrugator supercilii muscles, respectively. They found that the corrugator supercilii muscle was much more resistant to the action of the muscle relaxant than the two other muscles were. The mean maximum block at the corrugator supercilii was only 80% (coefficient of variation: 37-96%) compared to 100% (coefficient of variation: 97-100%) at the adductor pollicis muscle and 93% (coefficient of variation: 77-100%) at the orbicularis oculi muscle.

3

83 3.1 . Neu ro m uscu lar monitoring

This was yet another study where the onset at the adductor pollicis muscle was much quicker than at the two investigated mimic muscles: 83±28 s at the adductor pollicis muscle versus 218±78 s at the orbicularis oculi muscle and 194±59 s at the corrugator supercilii muscle (a Fig.3.3). Complete block was observed at the orbicularis oculi an average of 2 (!) minutes later than at the adductor pollicis. These differences were not only statistically significant, but also clinically relevant in that they put into question the concept that mon itoring at the mimic muscles can dictate the earliest possible time at which optimum intubating conditions prevail. Lastly, Koscielniak-Nielsen et al. [23] compared four different concepts to estimate the timing of tracheal intubation after twice the ED95 of vecuronium : by neuromuscular monitoring either at the adductor pollicis muscle or at the orbicularis oculi muscle or after waiting a set period of 3 and 4 minutes . When the timing for intubation was estimated at the orbicularis oculi muscle, the first patients could be intubated after just 100 s. In some

250

200

II)

150

"0

c: 0

o

c71

100

50

0

CS

AP

00

a Fig. 3.3. Onset of rocuronium blockade (0.5 mg/ kg) at various muscles [22]. CS, Corrugator supercilii; Ap,Adductor po llicis; 00. Orbicularis oculi

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Chapter 3 • Clinical application

30

D

• •

25 20 15

Not po ssibl e Poor Satisfactory Good

5

00

AP

3 Minutes

4 Minutes

a Fig. 3.4. Timing of tracheal int ubation at various test muscles or after a fixed time interval [23]. Intubating condit ions using four different methods to estimate the intubati on time. Group 1: Intubated at cessation of response to TOFstimulation at the orbicularis oculi; Group 2: Intubated at cessation of TOF response at the adductor poll icis; Group 3: Intubated after waiting a fixed time of 3 min; Group 4: Intubated after waiting a fixed time of 4 min. The intubating condit ions did not differ among the four groups. Intubating condit ions: 8-9: good, 6-7: satisfactory, 3- 5: poor, 0-2 : not possible

patients, however, it took up to 400 seconds before loss of response to trainof-four stimulation occurred. In this group, an average of 185 s elapsed before intubation. By contrast, the time to intubation in patients in whom the adductor pollicis was selected as test muscle took an average of 225 s (range 130-360 s). Even when the intubation timing was personalized, the intubating conditions did not improve whatsoever over the other two groups where all patients were intubated after a fixed interval of 3 or 4 min . In conclusion, the four groups did not differ in terms of intubating conditions. According to this study, monitoring at the orbicularis oculi muscle and intubation after a fixed time interval of 3 min were equally suited to estimate the timing for intubation after 0.1 mg/kg vecuronium (aFig.3.4). These data clearly show that there are currently no convincing arguments that favor giving preference to the orbicularis oculi or corrugator supercilii muscles over the adductor pollicis muscle as test muscles for intubation timing. If, in spite of the above, the anesthesiologist still chooses one of the two

85

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3.1 . Neuromuscular monitoring

mimic muscles, then the use of a quantitative nerve stimulator will yield at least one crucial disadvantage: they must switch test muscles over the further course of neuromuscular blockade and go back to the adductor pollicis. This is because neither the corrugator supercilii nor the orbicularis oculi are suitable for correctly assessing neuromuscular recovery. When the test muscles are switched, the initial calibration is lost. This situation does not allow recalibration since the nerve stimulator can only be calibrated prior to NMBA administration. As a result, after switching test muscles, neuromuscular block monitoring can only proceed with the uncalibrated stimulator, and that also means with acquired data that are no longer valid for reliably detecting any residual blockade. Hence, when performing quantitative neuromuscular monitoring with devices like the TOF Watch, the anesthesiologist must stick with the test muscle that was originally selected, and, therefore, has no choice but to select the adductor pollicis muscle right from the start.

o

The initial calibration data are lost when test muscles are SWitched. Therefore. it is recommended. to select a test muscle that can be used continually throughout the procedure. Key points - - - - - - - - - - - - - - - - - - - - - - - , -

Neither the orb icularis oculi nor the corrugator supercilii muscl es are superior to the adductor pollicis muscle for t iming int ubati on. When quantitative nerve stimulators are used, it is not recommended to switch test muscles intraoperatively as this causes the initial calibra tion data to be lost. Therefore. the adductor polli cis muscle should be selected as test muscle right from the start .

Stimulation patterns Typically, the TOF mode is used to determine the time for intubation. Accordingly, intubation can be initiated as soon as a pronounced fade is noted and/or loss of TOF response occurs. This method is simple and usually proves adequate in clinical practice. There are clinical situations, such as in patients with open eye injuries, where it is not merely good, but paramount to have perfect intubating conditions. The TOF mode comes up against its limits in situations where it is mandated that every potential reaction to irri-

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Chapter 3 • Clinical application

tation by intubation be reliably avoided. Under such circumstances, the DBS appears to be the more suitable mode [24]. In a total of 199 patients, Ueda et al. [24] investigated the intubating conditions after an intubation dose of vecuron ium (twice the ED9S) ' Intubation time was determined either by single twitch stimulat ion (STS), DBS and zero PTC. The patients were intubated immediately after obtain ing zero response to the respective stimulation patterns. While excellent intu bation conditions were established in only 70% and 55% of the patients in the STS and the PTC group conditions, respectively, 90% of the patients in the DBS group achieved this high score (aFig.3.5). With the DBS stimulation pattern, the response disappeared much later than after STS and PTC. Correspondingly, the neuromuscular blockade at the time of intubation

*

30 25 20 15 10 5 0

TOF

PTe

DBS

D Fig. 3.5. Determining the time for endotracheal intubation using three diffe rent stimulation patterns [24]. Y axis: Number of patients; TOF: Train of four ; PTC: Post-tetanic count ; DBS: Double-burst stimulation. Intubation was performed immed iately after absence of response. Blue: Excellent int ubating conditions; green: good intubating conditions; red: satisfactory int ubating conditions, yellow: poor int ubat ing conditions. • P <0.05

87 3.1 . Neuromuscular monitoring

3

was already advanced, which explained the better intubating conditions. Sometimes , the PTe is also proposed as the more suitable stimulation mode for such situations. Thus, stimulation can alternatively be continued in the TOF mode, and intubation initiated one minute after disappearance of the last TOF response. This also postpones the intubation time. As a result, the neuromuscular blockade has already progressed by the time of intubation. This means that the risk of intubation irritation causing adverse effects like coughing or bucking is that much less. Key points - - - - - - - - - - - - - - - - - - - - - - , Typically, intubation is initiated as soon as the TOF response is no longer detectable. Whenever good to excellent intubati ng conditions are mandated, the patient should not be intubated until 1 min after the TOF response has d isappeared completely. Alternat ively, the DBS or PTCmode can also be used in such situations; here intubation should not be initiated until cessation of response is detectable.

3.1.3

What level of neuromuscular block for intubation?

We discussed above that there are good arguments favoring the concept of a balanced induction technique that includes NMBAsfor endotracheal intuba tion. Now, we will address the question as to how deep the neuromuscular block should be at the time of intubation - a question that is certainly more difficult to answer. Having said that, a complete neuromuscular block is not imperative to reliably create good to excellent intubating conditions . This is primarily because NMBAs are not solely responsible for the quality of endotracheal intubation, but rather are to be regarded as part of an overall balanced strategy. In consequence, it suffices for the NMBA onset of action to be adequately advanced at the time of intubation, provided that anesthesia has a sufficient depth . To a certain degree, adverse reactions to intubation can be diminished specifically by administering high-strength and fast-acting opioids even when the neuromuscular blockade is markedly advanced, but still incomplete. From this fact directly follow two different clinical concepts:

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Chapter 3 • Clinical applicat ion

1. After a conventional intubation dose (twice the ED95), it is not imperative to wait for complete onset of action of the NMBA, but rather intubation can be performed at an earlier time provided the anesthesia is appropriately deep. In a pediatric patient cohort, Fuchs-Buder and Tassonyi [25) investigated the intubating conditions and the time course of neuromuscular blockade after 0.6 mg/kg rocuronium. Intubation was performed 60 s after injection of rocuronium. The intubating conditions were excellent in 29 of the 35 investigated patients and good in the remaining six, although the neuromuscular blockade, measured as a Tl response, was still 42% (± 24%) of baseline at the time of intubation. The control group was intubated at a much more advanced stage of neuromuscular blockade (Tl response of 25% [±19%)). Nevertheless, the prevailing intubating conditions did not differ. A complete neuromuscular blockade was consequently not necessary to achieve good to excellent intubating conditions. Moreover, the intubating conditions were comparably good and independent of whether Tl was still >40% of baseline or whether the neuromuscular blockade was already very advanced. 2. Given that incomplete neuromuscular blockade can create good to excellent intubating conditions when the level of anesthesia is at an appropriate depth, it should be possible to intubate with a reduced dose of NMBA. Schlaich et al. [14) have investigated this »low-dose concept«. After anesthesia induction with propofol and remifentanil, their patients received three different rocuronium doses for intubation: 0.6 mg/kg (equivalent to twice the ED95), 0.45 mg/kg (equivalent to 1.5 times the ED9S) or 0.3 mgt kg (equivalent to one times the ED9S) ' Additionally, the intubating conditions were assessed in a fourth group who likewise received propofol and remifentanil for induction, but were intubated without muscle relaxant. Despite remifentanil and propofol, the intubating conditions in the low-dose rocuronium group proved to be poor in 10 of 30 patients. Two of them could not be intubated at all without relaxant. Here, the Simple ED95 was already adequate to produce good to excellent intubating conditions in all patients, although only 13 of the 30 patients had excellent conditions after this reduced intubation dose of rocuronium. Even the lowest dose of rocuronium successfully prevented closed vocal cords, or, particularly, vocal cords that closed upon contact and also severe cough-

3

89 3.1 . Neuromuscular monitoring

ing fits in response to the irritation of intubation. After rocuronium doses of both 0.6 mg/kg and 0.45 mg/kg, most patients were found to have excellent intubati ng conditions . Despite different depths of neuromuscular blockade at the time of intubation, the latter two groups did not differ in this regard CD Fig. 3.6). Given the above, it becomes obvious that no generally valid recommendations can be made regarding the optimal depth of the neuromuscular blockade for intubation. Normally, intuba tion should not be initiated until complete neuromuscular blockade has been achieved, but if anesthesia is deep enough, the intubating conditions may already be good to excellent.

*

30 25 20

15 10 5 0

Roc 0.6

Roc 0.45

Roc 03

Placebo

a Fig. 3.6. Int ubatin g cond it ions after propo fol and remifentanil and various do ses of rocuronium and withou t mus cle relaxant [14]. Black: Excellent int uba tin g co nd itio ns; gray: Goo d intu bati ng conditions; white: Poor intubating conditions. Roc 0.6: rocuronium 0.6 mg/ kg (twice the ED9S)' Roc 0.45: rocuronium 0.45 mg/ kg (1.5 times the ED9S)' Roc 0.3: rocur oniu m 0.3 mgl kg (1 ti mes ED9S) ' ' P <0.05

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Chapter 3 . Clinical application

Key points - - - - - - - - - - - - - - - - - - - - - ---, No general pre-intubation block depth can be recommended because the extent of neuromuscular blockade not only influences the intubating conditions, but also the depth of anesthesia. -

If the anesthesia is deep enough, good intubating conditions can be achieved even when the neuromuscular blockade is incomplete; it suffices that the action of the NMBA administered is significantly advanced.

Important - - - - - - - - - - - - - - - - - - - - - - - - - , -

The clinical relevance of neuromuscular monitoring in determining the intubation time continues to be a controvers ial issue. Comparab ly good to excellent intubating conditions can also be achieved by wa it ing for an appropriate period of time . Notwithstanding the above. neuromuscular monitoring should be applied right at the outset of anesthes ia. This axiom is particularly valid when quantitative nerve stimulators are used. These devices need to be calibrated before they can produce accurate data (also with regard to neuromuscular recovery). However, calibration can only be performed prior to NMBA injection. That means that switching test muscles during the intervention is no longer possible, because it would cause the initial calibrat ion data to be lost. The adductor pollicis muscle alone is suitable for assessing the onset of action, the intraoperative course and recovery from neuromuscular blockade in equal measure. With the adductor pol llcls, there is no need to switch test muscles during the intervention.

-

Usually intubation can be started as soon asTOF response at the adductor pollicis muscle is lost. If the aim is to prevent a response to intubat ion with certainty, it is recommended to wait for one minute after cessation of the last TOF response before int ubati ng.

3.2

Intraoperative application of neuromuscular monitoring

Intraoperatively, neuromuscular monitoring lets the anesthesiologist adapt the reinjection of NMBA to both the individual needs of the patient as well as to the requirements dictated by the operative situation. The clinically relevant questions in this context are:

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3.2 . Intraoperative application

-

Can neuromuscular monitoring help prevent the accumulation of NMBAs, in particular after several repeated doses? How can deep neuromuscular blocks be optimally monitored when no more response is detectable after TOF stimulation?

3.2.1

Accumulation of NMBAs

Particularly for abdominal surgery, deep muscle relaxation is intraoperatively paramount for reliably creating good surgical conditions - a requirement that above all applies to epigastric procedures and laparoscopic procedures. Pronounced muscle relaxation is moreover desirable in innumerable other fields of surgery like gynecology, urology, neurosurgery, ophthalmology, and sometimes even traumatology. Here, repeated bolus injections of nondepolarizing NMBAs are usually given. Since the pharmacodynamic action of current NMBAs is subject to individual fluctuations, there is a risk that these drugs accumulate and, as a result, residual curarization of the NMBA occurs at the end of the intervention. This can prolong switchovers and upset the designated surgical schedule. Even worse than the associated organizational hindrances is the fact that the patient is put into direct jeopardy by the potential for residual neuromuscular blockade. A survey published in 2003 evaluating customs of NMBA application in Germany also investigated the criteria used for timing the reinjection of NMBA [26]. Clinical signs were by far the leading criteria most frequently employed for timing NMBA reinjection. In the survey, neuromuscular monitoring was placed a far second, followed by fixed time intervals ( a Fig.3.7). However, one limitation should be noted here: clinical signs frequently are nothing more than an expression of inadequate muscle relaxation and thus ill suited as criteria for proactive management of neuromuscular blockade. This situation is additionally associated with the risk of misinterpretations and a potential for under- or overdosing the NMBA. Similarly, the use of fixed time intervals for timing NMBA reinjection without any information about the current extent of muscle blockade can easily lead to misdosing. Critical scrutiny of these two criteria shows that they are not really suitable for establishing the optimal time for NMBA reinjection. Indeed, some of the »perceived accumulation" of NMBAs reported in clinical practice might actually be attributable to the fact that unsuitable criteria were employed for

3

92

Chapter 3 • Clinical application

100%

Ul

E 80% 0

Application customs

7ii :) 0

c

.2

iii 60%

.

.5:1

a. a.

• 61

~

80%

41 - 60%

III

«lD

81 -100%

o

21 - 40% 0 o - 20%

40%

z

0 Never 20%

0%

L.-.J....

--1----1

....L......L.

Clinical signs

NMT

L.-_ _

Fixed time intervals

a Fig. 3.7. Criteria for timing NMBA reinject ion [26]. Clinical signs were employed much more frequently to time NMBA reinject ion than NMT (neuromuscular monitoring) or than fixed time intervals

timing NMBA reinjection and, in turn, could be just as easily prevented by appropriate neuromuscular monitoring.

In this context, two current studies are particularly interesting. In more than 110 patients scheduled to undergo abdominal surgery lasting at least 3 hours, Geldner et al. [27] examined factors influencing the duration of action of repeat bolus injections of cisatracurium and rocuronium. The repeated doses of cisatracurium and rocuronium were always 0.5 times the ED95 and thus equipotent. The NMBAs were reinjected as soon as a T1 response of

93

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3.2 · Intraoperative application

25% was measured by acceleromyography. Time between two reinjections to recovery of the single twitch height to 25% was defined as Duration 25 (DUR 2s) ' The influence of various factors like age, sex, ASA score, duration of the intervention and core body temperature on the DUR 2s interval was analyzed. The surgical procedures lasted an average 4.6 h, with a 95% confidence interval of 3.6-5.3 h. A commensurately large number of repetitive doses of each NMBA were necessary intraoperatively. In this study, prolonged duration of action of the repeated dose of cisatracurium correlated excellently with core body temperature. The duration of action of repeated doses of cisatracurium increased by 2.4 minutes per degree Celsius decrease in body temperature (95% confidence interval: 0.7-4.1 min). The other variables did not affect cisatracuriums duration of action. By comparison, the prolonged duration of action of repetitive doses of rocuronium correlated very well with the duration of surgery. Each hour of surgery extended the duration of action by an average of 1.6 minutes (95% confidence interval: 0.6-2.8 min), whereas here, the other factors did not influence the duration of action. In both cases, the impaired elimination of the drug in question was responsible for the observed accumulation. However, the action of the drugs was prolonged by only 1-2 minutes, despite numerously repeated doses . In light of this data, it can be assumed that the overwhelming proportion of »perceived accumulation- cases is due to overdosing and consequently can be easily prevented by routinely applying neuromuscular monitoring [27]. A recent publication by Maybauer et al. confirmed these results [28] within a similarly large multicenter trial conducted in Germany. In total, over 300 patients undergoing lengthy abdominal surgeries were enrolled. The main study variables included, among others, the duration of action of equipotent repetitive doses of rocuronium and cisatracurium; the NMBAs were reinjected after recovery of T1 response to 20% of baseline. The two most important findings of this trial were: 1. The NMBAs investigated showed a large interindividual variability. While a repetitive dose can last approx . 20 min in one patient, the same dose may only last 7-8 min in another patient. This fact applied to both cisatracurium and rocuronium (D Fig. 3.8). Overdosing or underdosing is inevitable if reinjection of the NMBA is timed according to fixed intervals. In the end, only neuromuscular monitoring is fully able to account for patients' individual sensitivities.

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Chapter 3 . Clinical application

2. The use of neuromuscular monitoring can reliably prevent the accumulation of the two drugs despite highly repetitive dosing. For example, the first repetitive dose of rocuronium lasted a good 12 minutes on average, while the fifth lasted almost 14 minutes . After cisatracurium, the average duration of action of the individual repetitive dose varied across the range of 1 minute ( DFig.3.8). Neuromuscular monitoring lets the anesthesiologist adjust the timing for reinjection of NMBA to the individual needs of each patient. And this is the only way that accumulation of a drug can be avoided despite its great interindividual variability even when multiple repetitive doses are administered. Martin et al. [29] arrived at the same conclusions. These authors investigated the course of neuromuscular blockade in two groups of abdominal surgery patients : in one group, NMBA reinjection was timed according to clinical signs and in the second group, the NMBA was reinjected as soon as at least one TOF response could be detected . Both the duration of surgery and the use of NMBAs were comparable in the two groups. Nevertheless, an evenly

22

- Rocuronium ___ Cisatracurium

20

I

18 16

14

12

..-

10

8 #

.

6 -'-,.--- - - - -,-- - - - --r-- - - - --.-2 3 4

- -------,

5

D Fig . 3.8. Duration of repetitive doses of cisatracurium and rocuronium (modified after [28]). Y axis: duration in minutes. X axis: number of repeated dose

95

3

3.2 . Intraoperat ive application

deep intraoperative neuromuscular blockade could only be mainta ined in the neuromuscular monitoring group - the group who suffered neither recurarization nor postoperative residual blockade in spite of a deeper blockade. Key points - - - - - - - - - - - - - - - - - - - - - - - , -

Neither clinical signs nor fixed time intervals are suitable criteria for timing NMBA reinjection. This strategy will particularly lead to mlsdos ages and residual curarization at the end of surgery whenever multiple repeated doses are given .

-

Neuromuscular monitoring is the only method by which repetitive dosing can be adapted to the patient's individual needs and thereby prevent NMBA accumulation. This fact has been clearly proven by innu merable clinical studies.

3.2.2 Stimulation patterns and test muscles

TOF stimulation at the adductor pollicis muscle is the suitable method for a large portion of surgical procedures in which NMBAs need to be reinjected intraoperatively. A T1 recovery to 25% of baseline indicates the end of surgical relaxation and is an appropriate time to reinject the NMBA. When a simple qualitative nerve stimulator is used, this correlates excellently with the reappearance of the fourth TOF response. If a more deep intraoperative level of neuromuscular blockade is required , the NMBA can be reinjected at as little as a 10% T1 recovery. This corresponds to the reemergence of the second TOF response. By counting the stimulatory responses after TOF stimulation, NMBA reinjection can also be monitored with a simple nerve stimulator. During epigastric procedures like gastrectomy or laparoscopic cholecystectomy, it can happen that the neuromuscular blockade in the surgical field is perceived as insufficient although the anesthesiologist no longer detects any twitch at the adductor pollicis muscle after TOF stimulation. Frequently, the explanation for this is the fact that the diaphragm is much more resistant to NMBAs than the adductor pollicis muscle. The diaphragm is thus capable of reacting to direct stimulation and may hamper the surgical conditions although a TOF response is no longer detectable at the adductor pollicis muscle. In such situations , either the corrugator supercilii muscle, which is just as resistant to the action ofNMBAs as the diaphragm, can be selected as the test

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Chapter 3 . Clinical application

muscle, or, the anesthesiologist can decide to use the PTC as the stimulation pattern that enables monitoring of deep neuromuscular blockade. Here, the use of PTC is recommended as the stimulation pattern because it allows neuromuscular blockade to be detected at the adductor pollicis muscle that is no longer detectable by the TOF mode . It is thus accordingly easy to control the reinjection of NMBA as needed. Studies by D'Honneur et al. [30) have confirmed this strategy. These researchers performed electromyographic measurements of the diaphragm from surface electrodes and assessed whether the PTC at the adductor pollicis muscle or the TOF mode at the corrugator supercilii muscle were more suitable for monitoring deep neuromuscular blockade of the diaphragm. These measurements showed that PTC was significantly more suitable to detect deep neuromuscular blockade of the diaphragm than the TOF mode at the corrugator supercilii muscle. As soon as one of four TOF responses was detectable at the corrugator supercilii muscle, the EMG response of the diaphragm had already reached 25% of baseline. Hence, the TOF mode cannot be used to detect deeper neuromuscular blockades of the diaphragm even at the corrugator supercilii muscle. Of additional note is the fact that the corrugator supercilii muscle was not suitable for assessing neuromuscular recovery. That meant that the test muscle had to be switched over the course of the further procedure. If, by contrast , only a response of the adductor pollicis muscle was detected after PTC, the diaphragm EMG was only 10% of baseline. When such cases arise, an intraoperative switch of the test muscle should be avoided along with the associated loss of initial calibration of the quantitative relaxometer. Key points - - - - - - - - - - - - - - - - - - - - - - - . In the majority of cases, TOF stimulation at the adductor pollicis muscle is t he suitable method for intraoperatively monitoring neuromuscular blocka de and timing the reinjection of NMBA. A Tl response equ ivalent to 25% of baseline, i.e, the reemergence of the fourth TOF response, heralds the end of surgical relaxation . -

Particularly during procedu res on the epigastrium, reactions by the diaphragm can cause sustained impai rments of surgical conditions and shou ld t herefore be avoided with surety. This indeed mandates deep neuromuscular blockade.

97

3.3 · Monitoring neuromuscular recovery

pre at the adductor pollids muscle enables the monitoring of deep neuromuscular blockade as well as the controlled as-needed reinjection of NMBAs. Mo reover, no switching of test muscles is required - another advantage of this strategy, particularly when quantitative neuromuscular monitoring is employed.

Important - -- - - - - - - - - - - - - - - - - - - - ---, -

Neither clinical signs nor fixed time intervals are suitable criteria for timing reinjection of NMBAs.Both criteria can inevitably lead to misdos age, insufficient block depth and drug accumulation. If, by contrast, the timing of NMBA reinjection is based on relaxometric criteria, any no table accumulation of NMBAs is obviated, even with multiple repetitive doses.

-

For the majority of procedures, rOF stimulation at the adductor pol lids muscle is the suitable method for timing the reinjection of NMBAs. Particularly procedures on the epigastrium frequently require deeper neuromuscular blockade to create optimal surgical conditions. In such situations, the rOF mode is pushed to its limit. Here, the PTC mode is the more suitable method.

3.3

Monitoring neuromuscular recovery

Complete neuromuscular recovery?

The clinical duration of action of an NMBA ends when the T1 respon se has recovered to 25% of baseline. The recovery phase starts at this point in time and ends with complete neuromuscular recovery. Given the safety margin at the neuromuscular endplate, however, residual blockade is no longer detectable by the usual monitoring methods when as little as 30% of the acetylcholine receptors are free. In line with this fact, the TOF ratio for this point in time onward is 1.0, even during objective monitoring! Thu s, »complete- in this context should not be interpreted to mean that the NMBA has stopped blocking acetylcholine receptors at the endplate. Rather, only that the patient is no longer endangered by an existing residual blockade.

3

98

Chapter 3 . Clinical application

In the past 10 years, extensive new evidence has emerged about the pathophysiological implications of incomplete neuromuscular recovery. In fact, not only are the pulmonary muscles functionally impaired by this state, but respiratory control is also affected, particularly under hypoxic conditions. Residual blockade furthermore endangers the coordination of the pharyngeal muscles and the integrity of the upper airway. Patients report discomfort even with a low level of residual blockade above a TOF ratio of 0.8. These different factors have led to a rethinking of the »complete« neuromuscular recovery paradigm .

3.3.1

Pathophysiological implications of residual neuromuscular blockade

Pulmonary muscles

Back as early as the 1970s, researchers investigated the effects of residual blockades on the respiratory muscles of anesthetized patients by comparing the TOF ratio of the adductor pollicis muscle and breathing patterns during partial neuromuscular blockade [31]. - When the T1 response of the adductor pollicis muscle is less than 10% of baseline (clinically, a single muscle contraction is detected after TOF stimulation), the patient usually shows neuromuscular blockade-induced apnea. - Tachypnea and a reduced respiratory volume are typically observed from a T1 response > 25% of baseline (clinically, three muscle contractions are detectable after TOF stimulation). - The tidal volume of spontaneously breathing patients under anesthesia is usually sufficient at a T1 response of ~ 50% of baseline (TOF ratio: approx.0.3). The impairment of forced vital capacity (FVC) is a sensitive predictor of the development of respiratory symptoms in patients with neuromuscular disease and correlates excellentlywith the strength of the respiratory muscles in patients with myotonic dystrophy [32]. FVC recovery from the effects of neuromuscular blockade is also significant in the immediate postoperative period, since any weakness in respiratory muscles can reduce peak cough flow and impair secretion clearance from the upper airways [33].

99

3

3.3 . Monitoring neuromuscular recovery

-

At a TOF ratio of 0.5, FVC is reduced by 20-30% on average [34,35) . FVC recovery can usually not be expected until a TOF ratio of 0.8. When the TOF ratio has recovered to 1, any residual effects of NMBAinduced impairment ofFVC can be ruled out for the most part [34, 35).

During residual blockade inspiratory obstruction of the upper airway is of similar clinical relevance. - At a TOF ratio of 0.5, partial neuromuscular blockade causes a particularly strong impairment of inspiratory flow to around 50% of baseline (D Fig. 3.9). - In addition, the mean ratio of expiratory to inspiratory flow at 50% of vital capacity (MEFso/MIF so ratio) is significantly elevated during partial neuromuscular blockade and, at a TOF ratio of 0.5, averages 1.18 versus 0.87 before neuromuscular blockade (D Fig. 3.9). According to international recommendations, an MEFso/MIF ratio of> 1 is indicative of upper airway obstruction. Therefore, any reduction in inspiratory flow observed during partial neuromuscular blockade suggests that the patient has a dysfunction of the upper airway. The results of current magnetic resonance imaging and electrophysiological studies by Eikerman et al. clearly support the presumption that the decreased inspiratory flow observed indicates impaired function of the upper airway (36). - Even at a TOF ratio of 0.8, upper airway dysfunction persisted as manifest by decreased peak inspiratory flow, impaired ability to swallow [34, 35), diminished upper airway volume and impaired function of the genioglossus muscle (upper airway dilator function) (36). - After recovery of the TOF ratio to 1.0,with few exceptions, no more residual neuromuscular blockade-related obstruction of the upper airway was observed (36).

Respiratory control The body reacts to hypoxia by significantly stepping up respiratory volume and cardiac output per minute . This hypoxia-related increase in ventilation is mediated by chemoreceptors in the carotid body. In vitro, the increase in the neuronal activity of these chemoreceptors observed during hypoxia can be blocked by Nvcholine antagonists .

100

Chapter 3 . Clinical application

"1

1

0.8

0.4

*

*

100

(%] 80 60 40 -0-

FVC FIV1

*

20 0.4

0.5

0.6

0.7 0.8 TOF r tlo

0.9

1.0

a Fig. 3.9. Lung function dur ing partial neuromuscular blockade . Resultsof 12 subjects (study by Eikermann ). At a TOF ratio of 0.5, all lung function variables investi gated were impaired. At a TOF ratio of 0.8, the average forced vital capacity (FVC) had already recovered, wh ile the ratio of expiratory to inspiratory flo w at 50% of vital capacity (MEFsot'MIFsoratio) as well as the forced inspiratory volume in 1 s (FIV1) continued to remain impa ired by the part ial neuromu scular block. This indicated an upper airway ob struct ion. When the TOF ratio had recovered to 1, significant effects of part ial neuromuscula r bloc kade were no longer detect able [41]. *P
Eriksson et al. [37] systematically investigated the influence of residual neuromuscular blockade on hypoxic ventilatory regulation. In animal experiments and in awake subjects, residual blockade markedly weakened hypoxiastimulated increased ventilation and/o r even abrogated it altogether. In this context, it is of vital clinical relevance to note that the chemoreceptors of the carotid body react much more sensitively to non-depolarizing NMBAs than do peripheral muscles or pulmonary muscles. While it can generally be assumed that a patient can breathe and cough adequately with a TOF ratio of 0.7 at the adductor pollicis muscle, their hypoxia-related increase in ventilation will still be considerably limited. The values do not return to baseline

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3.3 . Mon itoring neuromuscular recovery

3

until the TOF ratio recovers to 0.9. This protect ive mechanism is important, especially given the risk of hypoxia during the early postoperative phase. Even a low level of residual blockade, however, can markedly potentiate the respiratory depression induced by opiates or volatile anesthetics in that this physiological protective response is blocked, which can ultimately lead to lifethreatening hypoxia. Accordingly, »complete« neuromuscular recovery cannot be assumed in this situation until the TOF ratio has recovered to 0.9.

Pharyngeal function

Eriksson et al. evaluated pharyngeal function during partial neuromuscular blockade using videoradiography and computerized pharyngeal manometry and demonstrated that the pharyngeal muscles have a particularly strong sensitivity to the effects of neuromuscular blockade [37]. - A TOF ratio of 0.6-0.7 is characterized by impairment of pharyngeal muscle coordination, a shortened bolus transit time [38], a reduction in resting tone of the upper esophageal sphincter, as well as by difficulties in swallowing [34]. _ Even at a TOF ratio of 0.9, swallowing difficulties were observed by videoradiography as a contrast medium swallowmisdirected to the upper glottis region. - Thus , it is probable that the risk of pulmonary aspiration is elevated even with a minimal neuromuscular blockade (TOF ratio -0.9). In this situation , complete neuromuscular recovery cannot be assumed until a TOF ratio of 1.0. Safety margin

The safety margin of neuromuscular transmission is defined as the proportion of acetylcholine receptors at the motor endplate that have to be occupied by the NMBA before the first signs of neuromuscular blockade become detectable. Physiologically, this proportion amounts to at least 70% of the acetylcholine receptors. In terms of neuromuscular recovery, this means that common clinical methods of neuromuscular monitoring will cease to detect a residual blockade when as few as 30% of the acetylcholine receptors are free! If the safety margin is cancelled, even tiny changes in the acetylcholine concentration at the motor endplate will cause recurarization.

102

Chapter 3 • Clinical applica tion

!

.':;.

i

a Fig. 3.1O. Neuromuscular safety margin and residual blockade. 1: Injection of vecuronium (0.1 mg/kgl, 2: Neuromuscular recovery to a rOF ratio of 0.7 followed by injection of magnesium with subsequent recurarization [39]

In the author's own studies on patients with residual blockade corresponding to a TOF ratio of 0.7, complete neuromuscular blockade was re-induced by magnesium concentrations that normally do not produce a measurable neuromuscular blockade [39] (a Fig.3.10). Similarly comparable implications have been described previously following administration of various antibiotics, antiarrhythmics, calcium antagonists and topical anesthetics . During the early postoperative phase, some extubated patients will develop apnea as a result. When free acetylcholine receptors exceed 30%, currently available methods of neuromuscular monitoring do not allow any further differentiation of neuromuscular recovery. Thus, these techniques are not able to supply relevant information about the neuromuscular safety margin . Only by means of reversal can the neuromuscular safety margin be reinstated dose-dependently. Therefore, reversal can make sense even in patients with supposedly »complete« neuromuscular recovery.

Patient comfort Alongside the fact that incomplete neuromuscular recovery can put the patient in harm's way, one frequently forgets that residual blockade can equally cause patient s discomfort [40]. - All volunteers subjectively felt discomfort at TOF ratios <0.75. The reasons varied among individuals, with articulation difficulties and swallowing difficulties being reported most frequently. - At TOF ratios <0.9, all subjects consistently reported visual impairment, particularly diplopia and difficulties focusing [40].

3

103 3.3 • Monitoring neuromuscular recovery

As the options for managing anesthesia improve with the use of agents such as remifentanil, sevoflurane or desflurane, patients are likely to undergo more rapid recovery of cognitive funct ion. As a result, the future can be expected to be fraught with an increasing number of patien ts in the recovery room complaining about impairments such as articulation and swallowing difficulties and/or visual disorders. Given that as many as 70% of the acetylcholine receptors at the motor endplate can be blocked with NMBAs even at an objectively measured TOF ratio of 1.0, the choice of the term »complete« to define neuromuscular recovery here may be slightly too ambitious and therefore mislead ing. »Sufficient- would appear to be the more appropriate description of neuromuscular recovery in this context. Indeed, curre nt evidence shows that any serious hazard for the patien t is banished at a TOF ratio of 1.0. Nevertheless, in clinical practice, even this degree of neuromuscular recovery can frequently only be accomplished by reversal. In the following, th e pathophysiological implications of residual neuro muscular blockade are summarized (DTab.3.3 and DTab.3.4). As a function of the TOF ratio, we differentiate between [41]: - Pronounced residual neuromuscular blockade, i.e. TOF ratio <0.5 - Minimal residua l neurom uscular blockade, i.e, TOF ratio -0.8 - Adequate neuromuscular recovery, i.e. TOF ratio - 1.0

D r ab. 3.3. Quantification of the clinically relevant effects of a partial neuromuscular blockade based on the rOF ratio at the adductor pollicis muscle. The data derive from the study results of two working groups obtained in awake healthy subjects during partial neuromuscular blockade [34, 381 rOF ratio 0.5

rOF ratio 0.8

rOF ratio 1.0

TIdal volume

Normal

Normal

Normal

FVC

Frequently Impaired

Frequently normal

Normal

Pharyngeal function (act of swallowing)

Significantly Impaired

Impaired

Usually normal

Integrity of the upper airway

Significantly impaired

Impaired

Usually normal

Hypoxic respiratory response

Frequently impaired

Frequently normal

Normal

MonitOring at the adductor polhcis muscl@

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Chapter 3 . Clinical application

a Tab. 3.4. Symptoms of partial neuromuscular blockade (m od ifi ed after [34]). Study on 12 awake, partially paralyzed volunteers. Even at a TOF ratio of 0.5 (m easured by accelerometry. TOF-Watch - SX). no fade of the adductor pollicis muscle was detectable afterTOF stimulation nor was the ability to sustain a head lift limited. In contrast. even when the TOF ratio recovered to 0.8. the volunteers subjectively perce ived an Inability to swallow normally TOF ratio

Inability to sustain head lift (>5 sl ln 12J

InabIlity to swallow normally [n-12J

0.5

1

10

0,8

0

7

1

0

1

Fade- visible (thumb) [n 121

1 - -0 0

Pronounced residual neuromuscular blockade Although tidal volume and respiratory frequency return to normal at a TOF ratio of 0.5, FVC, pharyngeal function , integrity of the upper airway and the hypoxic respiratory response are still considerably impaired during a pronounced residual neuromuscular blockade. In such states, the patient is acutely endangered and should not be extubated under any circumstances. Even such a deep level of residual neuromuscular blockade cannot be detected by clinical signs or by visual and/or tactile assessment of the TOF ratio. With a »simple« nerve stimulator, this kind of residual blockade can only be diagnosed by correctly interpreting the result of the DBS. With quantitative nerve stimulators, by contrast , neuromuscular recovery can be measured objectively and any a deep level of residual neuromuscular blockade detected with certainty.

Minimal residual neuromuscular blockade Even at minimal neuromuscular blockade (TOF ratio, 0.8), there is still a

relevant extent of impairment to important variables of respiratory function . However, this degree of neuromuscular transmission impairment cannot be reliably identified by clinical testing or by using simple nerve stimulators (Drab. 3.3 and D rab. 3.4). Variables like FVC, forced and maximum expiratory flow and the hypoxic respiratory response are usually normal. Nevertheless, dysfunction of

105

3

3.3 . Monitoring neuromuscular recovery

the upper airway continues to exist in the form of a decrease in inspiratory airflow, swallowing difficulties, reduction in upper airway volumes as well as impaired function of the upper airway dilator muscle (genioglossus force). Therefore, these »rninimal« neuromuscular blockade also presumably harbor an increased risk of aspiration. As a result, recovery of the TOF ratio to 0.8 is not a sufficiently reliable clinical sign for determining whether respiratory function or upper airway integrity, in particular, have recovered from the neuromuscular blockade (arab. 3.3 and a r ab.3.4). That means that »minimal« residual blockade may indeed have clinically relevant consequences for patients and can only be detected by the proper use of objective nerve stimulators.

Upper airway function during adequate neuromuscular recovery

In several studies, no significant impairment of respiratory function could be proven after the TOF ratio recovered to 1.0. In spite of this fact, individual subjects can have low-grade impairments of pharyngeal function and upper airway integrity, albeit of presumably negligible clinical relevance. Swallowing difficulties and fade of FVC may point to (rare, but) persistent respiratory effects of a neuromuscular block [18]. Therefore, careful monitoring during the direct postoperative phase is mandatory. Key points - - - - - - - - - - - - - - - - - - - - - - - , -

FVCrecovery cannot be assumed until a TOF ratio of 2: 0.8. Even at a TOF ratio of 0.8, a decrease in inspiratory airflow can persist and there is an additional risk of inspiratory airway obstruction.

-

During residual blockade corresponding to a TOF ratio <0.9, the patient's hypoxia-induced increase in ventilation is impaired.

-

The pharyngeal muscles are especially sensitive to residual neuromuscular blockade. An elevated risk of pulmonary aspiration exists until the TOF ratio has recovered to 1.0. Even at a TOF ratio of 1.0. there is still no neuromuscular safety marg in to speak of. In such situations, even minor changes in acetylcholine concentration at the motor end plate can lead to relevant recurarization .

-

Patients experience residual neuromuscular blockade as discomfort and suffer articulation difficulties, swallowing difficulties and visual impairment.

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Chapter 3 . Clinical application

3.3.2 Frequency of residual neuromuscular blockade

After exploring the pathophysiological consequences of incomplete neuromuscular recovery, the next critically significant question to ask concerns the frequency with which they occur. The extent of neuromuscular recovery at the end of an intervention not only depends on the NMBA administered, the duration of the intervention, and the anesthe sia technique, but also on any concomitant diseases the patient might have. In principle, residual neuromuscular blockade can be expected to occur with a higher frequency after long-acting NMBAs like pancuronium than is the case with intermediate- or short-acting agents. Moreover, the probability of residual blockade after administration of a single dose of a NMBA is that much greater, the shorter the duration of the surgical intervention lasts. After procedures lasting up to 90 minutes, a high percentage of incomplete neuromuscular recovery can be expected when intermediate-acting NMBAs are used. The anesthesia technique similarly influences the incidence of residual neuromuscular blockade. After repetitive bolus injections and/or continuous long-term NMBA administration, residual blockade can be anticipated with a greater frequency than after single administration of a conventional intubation dose (twice the ED9S) ' At the same NMBA dose and the same duration of anesthesia, residual blockade occur more often after volatile anesthetics than after i.v, anesthetics. Whenever non -depolarizing NMBAs are used, reversal with an acetylcholinesterase inhibitor, typically neostigmine , sustainably reduces the occurrence of residual blockade and demonstrably lowers anesthesia-related mortality [42]. Finally, concomitant diseases can also have an impact on the incidence of residual blockade; among others, myasthenia gravis is clinically relevant in this context. Furthermore, if the activity of pseudocholinesterase is depressed, the action of succinylcholine and mivacurium will likely be prolonged. Lastly, renal and/or liver failure prolong the action of several aminosteroids , most notably, pancuronium and vecuronium . Thus, it becomes evident that studies concerning the incidence of incomplete neuromuscular recovery are not intercomparable without clarification of the population and study conditions. One meaningful study in this context is that conducted by Debaene et al. in 2003 at a study center in

3

107 3.3 . Monitoring neuromuscular recovery

France [6]. Their prospective study on more than 500 patients investigated the frequency of residual neuromuscular blockade. The study only enrolled patients undergoing an intervention that did not require NMBA reinjection. All study patients received a single intubation dose (twice the ED9S) of an intermediate-acting NMBA; rocuro nium, vecuronium or atracuri um only, and no antagonist was given at the end of the intervention. A comparable procedure is common to other countries like Germany. This study design provided conclusive evidence about the incidence of residual neuromuscular blockade as a function of the duration of surgery (D Fig. 3.11). It was shown that as early as 2 h after a single intubation dose of one of the above three NMBAs, more than 60% of patients had a TOF ratio <1.0, 37% a TOF ratio < 0.9 and 10% showed neuromuscular recovery that did not even attain a TOF ratio of 0.7. Accordingly, the incidence of incomplete neuromusc ular recovery rose proportionally with the shortness of the procedure. After procedures lasting between 90-120 minutes, for example, over 45% of the patients did not achieve a TOF ratio of 0.9 by the end of the surgery, while 18% did not achieve a TOF of 0.7. The selection of

OF < 0.7 OTO F < 0.9 . TOF < 1

100 80 60 40 20

0 < 60

160-901

190-1201

> 120

D Fig. 3.11. Extent of neuromuscu lar recovery after an intubatio n do se of a non-depol arizin g NMBA (rocuronium, vecuronium and atracurium) as a function of t im e (modifi ed afte r [6]). Xaxis: TIme in minute s after injection of an intu batio n dose (twice t he ED9s ) of an intermedia te acti ng NMBA;V-axis: Numb er of patien ts with residu al blo ckade (%).

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Chapter 3 • Clinical application

an intermediate-acting NMBA appeared to be less significant in terms of expected frequency of residual blockade. In other words, there were no significant differences in the incidence of residual blockade between rocuronium, vecuronium and atracurium. This study impressively showed that many patients can be expected to suffer a residual neuromuscular block after just a single conventional dose (twice the ED9s) of an intermediate-acting NMBA given for intubation and even if the administration of the NMBA was 2 h or longer in the past. Key points - - - - - - - - - - - - - - - - - - - - - - - , -

The shorter the duration of anesthesia, the larger is the probability of

-

A large number of patients can be expected to experience relevant

incom plete neuromuscular recovery. residual blockade as late as 2 h after one single int ubation dose of an intermediate-acting NMBA.

3.3.3 Clinical implications associated with residual

neuromuscular blockade Faced with the pathophysiological implications and high incidence of incomplete postoperative neuromuscular recovery, we must now ask whether it has any relevant impact on patients in terms of higher postoperative morbidity or even mortality. Here, it should be noted that potential harm for the patient can arise, in particular, from impairment of the upper airway integrity, but also from limitations to major determinants of respiratory function. - In an Australian study published back in the 1970s, incomplete neuromuscular blockade was identified as a major factor contributing to anesthesia-related mortality. A later national survey carried out in 1987 confirmed these results [43,44]. - Lunn et al. [45] demonstrated that postoperative respiratory failure was at least a contributing factor in 11 out of 32 anesthesia-related deaths. The authors found that 6 of the fatal outcomes were related to postoperative residual curarization . - In England, Cooper et al. [46] investigated anesthesia-related complications leading to admission of patients on the intensive care unit. Accor-

109

3

3.3 . Monitoring neuromuscular recovery

-

-

-

ding to their report, nearly half of all cases were attributable to incomplete neuromuscular recovery. A survey in France on the causes of anesthesia-related mortality found that half of the 65 deaths analyzed were attributed to postoperative respiratory depression; incomplete neuromuscular recovery was one of the main causalities [47]. In this context, Berg et al. [48] showed a direct association between incomplete neuromuscular recovery,defined as a TOF ratio <0.7, and severe postoperative pulmonary complications, such as atelectasis and pneumonia. Postoperative pulmonary complications were four times more common in patients with residual blockade than in patients with a TOF ratio >0.7. The mechanisms leading to an elevated risk of postoperative pulmonary complications when neuromuscular recovery was incomplete were largely left unexplained at that time. Since then, however, it is known that impaired function of the pharyngeal muscles is likely a major contributor. By 2005, Arbous et al. [42] had supplied what appeared to be the ultimate piece of the puzzle. Over a 3-year period, these researchers analyzed more than 850,000 anesthesia procedures . Their case-control study determined the risk factors that led to severe anesthesia-related morbidity or mortality during the immediate postoperative phase, i.e., within the first 24 h after surgery. Besides organizational issues like daily checks of the anesthesia respirator equipment with protocol and checklist or the presence of a doctor and nurse during induction and reversal of anesthe sia, the authors also established that reversal ofNMBAs impacted the risk for occurrence of the most severe complications. One of the few factors associated with anesthesia management itself was the lack of reversal in patients administered NMBAs intraoperatively ; this proved to be an independent risk factor for anesthesia-related 24-hour postoperative morbid ity or mortality. Even the most cautious interpretation of these findings leads to the conclusion that an optimally complete recovery of respiratory function and upper airway integrity should be ensured before the patient is extubated. Based on current evidence, these characteristics are best ensured by careful intraoperative monitoring of neuromuscular blockade, while at the same time allowing a generous range for rendering the indication for reversal.

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Chapter 3 . Clinical application

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

Incomplete neuromuscular recovery in the immediate postoperative

-

Even during »minimal« residual block, key determinants of respiratory

phase is a critical factor for anesthesia-related morbidity and mortality. function and upper airway integrity may be significantly impaired. These impairments can directly result in swallowing difficulties associated with the risk of pulmonary inhalation and inspiratory obstruction of the upper airway.

3.3.4 Stimulation patterns and test muscle

Frequently, clinical signs are also used to assess neuromuscular recovery. One nation-wide survey of customs for administering NMBAs in Germany, for example, showed that clinical signs were the most favored criterion for excluding residual blockade (D Fig. 3.7). Sorgenfrei et al. [49] investigated the knowledge Danish anesthesiologists and anesthesia nurses have about the clinical signs needed to assess neuromuscular recovery. A large portion of them could not distinguish suitable from unsuitable clinical signs and less than half of them employed appropriate tests (DTab. 3.5). There is no reason to expect that knowledge about such clinical signs is fundamentally better elsewhere outside of Denmark. The following clinically significant signs should be listed in this context:

Paradoxical respiration or jerky, uncontrolled movements of the extremities Both are important clinical signs that indicate a severe residual neuromuscular blockade.

o

In this situation, the patient is at acute risk!

Every anesthesiologist should be in a position to detect these signs with certainty and initiate the appropriate measures . Obviously, monitoring the patient's neuromuscular recovery is designed to prevent exactly these situations from occurring. Therefore, these two clinical signs should not be regarded as good criteria for monitoring neuromuscular recovery, but rather as an ex-

3

111 3.3 . Monitoring neuromuscular recovery

la

Tab. 3.5. Clinical signs for assessingneuromuscular recovery

J

Clinical signs Suitable -

Head lift >5 s Leg lift >5 s Tongue depressor test Max. inspiratory pressure ;l:SOcmH20

UnSUitable - Opening the eye - Sticking out the tongue - Arm lift - Normal respiratory volume - Normal vital capacity - Max. inspi ratory pressure <25 cmH 20

pression of incomplete neuromuscular recovery and the result of insufficient monitoring.

Head lift test As early as 1961, Dam and Guldmann [50] proposed that the head lift be used as a reliable test for assessing neuromuscular recovery. Although the first description of this method did not state how long the head life was supposed to last, a test interval of 3 to 5 s was later recommended. After TOF stimulation was introduced, the two methods were compared and it was demonstrated that a head lift sustained for 3 seconds can be interpreted as a range equivalent to a TOF ratio ofOA-0.6. Extending the interval to 5 seconds will cover a monitoring range of 0.5-0.8; in other words, all patients with a TOF >0.8 will be able to perform this maneuver, but no patient with a TOF <0.5. Extending the time to 10 seconds does not increase the accuracy of the test. The merits of this test may be limited by the fact that the test is rarely actually performed for a total of 5 s. The shorter the test interval, however, the less powerful is the veracity of the findings.

Tongue depressor test This test is currently regarded as the most sensitive clinical sign for assessing neuromuscular recovery. The patient is requested to try to press a wooden tongue depressor against the roof of their mouth while the anesthesiologist tries to retract the depressor. A neuromuscular recovery >0.8 is required for the

112

Chapter 3 . Clinical application

patient to perform the test. The strength of this finding must be put into perspective, however, in that the test cannot be carried out on patients intubated by mouth . Moreover,in some patients, it can lead to gagging and vomiting. Although clinical tests certainly deliver important information that help the anesthesiologist make the decision to extubate, they are less suitable for delivering specific information about the extent of neuromuscular recovery. Another disadvantage to be mentioned is that they cannot be utilized until relatively late in the reversal phase since the patient's cooperation is required. Hence, early treatment of the residual block is not possible.

Stimulation patterns In principle, TOF, DBSand tetanic stimulation can be used for assessing neuromuscul ar recovery. By contrast, PTC has no relevance in the assessment of neuromuscular recovery ( Drab. 3.6). Visual or tactile assessment of the TOF can only reliably detect residual blockade up to a TOF ratio of 0.4-0.5 . Above this value, even an experienced anesthesiologist will no longer be able to detect fade and consequently no residual blockade any more either. With the DBS, this limit can be shifted to 0.6-0 .7. Beyond that value, this stimulation mode provides no additional inform ation about the extent of neuromuscular recovery. In this context, tetan ic stimulation plays a unique role. While 50-Hz tetanus is no more accurate than TOF stimulation, the main problem of tetanic stimulation at 100 Hz is its low specificity. For example, even with a complete neuromuscular recovery after a 100-Hz tetanu s, only half of all patient s really show no fade any more, particularly after volatile anesthetics [51] ( Drab. 3.6). Additionally, a wait of several minutes is required after tetanic stimulation before restimulation is possible. Therefore, this stimulation mode is not suitable for continuous monitoring of neuromuscular recovery. That is why the DBS mode is regarded as the most suitable stimulation pattern for tactile and/or visual detection of the stimulatory response. Nevertheless, even the DBS mode ceases to reliably detect residual blockade above a TOF ratio of 0.6-0.7. By contrast, the TOF mode is indicated whenever a quantitative nerve stimulator like the TOF-Watch" is used. Quantitative nerve stimulators only provide an objective measurement of the stimulatory response after TOF stimulation and/or after single twitch stimulation. With these neuromuscular

3

113 3.3 . Monitoring neuromuscular recovery

D Tab. 3.6. Recommendationfor useof individual stimulation patterns Stimulation form

Onset of action

Deep blockade

Maderat blockade

Neuromuscular rKovery

TOF

Suitable

Unsuitable

Suitable

Conditionally suitable'

DBS

Conditionally suitable

Unsuitable

Unsuitable

Conditionally suitable

PTC

Conditionally suitable

Geeignet

Unsuitable

Unsuitable

Tetanus (SO/I 00 Hz)

Unsuitable

Unsuitable

Unsuitable

Conditionally suitable

Suitable b

Deep blockade:TOFcount=O Moderate blockade:TOFcount=I -3 "-OF by visual/tactile assessment bTOF measuredobjectively

transmission monitoring devices, the twitch after both DBS and tetanic stimulation has to be assessed subjectively. Thus, the advantage of quantitative nerve stimulators does not come to the fore with these two stimulation patterns. In the TOF mode, on the other hand, acceleromyography is capable of quantitatively measuring neuromuscular recovery with sufficient accuracy.

Testmuscles The ideal test muscle for assessing neuromuscular recovery should react as sensitively as possible to NMBAs. Sufficient evidence for ruling out a residual blockade at the other more resistant muscles can be assumed as soon as this highly sensitive muscle ceases to show signs of incomplete neuromuscular recovery. The corrugator supercilii muscle ranks among the more resistant muscles. Therefore, incomplete neuromuscular recovery may be visible at a number of relevant muscle groups although no more residual blockade is detectable at the corrugator supercilii muscle. This characteristic makes the corrugator supercilii thus less suitable than the adductor pollicis muscle for monitoring neuromuscular blockade.

114

Chapter 3 · Clinical application

The adductor pollicis muscle only partially fulfills the requirements we stipulated at the beginning of this chapter. It is certainly much more sensitive than the diaphragm or the intercostal muscles. Hence, when there is adequate recovery of the adductor pollicis muscle, a residual block at the two important respiratory muscles can be ruled out with sufficient certainty. At the same time, however, the adductor pollicis muscle shows greater resistance than the pharyngeal muscles and the extrinsic muscles of the tongue and/or the floor of the mouth muscles. As a result, swallowing difficulties and inspiratory obstruction of the upper airway may arise in the immediate postoperative phase despite adequate recovery of the adductor pollicis muscle. This fact should be kept in mind when interpreting the neuromuscular recovery of the adductor pollicis muscle.

o

Swallowing difficulties and/or inspiratory obstruction of the upper airway can occur despite adequate recovery of the adductor pollicis muscle . Key points - - - - - - - - - - --

-

-

-

-

-

-

-

-

----,

Clinical test ing alo ne is ill suited as a sole criterion for assessing neuromuscu lar recovery, but does provide a valuable enhancement to neuromuscu lar monitoring strategies .

-

In term s of visual and/or tactile assessment of the stimula tory response, the DBSmo de is superior to the TOF mo de. However, above a TOF ratio of 0.7, the DBScan no longer detect any more fade either.

-

The TOF mo de should be used whenever objec tive monitoring of neu -

-

The corru gator supercilii muscle is no t suitable for assessing neuromus-

romuscular recovery is desired. cular recovery. -

A »com plete« recovery of th e adductor pollicis muscle does not rule ou t relevant resid ual blocka de of t he pharyngeal muscles and /or the muscles of the upper airway.

3.3.5

Prevention strategies for residual neuromuscular blockade

The call for effective prevention strategies is understandable in light of the high incidence of residual neuromuscular blockade, and given the serious clinical implications to be expected from even a »rninimal- residual block, i.e.,

115

3

3.3 . Monitoring neuromuscular recovery

at a TOF ratio -0.8, after just a single intubation NMBA dose. Current evidence indicates that routine use of neuromuscular monitoring and generous rendering of the indication for reversal are essential elements of every strategy for preventing residual blockade.

o

Routine use of neuromuscular monitoring and generous rendering of the indi cation for reversal will successfully help prevent relevant residual blockade.

Qualitative neuromuscular monitoring

Options like TOF, DBS and 100-Hz tetanus are available for the qualitative monitoring of neuromuscular recovery (i.e., tactile and/or visual assessment of the stimulatory response). Starting from a TOF ratio of 0.4-0.5, all four stimulatory responses will be detected by visual or tactile assessment of the TOF with the same intensity. Consequently, residual blockade above this value are no longer distinguishable. DBS, currently the best test for qualitative, i.e., tactile and/or visual, assessment of neuromuscular recovery, allows this limit to be shifted to 0.6-0.7; but beyond this, neither DBS nor 100-Hz tetanus provide any additional evidence about the quality of neuromuscular recovery. As described at the beginning, however, a clinically relevant impairment of upper airway function can be expected even when the residual blockade is »minirnal« (i.e, TOF ratio ~0.8) . Qualitative tests are therefore not suitable for determining whether respiratory function and, particularly, upper airway integrity have recovered sufficiently from the neuromuscular block. That means these modes are not appropriate for identifying the patients who do not need reversal. So, qualitative monitoring primarily only provides information about the possible timing for pharmacological reversal. Research by Kopman et al. [52] produced further evidence on the merits of qualitative monitoring for preventing residual blockade. The authors investigated a total of 60 patients of whom 30 intraoperatively received cisatracurium and 30 rocuronium. At the end of the operation, reversal was timed with a »simple« nerve stimulator. As soon as two of four TOF responses were detectable, 0.05 mg/kg neostigmine and 10 fig/kg glycopyrrolate were routinely administered. Over the subsequent 30 minutes, the further course of neuromuscular block was monitored. Here, the authors found that all patients except for one in each group had 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

<0.05

TOFratio after 10 min

0.72±O.10

0.76 ±O.11

n.s.

TOFratio at 15 min

0.84±O.07

0.82±O.10

n.s.

TOFratio <0.7 at 10 min (n)

9

9

n.s.

----

TOFratio <0.7 at 15 min (n)

n.s.

TOF ratio <0.7 at 30 min (n)

0

0

n.s.

TOFratio < 0.9 at 30 min (n)

2

5

n.s.

Time profile of neuromuscular recovery with cisatracurium and rocuronium . As soon as t wo of the four TOF responses were detecte d, all patient s received neost igmine (0.05 mg/ kg) and glycopyrrolate (10 Il g/k g). The state d times refer to the start of ant agonist injecti on. The values represent t he mean ± SO n.s., not significant

117

3

3.3 . Monitoring neuromuscular recovery

Quantitative neuromuscular monitoring

The advent of acceleromyography several years ago heralded the entry of quantitative neuromuscular monitoring into clinical practice. This method enables objective measurement of neuromuscular blockade and is more precise than the subjective tests described above. As recent studies have proven, the accuracy of acceleromyography critically depends on the type of application [55). In order to exclude even »rninimal" residual blockade with certainty and thereby identify those patients in whom reversal can be omitted at the end of the intervention, special demands must be placed on the acceleromyographic procedure. This includes calibrating the nerve stimulator prior to injection of the NMBA. On current models like the TOF-Watch·, the calibration procedure takes just a few seconds, while significantly raising the accuracy of the TOF ratio. Moreover, the course of the neuromuscular block should be monitored continuously throughout the entire intervention, not simply as an isolated test performed the minute the surgery comes to an end. These conditions are easily integrated into clinical practice and enable the anesthesiologist to reliably rule out even »minimal« residual blockade at an acceleromyographic TOF ratio of 1.0. In the author's own studies, over 95% of the patients with an acceleromyographic TOF ratio of 1.0 really had no residual neuromuscular block whatsoever [55). However, this percentage dropped, as soon as the nerve stimulator was used as an isolated test at the end of surgery - a frequently observed practice in clinical practice [51) (DTab.3.8).

a Tab. 3.8. Negative predictive value of different TOFvalues measured byacceleromyography (modified after [14]). TOFratio

TOF-Watch

TOF Watch

0.9

37 (20-56)

40 (23-59)

0.95

70 (51- 85)

69 (41-77)

1.0

97 (8 3- 100)

77 (58-90)

Negative predictive value: Proportion of pat ient s (in %) without residual neuromuscular blockade at acceleromyographic r OF ratios of 0.9, 0.95 and 1.0.

118

Chapter 3 . Clinical application

100 80 11\

C 60 Q) .~

0.

~

40 20 0

1995 n=435

2000 n=130

2002 n=1 01

2004 n=218

a

Fig.3.12. Neuromuscular monitoring and reversal to reduce residual block rates.Black diamonds: Numberof patientswith residual neuromuscular blockade; Blue bars: Numberof patientsrequiring intraoperative monitoring and/or reversal. Numbers given in percent. (Adapted from [54])

Citing examples from their own hospital, Baillard et al. [54] reported how postoperative residual blockade can truly be avoided by using quantitative neuromuscular monitoring and reversing as needed ( a Fig. 3.12). The details of th is work are presented in ~ Chapter 4.7.5. If, however, a residual neuromuscular block cannot be reliably ruled out at the end of a surgical procedure, the patient should be managed by reversal or even postoperative ventilation until recovery is complete. Key points - - - - - - - - - - - - - - - - - - - - - - - - - , Even with residual blockade above a rOF ratio of 0.6. incompl ete neuromuscular recovery can be expected to lead to clinically relevant consequences. Particularly upper airway integrity and swallowing abil ity are often still markedly impaired. Simple. Le.•qualitative nerve stimulators are not able to detect neuromuscular recovery above th is level. -

Quantitative nerve stimulators are therefore also not suitable for identi-

~

i1yare useful for providing information about the possible time to ad-

fying those patients who do not need to be reversed either, but pr imar-

119

3.3 . Monitoring neuromuscular recovery

3

minister pharmacological reversal. Given the above, when quantitative nerve stimulators and reversal are applied as rout ine procedures, then relevant residual blockade should occur w ith a rare frequency. Used properly, quantitat ive neuromuscular mon itoring can detect even m inimal residual blockade, making it possib le to reliably identify patient s who really no longer requ ire reversal. -

Whenever a residual neuromuscular blockade cannot be ruled out w ith certainty at the end of a surgical procedure, th e pat ient should either be reversed or vent ilated until adequat e neuromuscular recovery has been accompl ished.

Important - - - - - - - - - - - -- - - - - - - - - - - - , -

Even when administered at clinically conventi onal doses, NMBAs can lead to residual neuromuscular blockade that elevate the risk of severe postoperative pulmonary complications.

-

Partial neuromuscular blockade can reduce vital capacity and obstruct the upper airway in addition to impairing both pharyngeal function and the hypox ic respiratory response; yet, even when the added effect s of analgesics, sedatives or anesthet ics are om itted, anesthesiologists cannot rule out part ial neuromuscular blockade w ith certainty (TOF ratio: 0.5-0.9) by merely relying on the ir senses to interpret th e respon se to a simple nerve stimulator.

-

The extent of neuromuscular recovery at the end of surgery depends on the NMBA adm inistered, th e duration of th e surgery as well as on the anesthesia technique and any concom itant diseases. Thus, in principle , it can be assumed that residua l neuromuscular blockade will occur w ith a higher frequency after long-acti ng NMBAs than after intermediate-acti ng drugs .

-

When the course of neuromuscular blockade is continuously managed by quan titative neuromuscular monitoring from the beginning to end of anesthesia, and not just as an isolated test at the end of surgery, then a TOF ratio of 1.0 measured by acceleromyography (e.g. TOF-Watch- ) can be equate d with sufficient recovery of the neu romuscu lar blockade . This method can thus reliably identify pat ients who really do not need

"

to be reversed.

120

Chapter 3 • Clinical application

-

Given their limited accuracy, the indication for reversal should be ren dered more generously when »sim p le« qualitative nerve stimulators are employed.

References Griffith HR, Johnson GE (1942) The use of curare in general anaesthesia. Anesthesiology 3:

418-420 2 Katz RL (1967) Neuromuscular effects of d-tubocurarine, edrophon ium and neostigmine in man. Anesthesiology 28: 327-336 3 Levano 5, Ginz H, Siegemund M, Filipov ic M, Voronkov E,Urwyler A, Girard T (2005) Geno-

4

5 6

7

8 9 10 11

typing the butyrylcholinesterase in pati ent s with prolonged neuromuscular block after succinylcholine. Anesthesiology 102: 531-535 Lang C, Lukasewitz P, Wulf H, Geldner G (2002) Plasmacholinesterasevarianten als Ursache prolongierter neurornuskularer Blockaden: Obersicht und Problemdarstellung anhand zweier Fallberichte prolongierter neuromuskularer Blockaden nach Muskelrelaxation mit Succinylbischolin und Mivacurium . Anaesthesist 51: 134-141 Sparr HJ, BeaufortTM, Fuchs-BuderT (2001) Newer neuromuscula r blocking agents: how do they compare with established agents? Drugs 61: 919-942 Debaene B,Plaud B, Dilly MP.Donat i F (2003) Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action . Anesthesiology 98: 1042-1048 Lambert P. Junke E, Fuchs-Buder T, Meistelman C, Longrois D (2006) Inter-patient variability upon induction with sevoflurane estimated by the time to reach predefined endpoints of depth of anaesthesia. Eur J Anaesthesiol 23: 311-318 Landau R (2006) One size does not fit all: genetic variability of u-op loid receptor and postoperative morphine consumption (Editorial) . Anesthesiology 105: 235-237 Lewis CB (1948) Endotracheal Intubation under Thiopentone. Anaesthesia 3: 113-115 Mc Keating K, Bali M, Dundee JW (1988) The effects of thiopentone and propofol on upper airway integrity. Anaesthesia 43: 638-640 Scheller MS, Zornow MH, Saidman U (1992) Tracheal int ubati on without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg

75:788-793 12

Grant S, Noble S, Woods A, Mu rdoch J, David son A (1998) Asse ssment of int ub ati ng conditions in adults after induction with propofol and varying doses of remifentanil. Br J Anaesth 81: 540-543 13 Baillard C, Adnet F, Borron SW, Racine SX, Ait Kaci F, Fournier JL, Larmignat P. Cupa M, Samama CM (2005) Tracheal intubation in rout ine practice with and without muscular relaxation : an observat ional study. Eur J Anaesth 22: 672-677 14 Schlaich N, Mertzlufft F. Soltetsz 5, Fuchs-Buder T (2000) Remifentanil and Propofol without muscle relaxants or w ith different doses of rocuron ium fortracheal intubation in outpatient anaesthesia. Acta Anaesthesiol Scand 44: 720-726

121

3

References

15 Mencke T, Echternach M, Kleinschmidt 5, Lux P. Barth V, Plinkert PK, Fuchs-Buder T (2003)

16

17

18 19

20

21

22

23

24

Laryngea l morbidity and quality of tracheal int ubat ion: a randomized controlled trial. Anesthesiology 98: 1049-1056 Combes X, Andriamifidy L, Dufresne E, Suen P, Sauvat 5, Scherrer E, Feiss p. Marty J, Duvaldestin P (2007) Comparison of tw o induct ion regimens using or not using muscle relaxant: impact on postoperative upper airway d iscomfort. Br J Anaesth 99: 276-281 Adnet F, Borron SW, Racine SX, C1emessy JL, Fournier JL, Plaisance P. Lapandry C (1997) The int ubati on difficulty scale (IDS): proposal and evaluat ion of a new score characterizing the complexity of endotracheal intubation. Anesthesiology 87: 1290-1297 Hemmerling TM, Donati F (2003) Neuromuscular blockade at the larynx , the diaphragm and the corrugator supercilii muscle: a review. Can J Anaesth 50: 779-794 Debaene B, Beaussier M, Meistelman C, Donat i F, Lienhart A (1995) Monitoring the onset of neuromuscular block at the orbicularis oculi can predict good intubat ing conditions during atracur ium- induced neuromuscular block . Anesth Analg 80: 360-363 Rimaniol JM, D'honneur G, Sperry L, Duvaldestin P (1996) A comparison of the neuromuscular block ing effects of atracurium, mivacurium, and vecuronium on the adductor poll icis and the orbicularis oculi muscle in humans . Anesth Analg 83: 808-813 Larsen PB, Gatke MR, Fredensborg BB, Berg H, Engbaek J, Viby-Mogensen J (2002) Acceleromyography of the orbicularis oculi muscle II: comparing the orbicualris oculi and adductor pollicis muscles. Acta Anaesthesiol Scand 46: 1131-1136 Plaud B, Debaene B, Donati F (2001) The corrugator supercilii, not the orbicularis oculi , refects rocuronium neuromuscular blockade at the laryngeal adductor muscles. Anesthesiology 95: 96-101 Koscielniak-Nielsen ZJ, Horn A, Stzuk F, Eriksen K, Skoovgard LT, Viby-Mogensen J (1996) Tim ing of tracheal intubation: monitoring the orb icular is ocu li, the adductor pollicis or use a stopwatch? Eur J Anaesth 13: 130-135 Ueda N, Muteki T, Tsuda H, Masuda Y, Ohishi K,Tobat a H (1993) Determining the optimal time for endotracheal intubation during onset of neuromuscu lar blockade. Eur J Anaesth

10:3-8 25 Fuchs-Buder T, Tassonyi E (1996) Intubating conditions and time course of rocuron iuminduced neuromuscular block in children. Br J Anaesth 77: 335-338 26 Fuchs-Buder T, Hofmockel R, Geldner G, Diefenbach C, Kulm K, Blobner M (2003) Einsatz des neurornuskularen Monitorings in Deutschland. Anaesthesist 52: 522-526 27 Geldner GF, Fassbenderp.Blobner M, Gautam 5, Eikermann M (2007) Predictors of durat ion of action of repetitively adm inistred cisatracurium and rocuronium. Anesthesiology A393 28 Maybauer DM, Geldner G, Blobner M, Puhrinqer F, Hofmockel R, RexC, Wulf HF, Eberhart L, Arndt C, Eikermann M (2007) Incidence and durat ion of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium . Anaesthesia 62: 12-17 29 Mart in R. Bourdua I, Theriault 5, Tetrault Jp. Pilote M (1996) Neuromuscular monitoring: does it make a difference? Can J Anaesth 43: 585-588 30 D'honneur G, Kirov K, Motamed C, Amath ieu R, Kamoun W, Siovov V, Ndoko S-K. (2007) Post-tetaniccount at adductor pollicis is a better indicator of early diaphragmatic recovery than train-of-four count at corrugator supercilii. Br J Anaesth 99: 376-379 31 Ali HH, Wilson RS, Savarese JJ (1975) The effect of tubocurarine on indirectly elicided tra in-of-four muscle response and respiratory measurements in humans . Br J Anaesth 47:

570-574

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Chapter 3 • Clinical application

32 Begin P, Mathieu J, Almirall J, Grassino A (1977) Relationship between chronic hypercapnia and respiratory muscle weakness in myotonic dystrophy. Am J Respir Crit Care Med 156: 133-139 33 Arora N5, Gal TJ (1981) Cough dynamics during progressive expiratory muscle weakness in healthy curarized subjects. J Appl Physiol 51: 494-498 34 Eikermann M, Groeben H, Husing J, Peters J. (2003) Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Anesthesio logy 98: 1333-1337 35 Eikermann M, Groben H, Bunten B, Peters J (2005) Fade of pulmonary function during residual neuromuscular blockade. Chest 127: 1703-1709 36 Eikermann M, Vogt FM, Herbstreit F,Vahif-Dastgerd i M, Zenge MO, Ochterbeck C, de Greiff A, Petres J (2007) The predisposition to insp iratory upper airway collapse during partial neuromuscular blockade. Am J Respir Crit Care Med 175: 9-15 37 Eriksson LI (1996) Reduced hypoxic chemosensitivity in partially paralysed man. A new property of muscle relaxants? Acta Anaesthesiol Scand 40: 520-523 38 Eriksson L1, Sundman E, Olsson R, Nilsson L, Witt H, Ekberg 0, Kuylenstierna R (1997) Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers . Anesthesiology 87: 1035-1043 39 Fuchs-Buder T,Tassonyi E (1996) Magnesium sulphate enhances residual neuromuscular block induced by vecuronium. Br J Anaesth 76: 565-566 40 Kopman AF, Vee PS, Neuman GG (1997) Relationship of the train-of-four fade ratio to clinical signs and symptoms of residual paralysis in awake volunteers. Anesthesiology 86: 765-761 41 Fuchs-Buder T, Eikermann M (2006) Neurornuskulare Restblockaden : Klinische Konsequenzen, Hauflqkelt und Vermeidungsstrategien. Anaesthesist 55: 7-16 42 Arbous MS, Meursing AEE, van Kleef JW, de Lange JJ,Spoormans HHAJM, Touw P, Werner FM, Grobbee DE (2005) Impact on anesthesia management character istics on severe morbidity and mortality. Anesthesiology 102: 257-268 43 Holland R (1970) Special committee invest igat ing deaths under anaesthesia: Report on 745 classified cases. Med J Aust 1: 573-580 44 Holland R (1987) Anaesthesia Mortality in New South Wales. Br J Anaesth 59: 834-841 45 46 47 48

49

SO

Lunn IN , Hunter AR, Scott DB (1983) Anaesthesia-related surgical mortality. Anaesthesia 38:1090-1096 Cooper ALO, Leigh JM, Tring IC (1989) Admission on the intensive care unit after complications of anaesthetic techniques over 10 years. Anaesthesia 44: 953-958 Tiret L, Desmonts JM, Halton F,Vour'ch G (1986) Complications associated with anaesthesia: A prospective survey in France. Can J Anaesth 33: 336-344 Berg HJ, Viby-Mogensen J, Roed J, Mortensen CR, Engbaek J, Skovgaard LT, Krintel JJ (1997) Residual neuromuscular block is a risk factor for postoperative pulmonary complications. Acta Anaesthesiaol Scand 41: 1095-1103 Sorgenfrei IF, Norrild K, Larsen PB, 5tensballe 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 104:667-674 Dam WH, Guldmann N (1961) Inadequate postanesthetic ventilation. Anesthesiology 22: 699-707

123

References

51

52

53 54 55

SametA, CapronF, Alia F, MeistelmanC, Fuchs-BuderT (2005) Single acceleromyographic train-of-four, 1DO-hertz tetanus or double-burst stimulation: which test performs better to detect residual paralysis? Anesthesiology 102:51 -56 Kopman AF, Zank LM, Ng Jennifer,NeumannGG(2004) Antagonism of cisatracurium and rocuronium block at tactile train-of-four count of 2: should quantitative assessment of neuromuscularfunction be mandatory?AnesthAnalg 98: 102-106 KopmanAF, 5hina N (2003) Acceleromyography asa guide to anaestheticmanagement: a case report J Clin Anesth 15: 145-148 Baillard C,C1ec'h C,Catineau J, Salhi F, Gehan G, CupaM, Samama CM (2005) Postoperative residual neuromuscular block: a surveyof management. BrJ Anaesth95: 622-666 Capron F, Alia F, Hottier C, Meistelman C, Fuchs-Buder T (2004) Can acceleromyography detect low levelsof residual paralysis?A probability approach to detect a mechanomyographic train-of-four ratio of 0.9. Anesthesiology 100: 1119-1124

3

4

Acceleromyography

4.1

Principles

- 126

4.2

The Accelograph and the TOF-Guard

- 127

4.3

TOF-Watch models

4.3.1

The TOF ratio algorithm

4.3.2

Calibration modes

4.3.3

Nerve localization in regional anesthesia procedures

4.4

TOF-Watch

4.4.1

Short set-up instructions

- 130 - 130

- 133

- 138 - 138

4.4.2

Brief overview

4.4.3

Scheme of buttons and display symbols

- 139

4.5

TOF-Watch- S

4.5.1

Short set-up instructions

4.5.2

Brief overview

4.5.3

Scheme of buttons and display symbols

4.6

TOF-Watch- SX

4.6.1 4.6.2

Short set-up instructions Brief overview - 165

4.6.3

Scheme of buttons and display symbols

- 166

4.6.4

Scheme of buttons and display symbols

- 168

- 140

- 150 - 150

- 151 - 152

- 164 - 164

- 136

4 4.7

FAQS

4.7.1

Can acceleromyography also be used in infants?

179 - 179

4.7.2

Is neuromuscular monitoring painful for patients?

4.7.3

What to obs rv when attaching rOF -Watch nerve

4.7.4

Is calibration really n cessary?

4.7 .5

Can neuromuscular monitoring with the rOF -Watch

stimulators?

- 182 - 184

n rye stimulator prey nt residual blockade? 4.8 4.8.1

- 180

Acceleromyogr phy

10

r s

rch

- 190

193

Neuromuscular monitoring for scientific purposes: What should an sth siologists g nerally look out for?

- 194

4.8.2

Particulars of performing accel romyography

4.8.3

Guidelines for measuring onset and time profile of neuromuscular blockad Concluding r m rks R f renc s

- 202

- 198 - 200

- 197

126

Chapter 4 · Acceleromyography

4.1

Principles

Thanks to acceleromyography (AMG), routine objective monitoring of neuromuscular blockade has become possible for the first time in clinical practice. Not only is this monitoring method much easier to apply than the other two established quantitative neuromuscular monitoring methods, i.e., mechanomyography and electromyography, but acceleromyography is also clearly more precise than the »simple- qualitative nerve stimulators which only allow subjective assessment, but no objective measurement of the stimulatory response. Surveys have shown that TOF-Guard acceleromyographs and their successor models in the TOF-Watch" series are by far the most frequently used nerve stimulators for clinical monitoring of neuromuscular blockade in Germ any and many other countries a Fig.4.1 [1].

* Applikation customs

. .

81 - 100% 61 • 80%

41 • 600/. 021 • 40%

o

0 - 20%

o

Never

20%

0%

..L-L.-_ _.J.-....l-_ _.....L.- . I: ' -_ _J..-....I-_

_

......1.._

TOF-Gu ard. simple Electromyograph NMT module TOF·Watch nerve stimulator (Relaxograph) e.g. Datex AS-3

D Fig.4.1. Neuromuscular monitoring method s. The frequency with wh ich the indiv idual nerve stimulators are used is presented [1]

127

4

4.2 . The Accelograph and the TOF-Guard

Acceleromyography is based on the principle that mechanical forces at play on the surface of certain materials, such as crystals or ceramics, can induce an electrical current. This is termed the piezoelectric effect. Modern AMG-based nerve stimulators use a piezoelectric wafer made of ceramic as the acceleration transducer. Acceleration of the transducer produces an electrical charge. According to Newton's second law of motion, force equals mass times acceleration (F=mxa). At constant mass, the acceleration measured and the voltage thereby generated can be used to derive the force of the stimulated muscle. Thus , acceleromyography can be performed on all muscles whose movement or acceleration is easily measured after electrical stimulation of its innervating nerve. Usually, the ulnar nerve is stimulated and the acceleration is subsequently measured with a piezoelectric sensor fixed to the thumb. Th is method allows objective assessment of the degree of neuromuscular blockade at the adductor pollicis muscle. Alternatively, acceleromyography can also be applied to other muscle-nerve units . The flexor hallucis brevis muscle and the posterior tibial nerve are primarily used as the muscle-nerve unit of the lower extremity. For the facial region, the orbicularis oculi muscle and the corrugator supercilii muscle are the two test muscles available. Both of these muscles are innervated by branches of the facial nerve, allowing them to be stimulated by surface electrodes placed near the eye.

4.2

The Accelograph and the TOF-Guard

The design of nerve stimulators based on the principle of acceleromyography was predicated on the invention of suitable acceleration transducers . The year 1988 marked the development and validation of the first acceleration transducer especially designed for monitoring neuromuscular blockade [2]. Concurrently, a novel concept for monitoring neuromuscular blockade emerged [3, 4]. The first ready-for-market nerve stimulator based on acceleromyography was also introduced that very same year [5]. The device was dubbed the »Accelograph« in line with the new measuring method on which it was based. While not being very compact in design, the original Accelograph was relatively fast and easy to implement; including calibration, it was operational within a few minutes. In 1989, Ueda et al. [5] were the first

128

Chapter 4 . Acceleromyography

to compare the Accelograph with the reference method, i.e., mechanomyography. According to these authors, both the single twitch stimulation and the TOF response were identical on the two nerve stimulator models, the AMG device proving much easier to handle. Contingent upon the anesthesiologist's good intentions, objective monitoring of neuromuscular blockade was now possible in clinical practice. Just a few years later, the TOF-Guard came out on the market - a truly compact, portable and battery-operated device based on the principle of acceleromyography [6] (a Fig. 4.2). This was the first device to become available for routine clinical use that not only met anesthesiologists' basic requirements, but also enabled a sufficiently accurate intraoperative assessment of neuromuscular function . Undoubtedly, this first model had its weaknesses in terms of both ergonomics and technique . The TOF-Guard was designed as an all-purpose

a Fig. 4.2. TOF-Guard nerve stimulator

129

4

4.2 . The Accelograph and the TOF-Guard

device for applications in clinical anesthesia, intensive care medicine and research. Moreover, this nerve stimulator featured no less than 19 (!) different buttons, some programmed with multiple and/or freely programmable functions . Not surprisingly, it was cumbersome to operate and rather unmanageable. During routine clinical use, the first generation of acceleration transducers and their original cable designs were also subject to malfunction. These problems were compounded by the fact that the model did not yet incorporate a technical solution for the inherent overshoot that occurred when measuring the TOF ratio. This problem was the reason that the TOF-Guard frequently measured TOF ratios greater than 100%, which occasionally led to a certain amount of uncerta inty when interpreting the results. To improve on these bugs, the TOF-Watch" series - representing a completely overhauled and optimized version of compact acceleromyographs - was launched in 1997 (D Fig.4.3).

D Fig.4.3. TOF-Watch" nerve stimulator

130

Chapter 4 • Acceleromyography

4.3

TOF-Watch'" models

The most notable change over its predecessor was the diversity of models offered by the TOF-Watch" series. Instead of a single TOF-Guard model, the new product family included three nerve stimulators : the TOF-Watch", TOFWatch" Sand TOF-Watch" SX - each featuring different application profiles. These differences involved the calibration modes and the algorithms used for calculating the TOF ratio. Common to all three TOF-Watch" models is that they can also be used to localize nerves during locoregional anesthesia procedures. The following sections will address these particulars and explain which models are best suited for which applications.

4.3 .1 The TOF ratio algorithm It has been frequently observed in clinical practice that acceleromyographic TOF baseline values measured prior to NMBA injection exceeded 100%. Suzuki et al. [7] investigated this phenomenon in a total of 120 patients. In their study, the average baseline response after TOF stimulation was 111%, across a range of 94-147% (aTab.4.1). This overshoot-type TOF response is a unique characteristic of acceleromyography and is not observed with mechanomyography or electromyography to such an extent. The reason for this phenomenon has not been explained fully, but is assumed to be caused by the thumb not returning to its exact original position after stimulation of the ulnar nerve. Therefore, successive stimulations keep producing subsequent response values exceeding 100% until the thumb has finally returned to a stable starting position. This theory is reinforced by the observation that the phenomenon is significantly reduced by using a hand adapter to ensure that the thumb returns to its baseline position after every stimulation. Overshoot-type baseline responses after TOF stimulation cause problems with interpreting neuromuscular recovery. Adequate neuromuscular recovery is strictly defined as a TOF ratio of 0.9, i.e., 90% of the baseline value. At a baseline TOF ratio of 147% (as Suzuki et al. reported in the study cited above), a TOF ratio measured as 90% however is barely 61% of baseline. In this example, a recovery to 90% of baseline is thus not accomplished until the TOF ratio equals 132%, i.e., 90% of 147%. Neuromuscular recovery will be overestimated when the value of 90% is indicated on the display. That

4

131 4 .3 . TOF·Watch- models

a Tab. 4.1. Proqress of T, response and TOF ratio over 30 minutes (modified after (7)) n=120

5tart

5mon

10mon

20min

30 min

%T,

100

121 (100-168)

131 (102- 188)

136 (100- 192)

136 (92-192)

1.10 (0.92-1.47 )

1.12 (0.97- 1.45)

1.12 (0.94-1. 45)

1.13 (0.95- 1.47)

TOFratio

1.11 (0.94-1.47)

Data are presented as mean [range] .

means that particularly moderate residual blockade, corresponding to a TOF ratio between 60% and 90%, i.e. where severe functional impairment of the upper airway can be expected, will not be detected properly under the above circumstances. Calibration does not solve the problem of overshoot -type TOF ratios either, but only initially sets the T I response to 100%. The study by Suzuki et al. showed however that TOF ratios > 1 were measured regularly despite calibration [7]. During a 30-minute stabilization phase prior to administration of the NMBA, the average T I response rose continuously from an original 100% to 136%(SD range: 92-192%). By contrast, the TOF ratio (i.e., the ratio of the T4 to the T I response) remained very constant : from an initial 1.11 (SD range: 0.94-1.47), it was still only 1.13 (range 0.95-1.47) after 30 min (aTab.4.1). The only explanation for why the ratio of the fourth to the first response remained largely constant is that all four responses to TOF stimulation increase in equal measure during the stabilization phase. Therefore, when acceleromyographic nerve stimulators are used in research studies, a 20- to 30-minute stabilization phase followed by re-calibration is required before injecting the NMBA. Moreover, the TOF recovery should be stated as a percentage of the TOF ratio measured at baseline [8]. This will ensure that a recovery of the TOF ratio to 0.9 really equals 90% of baseline. This procedure is called »norrnalization«. Because it is timeconsuming, this method is not suitable for clinical application and therefore other solution s must be sought. Detailed analyses of the four single TOF responses showed that, after acceleromyographic stimulation, a differential is observed between the first and second TOF response, while the responses T2 up to and including T4 do not essentially differ (aFig.4.4). In light of these

132

Chapter 4 . Acceleromyography

facts, the factory-set algorithm for calculating the TOF ratio built into the TOF-Watch· and TOF-Watch" S models was modified as follows: - When the second TOF response (T2 response) is greater than the first (T, response) , the TOF ratio is not calculated as a ratio of TiT l' but automatically as a ratio of T4/ T 2' - If the TOF ratio continues to be >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<)' ../'..

response Transducer 9 ln 157

Transducer gain 170

Transducer gain 178

a Fig.4.5. Calibrationfunction (CAL 2) and sensitivity settings

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Chapter 4 . Acceleromyography

The other three stimulation modes on TOF-Watch" nerve stimulators, namely the DBS,the PTC and tetanic stimulation, are not affected by calibration because these stimulation modes do not measure the twitch, but only enable its tactile or visual assessment.

o

TOF-Watch- neuromuscular transmission mon itors should always be calibrated before starting the measurement. The calibration procedure takes little extra time and improves the accuracy of the acquired data .

4.3.3

Nerve localization in regional anesthesia procedures

In addition to their original function as neuromuscular transmission monitors, the three TOF-Watch" models can also be used to localize nerves during regional anesthesia procedures . For this purpose, they need a special stimulation cable. This cable contains a connection for a surface electrode as well as a standard plug for the stimulation needle. As soon as this cable is plugged in, the nerve stimulator switches to the regional anesthesia function and the stimulation parameters are adjusted to the new application. A mechanical barrier prevents the regional anesthesia cable from being plugged into the wrong outlet. In the regional anesthesia mode, the TOF-WatchO models stimulate with the following parameters: - Square wave constant current - Pulse width of 40 fIs - Stimulation current between 0-6.0 mA and/or 0-0.24 fIC infinitely selectable (pre-set default 0 fIC set) - Stimulation frequency 1 Hz (i.e., one stimulation per second) Thus, the TOF-Watch" models similarly fulfill the requirements placed on nerve stimulators used to localize peripheral motor nerves in regional anesthesia procedures [11]. Besides their application in neuromuscular moni toring, these devices can be used as fully fledged nerve stimulators during regional anesthesia as well. This feature is a further improvement over the earlier TOF-Guard model, which was not equipped with this double function . The different features provided by the three TOF-Watch" nerve stimulators (DTab.4.2) allow them to be classified according to the various areas of application.

4

137 4 .3 . TOF-Watch- models

a Tab. 4.2. Features and functlonalltles of the various TOF-Watch" models Model

TOF-Watch

TOF-Watch S

TOF Watch SX

Stimulation mode Train-of-four (TO F) Post-tetanic count (PTC) Single twitch - 1 Hz Single twitch - 0.1 Hz Double-burst stimulation (DBS)3.3 or 3.2 Tetanus - SOor 100 Hz . Slow« TOF (TOFs) TOF ratio algorithm

Always T.tT I Current (0-60 mAl Pulse w idth Monophasic 200 ps Monophasic 300 liS C Iibration mode CALl CAL2 Manual transducer sensitivity setting TOF and /or TOFs alarm Loudspeaker Automatic power switch off Surface temperature sensor PC connection option Nerve localization In reg ional anesthesia

"Slow«TOF and/or TOFs: TOFinterval infinitely selectable between 1-60 min TOFalarm and/or TOFs alarm:TOF mon itor ing with alarm limits for the number ofTOF responses (TOFcount) or the TOF ratio, the alarm limits are infinitely selectable Manual transducer sensitivity setting : If no supramaximal stimulation current can be found, the transducer sensitiv ity can be manually set from 0 to 600. Pre-set default is a unit- less value of 157. Automatic pow er switch off :The device switches off auto matically after 2 hours of no operat ion.

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Chapter 4 . Acceleromyography

Key points - - - - - - - - - - - - - - - - - - - - - - - - , - Due to theirT.fT2 algorithm. the models TOF-Watch- and TOF-Watch- S are suited for clinical applications exclusively. They should not be used for research studies. The TOF-Watch- model fulfillsthe basic require ments placed on quantitative nerve stimulators and is completely ad equate for routine clinical applications. - The most notable feature distinguishing these two models is their calibration mode. In addition to the standard calibration funct ion (CAL 1). the TOF-Watch- S model can also determine the supra maximal current during the calibrat ion procedure (CAL2).This feature prevents the st imulation current from becoming too strong and thereby prevents any risk of direct muscle stimulation or the risk of insufficient. i.e. submaximal stimulation. Moreover. the TOF-Watch- S gives users the option to define the TOF interval within a range of 1-60 minutes. This function was specifically developed for applications on the ICU. - The TOF-Watch- SX was designed as a nerve stimulator for research. Accordingly, it is the only one of the three models that features a data exchange option with a PC interface. When using th is model for clinical purposes. the anesthesiologist must wait for calibrat ion unt il the T. response or the TOF ratio have stabilized . - Furthermore. all three TOF-Watch- models can be employed to localize peripheral motor nerves for regional anesthesia procedures.

4.4

TOF-Watch Gil

4.4.1

Short set-up instructions

1. Place the electrodes on the distal course of the ulnar nerve, attach the acceleration transducer to the thumb. . , Clean, degrease, and if necessary, shave the skin where the electrodes are to be attached. The distal electrode should be connected to the black (negative) clip. Fasten the acceleration transducer with its largest flat side to the thumb. 2. Turn TOF-Watch" on by pressing the on-off button and holding it down for 1 second (this will be acknowledged by a short beep)

139

4

4.4 . rOF-Watch-

8

The device can be switched on while the patient is awake.

3. Pre ss the calibration button; after not more than 10 single stimulations at 1 Hz the device is calibrated and operational

o

Always calibrate after anesthesia induction, but before muscle relaxation! Never calibrate if the patient is not yet anesthetized; calibration is equally pointless if the patient is already relaxed.The suitable time point for calibrating is during test ventilation directly prior to NMBA injection.The stimulation current strength on this device is pre-selected (50 rnA). Ifdesired, it can also be freely selected between 0 rnAand 60 rnA.

4. Hold down the rOF button for at least 1 s, repetitive TOF stimulation occurs in IS-second cycles . Switch to the PTC mode if the aim is to monitor deep neuromuscular blockade during the further procedure.

o

These three buttons are allthat is needed to quickly set up the rOF-Watch- for objective ly monitoring the course of neuromuscular blockade!When neuromuscular monitoring is initiated intraoperatively on already relaxed patients, the procedu re is the same as described above, but the calibration step is left out; calibration here would be pointless. A pre-NMBA administration baseline value can no longer be determined in this situation. Calibration here would thus be pointless.

4.4.2 -

-

Brief overview

Calibration: Press CAL 1, i.e., automatically adjust gain to 100% control twitch height; the stimulation current is set to default (50 rnA) Stimulation modes: TOF, DBS (3.3 and 3.2), PTC, tetanic stimulation (50 Hz and 100 Hz), single twitch (l Hz and 0.1 Hz) Output in neuromuscular monitoring: Constant current, infinitely selec table between 0-60 rnA, default pre-set to 50 rnA, pulse width of 200 fls Output in regional anesthesia: Constant current, infinitely selectable between 0-6 rnA, default pre-set to 1.5 rnA, pulse width of 40 fls The TOF-WatchO will automatically switch to the regional anesthesia mode when the special stimulation cable is connected

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Chapter 4· Acceleromyography

4.4.3 Scheme of buttons and display symbols

Scheme of buttons and display symbols on the TOF-Watch IDFig.4.6) 1. Stop / on-off button 2. Post-tetanic count (PTC) or tetanic stimulation button 3. Train-of-four (TOF) or double-burst stimulation lOBS) button 4. Secondary function button S. Secondary function symbol 6. Calibration symbol 7. Device on / stopped symbol 8. Battery status symbol 9. Internal error symbol 10. Stimulation beep symbol 11. Acceleration transducer symbol 12. Resistance too high symbol 13. Needle electrode symbol 14. TImer / stimulation symbol 15. Stimulation mode indication 16. Frequency symbol 17. Microcoulomb symbol 18. Milliampere symbol 19. Value for TOFratio, twitch height, PTC or stimulation current 20. Percent symbol: used for TOF ratio or twitch height 21. rnA I~C) up button 22. Calibration button 23. mAI~C) down button 24. 1 Hz / 0.1 Hz stimulation button

All buttons except for the calibration button on the TOF-Watch" nerve stimulator have a double function . Depending on the button, the secondary function is activated in different ways: The double function is depicted in the background on the three buttons used for selecting the stimulation mode; the secondary function is activated by first pressing the double function button and directly thereafter the corresponding stimulation mode button.

141

4

4.4 . TOF·WatchO

a Fig. 4.6.TOF-Watcho: Schemeof buttons and display symbols

-

For the other double function buttons, the period of time that a button is activated determines the selection of the function . The desired function is selected by pressing this button for less than 1 s (short activation) or by pressing the button for more than 1 sec (long activation).

The buttons and display symbols on the TOF-Watch" can be classified into four categories according to their function :

142

1. 2. 3. 4.

Chapter 4 · Acceleromyography

Starting up the TOF-Watch" Selecting the stimulation mode Alarm functions Settings

Starting up the r OF-WatchWhile the nerve stimulator can be switched on in the still awake patient, the button for selecting calibration and/or stimulation mode may only be operated after induction of anesthesia (but before injection of the NMBA). On-off button and /or stop-button The function activated by this button is determined by how long it is pressed. To switch the unit on and/or off, the button must be pressed for at least 1 s. As soon as the device is switched on, the corresponding symbol appears in the display

o

Long activa tion (> 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.

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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.

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Chapter 4 . Acceleromyography

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.

<:.

Stimulation units

The TOF -Watch" can show the strength of the electrical stimulation in both milliamperes [rnA) and microcoulomb [flC). 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 flC. ~C

Microcoulomb is the unit of electric charge and measures the quantity of electricity.

rnA Milliampere is the unit for current.

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Chapter 4 · Acceleromyography

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:

§

Battery status symbol: This symbol only appears on the display, if the battery is low and/or empty. 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.

t 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. If the acceleration transducer symbol flashes during calibration, the acceleration transducer signal is either too low or unstable. If this happens, the stimulation current should be increased manually. Three different error signals alert the user to problems with the stimula tion electrodes and/or any of the cables.

~J-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 .

4

149

4.4 . rOF-Watch"

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 recommendable to define standard

Set-up parameter.

Set-up Display

sudace electrode flashing (stimulation units) mA: Surfaceelectrode stimulation strength in milli-amperes, ~: Surfaceelectrode stimulation strength in micro-coulomb, 5urface electrode flashing (stimulationsize)

50 rnA:

Default surfaceelectrode stimulation strength can be adjusted between 0 and 60 mA/12 ~.

~

0

....

....

:==~~

o

Needle electrode flashing (stimulationunits) ~C:

rnA:

Needlestimulation strength shown in micro-coulomb. Needlestimulation strength shown in milli-amperes,

o

Needle electrode flashing (stimulation size)

0.0 IJC:

Default needle electrode stimulation strength can be adjusted between 0.0 and 6.0 mAlO.24 1Jc.

Loudspeaker flashing

0: 1:

Stimulation beep off. Stimulation beep on.

o

DB53.2 is used DB533 is used

o db5

n

085 flashing

3.2: 33 :

100Hz(or 50 Hz) flashing 100 Hz tetanic stimulation.

100 Hz: 50 Hz:

50 Hz tetanic stimulation.

a Fig.4.7.rOF-Watch" set-up parameters.Thestandard settings are printed in bold and shown in the display.

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Chapter 4 . Acceleromyography

settings for these parameters and only make changes as agreed. Otherwise , use of the nerve stimulator could easily lead to malfunctions, misunderstandings or misinterpretations. The set-up mode can only be accessed when the TOF-Watch" is switched on, but in the suspended mode , i.e., not during stimulation. 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.

4.5

TOF-Watch l8l S

4.5.1

Short set-up instructions

1. Place the electrodes on the distal course of the ulnar nerve, attach the ac-

celeration tran sducer to the thumb .

f)

Clean, degrease, and ifnecessary, shave the area where the electrodes are to be attached. The distal electrode should be connected to the black(negative) clip. Fasten the acceleration transducer with its largest flat side to the thumb.

2. Turn TOF-Watch" on by pressing the on -off button and holding it down for 1 second (this will be acknowledged by a short beep).

f)

The devicecan already be switchedon whilethe patient isawake.

3. Press the calibration button: The calibration function CAL 2 automatically sets the supramaximal current. Within a maximum of 30 seconds, the device is calibrated and operational.

151

4 .5 . TOF-Watch- S

o

4

Always calibrate after anesthesia induction. but before muscle relaxation! Never calibrate if the patient is not yet anesthetized; calibration is equally pointless if the patient is already relaxed. The suitable time point for calibrating is during test ventilation directly prior to NMBA injection.

4. Hold down the rOF button for at least 1 s, repetitive TOF stimulation occurs in IS-second cycles. Switch to the PTC mode if the aim is to monitor deep neuromuscular blockade during the further procedure.

o

These three buttons are all that is needed to quickly set up the TOF-Watch- S for objectively monitoring the course of neuromuscular blockade!When neuromuscular monitoring is initiated intraoperatively on already relaxed patients. the procedure is the same as described above. but the calibration step is left out. A pre-NMBA administration baseline value can no longer be determined in this situation. Calibration here would thus be pointless.

4.5.2 Brief overview -

-

-

Calibration: Press CAL 1, i.e., automatically adjust gain to 100% control twitch height; the stimulation current is set to default (50 rnA). Press CAL 2, i.e., automatically adjust gain to 100% control twitch height; the supramaximal current is set automatically. Stimulation modes: TOF, TOFs (slow TOF) , DBS (3.3 und 3.2), PTC, single twitch (l Hz and 0.1 Hz) Output in neuromuscular monitoring : Constant current, infinitely selectable between 0-60 rnA, default is pre-set to measure supramaximal current, pulse width between 200 f.ls and 300 f.ls Output in regional anesthesia: Constant current, infinitely selectable between 0-6 rnA, default pre-set to 1.5 rnA, pulse width of 40 f.ls. The TOF-Watch" will automatically switch to the regional anesthesia mode when the special stimulation cable is connected.

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Chapter 4 . Acceleromyography

4.5.3 Scheme of buttons and display symbols

Scheme of buttons and display symbols on the TOF-Watch e S (D Fig. 4.8) 1. Stop / on-off button 2. Post-tetanic count (PTC) or double-burst stimulation (DBS) button 3. Train-of-four (TOF) or slow train -of-four (TOFs) 4. Secondary function button 5. Secondary function symbol 6. Calibration symbol 7. Device on / stopped symbol 8. Battery status symbol 9. Internal error symbol 10. Stimulation beep symbol 11. Acceleration transducer symbol 12. Resistance too high symbol 13. Needle electrode symbol 14. Timer / stimulation symbol 15. Stimulation mode indication 16. Frequency symbol 17. Microcoulomb symbol 18. Milliampere symbol 19. Value for TOF ratio, twitch height, PTC or stimulation current 20. Percent symbol : used forTOF ratio or twitch height 21. rnA (IJC) up button 22. Calibration button 23. mA(IJC) down button 24. 1 Hz / 0.1 Hz stimulation button

153

4.5 .TOF·Watch· S

a Fig. 4.8. TOF-Watch"; Scheme of buttons and displaysymbols

4

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Chapter 4 . Acceleromyography

All buttons on the TOF-Watch' S nerve stimulator have a double function . Depending on the button, the secondary function is activated in different ways: - The double function is depicted in the background on five buttons; the secondary function is activated by first pressing the double funct ion button and directly thereafter the corresponding stimulation mode button. - For the other double function buttons, the period of time that a button is activated determines the selection of the function . The desired function is selected by pressing this button for less than 1 s (short activation) or by pressing the button for more than 1 sec (long activation). The buttons and display symbols on the TOF-Watch' can be classified into four categories according to their function . 1. Starting up the TOF-Watch· S 2. Selecting the stimulation mod e 3. Alarm functions 4. Settings

Starting up the TOF-Watch 8 S

While the nerve stimulator can be switched on in the awake patient, the button for selecting calibration may only be operated after induction of anesthesia (but before injection of the NMBA). The same applies to the selection of the stimulation mode. On-off button and/or stop -button The function activated by this button is determined by how long it is pressed. To switch the unit on and/or off, the button must be pressed for at least 1 s. As soon as the device is switched on, the corresponding symbol appears in the display.

o

Long activation (> 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.

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Chapter 4 . Acceleromyography

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

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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.

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.,.

.: ~:. 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.

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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
o

o

D o

aion) Determ of sup 1m threshold, folIawed I¥ alib tlon of tllInsducer se Ivlly It ·threshold + 1~· [ ( 6OmAorl21181£). 0 I bratlon c:A transducer sensitivity t user set '--

amenVch rge.

a Fig.4.9.rOF-Watch" S set-up parameters

.

..

lo..-J

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Chapter 4 . Acceleromyography

4.6

TOF-Watchlil SX

4.6.1

Short set-up instructions

1. Place the electrodes on the distal course of the ulnar nerve, att ach the acceleration transducer to the thumb.

8

Clean, degrease, and if necessary, shave the area where the electrodes are to be attached. The distal electrode should be connected to the black (negative) clip. Fasten the acceleration transducer with its largest flat side to the thumb.

2. Turn TOF-Watch" on by pressing the on-off button and holding it down for 1 second (this will be acknowledged by a short beep).

8

The device can be switched on while the patient is awake.

3. Press the calibration button: The calibration function CAL 2 automatically measures the supramaximal current. W ithin a maximum of 30 seconds, the device is calibrated and operational.

o

Alwayscalibrate after anesthesia induction, but before muscle relaxation! Never calibrate if the patient is not yet anesthetized; calibration is equally pointless if the patient is already relaxed. The suitable time point for calibrat ing is during test ventilation directly prior to NMBA injection .

4. Hold down the rOF button for at least 1 s, repetitive TOF stimulation occurs in IS-second cycles . Switch to the PTC mode if the aim is to monitor deep neuromuscular blockade during the further procedure.

o

These three buttons are all that is needed to quickly set up the rOF-Watch- SX for objectively monitoring the course of neuromuscular blockade! When neuromuscular monitoring is initiated intraoperatively on already relaxed patients, the procedure is the same as descr ibed above, but the calibration step is left out ; calibration here would be pointless .

165

4

4.6 . TOF-Watch- SX

4.6.2 -

-

-

-

-

Brief overview

Calibration: Press CAL I, i.e., automatically adjust gain to 100% control

twitch height; the stimulation current is set to default (50 rnA). Press CAL 2, i.e., automatically adjust gain so that the T1 response is 100% control twitch height; the supramaximal current is measured automatically. Stimulation modes: TOF, TOFs (Slow-TOp), PTC, single twitch (l Hz and 0.1 Hz) , moreover, the user-programmable button (P button) can be programmed to produce either DBS (3.3 or 3.2) or tetanic stimulation (50 Hz or 100 Hz) . Output in neuromuscular monitoring: Constant current, infinitely selectable between 0-60 rnA, the default is pre-set to mea sure supramaximal current, pulse width between 200 Ils and 300 Ils. Output in regional anesthesia: Constant current, infinitely selectable between 0-6 rnA, default pre -set to 1.5 rnA, pulse width of 40 Ils. The TOF-WatchO will automatically switch to the regional anesthesia mode when the special stimulation cable is connected.

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4.6.3

Scheme of buttons and display symbols

Scheme of buttons and display symbols on the TOF-Watch SX (D Fig. 4.10) 1. Stop l on-off button 2. Post-tetanic count (PTC) or pre-programmed stimulation button 3. Train-of-four (TOF) or slow train -of-four (TOFs) button 4. Secondary function button 5. Secondary function symbol 6. 7. 8. g.

Calibration symbol Device on I stopped symbol 8attery status symbol Internal error symbol

10. Stimulation beep symbol 11. Acceleration transducer symbol 12. Resistance too high symbol 13. Needle electrode symbol 14. Timer I stimulation symbol 15. Stimulation mode indication 16. Frequency symbol 17. Microcoulomb symbol 18. Milliampere symbol 19. Value forTOF ratio, twitch height, PTC or stimulation current 20. Percent symbol : used for TOF ratio or twitch height 21. 22. 23. 24.

rnA ( ~C ) up button Calibration button rnA ( ~C ) down button 1 Hz I 0.1 Hz stimulation button

25. Temperature button 26. Microsecond (us) symbol 27. Degree Celsius (OC) symbol

167 4 .6

. TOF·Watch e

SX

a Fig. 4.1 O.TOF-Watch " SX: Scheme of buttons and display symbols

4

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Chapter 4 · Acceleromyography

4.6.4 Scheme of buttons and display symbols

All buttons on the TOF-Watch· SX nerve stimulator have a double function. Depend ing on the button, the secondary function is activated in different ways: - The double function is depicted in the background on six buttons; the secondary function is activated by first pressing the double function button and directly thereafter the corresponding stimulation mode button. - For the other double function buttons, the period of time that a button is activated determines the selection of the function . The desired function is selected by pressing this button for less than 1 s (short activation) or by pressing the button for more than 1 sec (long activation) . The buttons and display symbols on the 'I'Olt-Watch" can be classified into four categories according to their function. 1. Starting up the TOF-Watch" SX 2. Selecting the stimulation mode 3. Alarm functions 4. Settings

Starting up the TOF-Watch 8 SX While the nerve stimulator can be switched on in the still awake patient , the button for the selecting calibration mode may only be operated after indu ction of anesthesia (but before injection of the NMBA). The same applies to the selection of the stimulat ion mode. On-off button and /or stop -button

The function activated by this button is determ ined by how long it is pressed. To switch the unit on and/or off, the button must be pressed for at least 1 s. As soon as the device is switched on, the corresponding symbol appears in the display.

o

Long activation (> 1 s) of this bu tton is required to switch the unit on and/or off.

Short activation « 1 s) toggles the ongoing stimulation off and clears the last twitch while the device continues to rema in operational. For example,

169 4.6 . TOF-Watch- SX

4

if the stimulation was performed in the TOF mode, the TOF stimulation will be toggled off and the last TOF value 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" SX 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 activation) to switch the device to stand-by.

Calibration button On this model, the calibration routine takes 30 seconds at the most. In the pre-set default CAL 2 function, the TOF-Watch" SX automatically determines the supramaximal current and simultaneously calibrates the device. Alternatively, the CAL 1 calibration function can be selected in th e set-up menu. In this case, calibration only takes 10 s, 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 operational 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 indi cated 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.

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Chapter 4 . Acceleromyography

On the TOF-Watch- SX, the calibration procedure (Cal 2) takes no more than

30 s, the supramaximal current is measured automatically.

Up and down rnA (IlC) buttons

These buttons are used to manually set the stimulation current. On the TOF-Watch" Sand TOF-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 continuous ly 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) continuous ly 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 TOF-Watch- model. the supramaximal stimulation current is determined automatically. Any settings other than this must be made manually.

The secondary function on this button can be used to activate the TOF alarm. This function will be described in more detail in the »Alarms- section.

Selecting the stimulation mode

Four of the remaining buttons on the TOF-Watch" SX are used for selecting the stimulation mode. Without exception, all of them have a double function. With the three stimulation buttons, a total of five pre-set stimulation modes can be selected. Additionally, another stimulation mode, either DBS or tetanus, can be freely programmed with the user-programmable button . The respective double function is activated by pressing the secondary function button. The twitch after TOF stimulation and/or after single twitch (1 Hz or 0.1 Hz) is objectively measured and the result indicate d in the display.

171

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4.6 .TOF·Watch" SX

In addition, the PTC, DBS and the tetanic stimulation modes are available. None of these stimulation patterns are suitable for objective monitoring. Therefore, they should be assessed subjectively, i.e., either tactilely or visually, with the TOF-Watch" SX nerve stimulator. The display only shows the mode selected and the stimulation strength. Secondary function button

The three stimulation buttons on the TOF-Watch" SX have the double functions as listed below: TOF stimulation and slow (TOFs) button PTC and user-programmable button I-Hz single twitch and/or Ol-Hz-single twitch button. The secondary function of these buttons is activated by first pressing the »secondary function button- for less than I 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. 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.

Pressing the secondary function button for > I s (long activation), switches the acoustic stimulation signal on/off and the corresponding symbol is indicated in the display for I 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 .

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Chapter 4 . Acceleromyography

Train-of-four (TOF) or slow train-of-four (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 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) of rOF button starts a single rOF stimulation; Long activation (> 1 s) of the button starts a repetitive rOF stimulation.

Slow TOF mode. To switch to the Slow-TOF 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. Post -tetanic count (PTe) or user-programmable button This button also has a double function . PTe is the primary function; the secondary can be used to either select DBS (3.2 or 3.3), tetanic stimulation (50 Hz or 100 Hz) or no function . This button is not assigned a secondary function as a pre-set default. The set-up menu can be used to assign the desired stimulation mode to the button. PTe mode. When the PTe mode is activated, the TOF-Watch' SX device starts by performing IS single stimulations at a frequency of 1 Hz. Since the PTe can only be used during deep blockade, the device automatically stops the PTe stimulation and switches to the TOF-mode if after the first

173

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4.6 . TOF-Watch- SX

15 single stimulations the patient responds to more than five consecutive stimulations. Only if fewer than five 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" 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 activated in deep neuromuscular blockade. If the block is not sufficiently deep, the unit automatically switches back to TOF stimulation.

DBS mode or tetanic stimulation. It is not until the user-programmable button has been assigned the corresponding function, either DBS or tetanic stimulation, in the set-up menu, that these modes can be accessed. This button is not assigned a secondary function as a pre-set default. To assign a function, first press the secondary function button for < 1 s and then the corresponding stimulation button . The twitch is assessed by visual or tactile evaluation after both DBS and tetanic stimulation. The display only shows the selected current and the stimulation mode. Compared to the TOF mode, the DBS cannot be used as a continuous stimulation mode, but only ondemand as a single stimulation. Another DBS cannot be started until 20 s after the last DBS stimulation. The 'I'Of-Watch" SX 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. If the user-programmable button has been assigned with the tetanic stimulation function, tetanic stimulation will be carried out for 5 s at 50 Hz or 100 Hz; the desired stimulation frequency can be set in the set-up menu . 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 and the stimulation mode. Like with the PTC mode, in this mode, the TOF-Watch· SX excludes the use of another tetanic stimulation for 2 minutes.

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Chapter 4 • Acceleromyography

Both in the DBSmode and after tetanic stimulation, the response has to be evaluated visually or tactilely. The display only shows the stimulation mode and the stimulation strength.

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 « Is) starts a single stimulation; long activation (> 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.

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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

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Chapter 4 · Acceleromyography

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

Chapter 4 . Acceleromyography

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 l1Iicro
NtMf, tarodt + 5rimulotion flo5hing (5rimrJorion size)

0.0 IJC:

Det ult need elealOdestil1lulation st~ngth can be adjusted een 0.0 and 6.0 mAl014 1JC.

p no5hing (P buttonfuncrion) no functloo assigned to P button

OIlS 33: OIlS 31 : 50 Hz: 100Hz Lo + loud

1-4: 3 • lOO'lb:

OIlS 3J stil1lulatlon assignedto Pbutton OIlS 31 stil1lulatlon assignedto P button 50 Hz ltUInicstiR.I ion assigned to P button 100 Hz let nicstlllU tion assignedto P button II + tromducer noshing ([ow TOF of111m) Imt TOF I rm not actlile TOF I rmwill sound If the number of TOF ~ponses a~ below the numberof set responses. Imt TOF alarmwill sound If the TOF ratio is below set percentage.

a Fig. 4.11. TOF-Watch" SX set-up parameters

Set·up Disp

rTiiFl rr..

D o

o

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4

4 .7 · FAQS

4.7

FAQS

The following section will address several of the questions that frequently arise in connection with the application of neuromuscular monitoring and acceleromyography.

4.7.1

Can acceleromyography also be used in infants?

The pharmacokinetics and pharmacodynamics of NMBAs vary markedly between neonates and infants compared to older children and adults. The most important of the reasons for this include the fact that their body compartments differ in composition, their organ development is still immature and that the ACh receptor is still in transition from the fetal to the adult form . Therefore, particularly in these tiny patients, neuromuscular monitoring makes sense to ensure safe application of NMBAs. Another aspect is that the usual clinical tests are obviated in this patient cohort. For example, babies will very rarely lift their head for 5 seconds when asked, even if a residual blockade is no longer present! Driessen et al. [12] investigated whether acceleromyography is also safe to use in neonates and small infants. They included a total of 22 babies in their study; the average age was 3 months and the average weight 4 kg. In all 22 patients, the authors were able to calibrate the TOF-Guard nerve stimula tor successfully. In 13 patients, however, the transducer signal gain factor had to be increased manually to maintain a baseline value of 100%. Once this was achieved though, the course of neuromuscular blockade was easily recorded after 0.3 mg/kg rocuronium; the T1 response recovered to 101 (±15)% and recovery of the TOF ratio was 92 [12]. On the current TOF-Watch· Sand TOF-Watch· SX models, the secondary function on the calibration button can be used to manually modify the sensitivity of the transducer signal gain factor. In this pediatric patient group, TOF-Watch" nerve stimulators can also be used to objectively monitor the course of neuromuscular blockade - an option that should lead to enhanced safety when administering NMBAs to neonates and infants.

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Chapter 4· Acceleromyography

4.7.2 Is neuromuscular monitoring painful

for patients? Neuromuscular monitoring is recommended to be continuous. When neuromuscular monitoring is performed continuously, a suitable time point for reinjection ofNMBAs can be determined intraoperatively and the progress of neuromuscular recovery followed over a longer period. In conjunction with clinical signs, this strategy allows a more reliable assessment of neuromuscular blockade than when neuromuscular monitoring is used only as an isolated test at the end of the surgery. Moreover, more accurate measurements and results are obtained with quantitative nerve stimulators if they have been pre-calibrated. The above statement is valid for acceleromyographs as well as for the neuromuscular transmission (NMT) module. For this reason, quantitative neuromuscular monitoring should be applied continuously throughout the entire procedure. Occasionally, the concern is expressed that continuous intraoperative monitoring of neuromuscular blockade may be associated with postoperative skin irritation around the stimulation site or myalgia of the test muscle for patients. Neuromuscular monitoring is a noninvasive monitoring method that is regarded as safe and generally risk-free for patients. The literature contains at least two publications that address the subject of erythema at the stimulation site and myalgia of the test muscle. Nakamura et al. [13] reported on three patients who developed skin erythema after neuromuscular monitoring. The surgical interventions lasted 4 h 50 min, 8 h 20 min and 8 h 50 min, respectively. All patients were monitored by electromyography (Relaxograph). In two patients, carbon-coated EeG electrodes were used and in one patient, electrodes especially designed for neuromuscular monitoring which were also carbon-coated. In all three observed cases, the erythema completely resolved within a few days without additional treatment; none of the affected patients suffered any late sequelae. All three cases showed loss or damage of the carbon when the electrodes were detached. The authors of this case report considered this to be the cause for the erythema. Obviously, it is not recommended to use damaged electrodes . Irrespective of this report, it is very important that the electrodes are sufficiently coated with electrode gel to guarantee optimal conduction of the stimulation current.

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4.7 · FAQS

o

It is very important to ensure that the stimulation electrodes are not damaged and are sufficiently coated with gel.

A report published in 2007 addressed, among others, the question of skin tolerability and muscle pain after the continuous application of neuromuscular monitoring [14]. This prospective study enrolled a total of 220 patients. The duration of anesthesia was 120 min (±60 min). All patients received continuous monitoring of their neuromuscular blockade with the TOF-Watch" S throughout the entire intervention. Stimulation was administered at a constant current of 50 mAoThe following parameters were evaluated during the first 24 hours after surgery: - Local irritation around the stimulation site - Redness around the stimulation site - Contact dermatitis around the stimulation site - Muscle ache of the test muscle In none of the patients investigated did the authors detect any anomalies at the stimulation site or at the target muscle, thereby confirming that neuromuscular monitoring is simple and easy to perform, and harmless for the patient. Several authors have proposed using neuromuscular monitoring in the postanesthesia care unit to check the patient's neuromuscular recovery [10]. Within this context, they asked whether neuromuscular monitoring was painful and/or caused discomfort when administered postoperatively to awake patients. To answer this question, Saitoh et al. investigated the pain sensation patients subjectively experience at different stimulation currents [15]. Based on their results, the authors concluded that a stimulation strength of 30 mA represents the best compromise between the requirements placed on neuromuscular monitoring techniques and patient discomfort. This conclusion can be interpreted to imply that conscious patients regularly experience discomfort at stimulation currents above 30 mA, whereas stimulation currents less than 30 mA are usually insufficient to obtain a reproducible measurement. Overall, however, there are numerous other arguments that speak against the concept of neuromuscular monitoring in conscious patient s in postanesthesia care units . The major ones are listed below:

182

-

-

-

Chapter 4 • Acceleromyography

Even when subjected to low currents « 30 rnA), patients have frequently been observed to exhibit involuntar y defensive movements that could falsify the measurement. If neuromuscular monitoring is not admini stered until the patient is in the postanesthesia care unit, the measurement must be taken without calibration. This limits the accuracy of the acquired data. The question concern ing whether neuromu scular recovery is adequate should not wait to be addressed until patients are awake in the postanesthesia care unit, but rather while they are still in the operating room, prior to extubation . Notwithstanding the above, it is paramount that every residual block be detected in a timely fashion and treated with the appropriate measures.

The results of a survey on German customs for administering NMBAs and neuromuscular monitoring have shown that, in Germany, no clinical relevance is attached to the concept of neuromuscular monitoring on the awake patient in recovery rooms.

o

The question of adequate neuromuscular recovery should not wait until patients awaken in the recovery room, but while they are still in the operating room, prior to extubation.

4.7.3 What to observe when attaching TOF-Watch 8 nerve stimulators?

This chapter deals with specific questions such as whether the polarity of the stimulation electrodes affects the measurement, how to properly attach the acceleration transducer, how to position the patient's arm and whether the thumb should move freely or not. The question as to whether stimulation electrode polarity affects the stimulatory response was pursued by Brull and Silverman [16]. These author s established that the polarity of the electrodes indeed influenced amplitude and that, in most cases, the amplitude of the evoked response was greater when the negative electrode of the stimulation cable (black terminal) was connected to the distal electrode. Based on this evidence, it is recommended to consider electrode polarity when setting up neuromuscular monitoring

183

4

4.7 · FAQS

and to confirm the consistency of the »baseline« evoked response. Subject to inter-disciplinary discussion, the negative end of the cable (black) should be attached to the distal electrode (a Fig.4.12) . Such a standardized procedure is important in research because it contributes to making the results comparable. This recommendation should be given equal consideration in clinical practice, since the negative-to-distal electrode configuration ensures the greatest probability that the optimal stimulatory response will be obtained at the pre-set current. Moreover, the recommendations for the stimulation electrodes detailed in ~ Chapter2 should also be observed.

o

The negative connection on the TOF-Watch- stimulation cable (black) shou ld be attached to the distal stimulation electrode.

a Fig. 4.12.Polarityof the stimulation cable.The negativestimulation cable (black) isconnected to the distal electrode

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Chapter 4 · Acceleromyography

When connecting the acceleration transducer, the following should be observed: The acceleration transducer must be taped with its largest flat side to the inner side of the thumb . It is best to fasten the cable in such a way that no drag is exerted on the transducer. It is additionally important to note that the more distal the transducer is placed on the thumb, the stronger the acceleration signal. This technique also makes the measurement less susceptible to artifacts and disturbances. Finally, the best position in which the arm should be placed needs to be discussed and whether the thumb should move freely or not. Not only is the acceleration of the transducer influenced by the force development of the stimulated muscle, but also by the direction of gravity, its starting position and the elastic components of the test muscle being examined. To produce reliable measurements, the patient's hand should therefore be fixed in the supinated position. Moreover, the thumb should strictly be allowed to move in a horizontal direction in order to keep the influence of gravity constant. For the reasons mentioned above, it was originally demanded that the thumb be allowed to move freely. Meanwhile, the recommendation for research studies, at least, is to measure with a preload. The use of a preload indeed makes sense for clinical applications of acceleromyography, too. In clinical practice, intraoperative repositioning of patients is not uncommon, e.g. lowering their head or turning them on their side. Without a preload, the starting position of the thumb can also shift in relation to the patient's position and thereby influence the twitch measured by acceleromyography. The advantage of preloading primarily lies in the fact that it ensures that the thumb always returns back to its exact original position and thereby prevents the measurement from being confounded by intraoperative repositioning of the patient. Against this background, the TOF-Watch· hand adapter was developed as a special accessory similar to the »clamp« on the NMT module ( a Fig.4.13).

4.7.4 Is calibration really necessary?

All that is needed to calibrate TOF-Watch" nerve stimulators is a press of the corresponding button. Depending on the program, the calibration procedure itself takes approx. 10 seconds (CAL 1), but no longer than 30 seconds (CAL 2) and runs automatically.

185

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4.7 · FAQS

a Fig. 4.13. rOF-Watch" hand

adapter

And, there is much more behind the question concerning the necessity for calibration than the few seconds time required to make the device operational. Calibration is performed prior to NMBA injection. This means that neuromuscular monitoring should be initiated during anesthesia induction, when calibration of the nerve stimulator is intended . In most cases, however the neuromuscular monitor is not used until the surgery is underway and/or at the end of the surgery and, consequently, can no longer be calibrated. On the heels of the question of calibration follows the next: How should TOFWatch" nerve stimulators be employed - continuously throughout the entire surgery or only as an isolated test, e.g. at the end of the operation? The extent to which the type of application affects the accuracy of the findings obtained with the TOF-Watch" nerve stimulators was investigated in the following studies performed by the author's own working group. First, we examined which test is best suited to assess neuromuscular recovery at the end of the surgical procedure when used in isolation [17]. With this objective, 40 patients scheduled to undergo abdominal surgery

186

Chapter 4· Acceleromyography

were enrolled. Neuromuscular blockade was continuously monitored by mechanomyography on one hand. Upon skin closure, a DBS, an acceleromyographic TOF and a 100-Hz tetanus were applied in direct succession to the other hand. The twitches after DBS and tetanus were evaluated tactilely, whereas the TOF ratio was measured objectively with a TOF-Watch· nerve stimulator. The measurement was performed without calibration; the stimulation strength was manually set to 50 rnA. The results are summarized in a Tab.4.3. Of the 40 patients investigated, 31 had a residual blockade. Above a mechanomyographically measured TOF ratio of 0.5, no more fade could be detected after DBS. As a result, the residual blockade that actually existed was not diagnosed in 22 of 31 patients . By comparison, several patients still showed marked fade after tetanic stimulation despite adequate neuromuscular recovery. With the TOF-Watch" nerve stimulator, however, residual blockade was not detected in only 9 of 31 patients , whereas 8 of the 9 patients had at least a TOF ratio > 0.75. Even by this »minimalistic « approach, i.e., a single TOF stimulation at the end of the operation without initial calibration, neuromuscular recovery was evaluated correctly in the overwhelming proportion of patients (aTab. 4.3). In this test, the probability of actually detecting residual blockade was 47% compared with 29% for DBS [17]. When the TOli-Watch" nerve stimulator was used, albeit without calibration, but throughout the entire recovery phase and not just for a single TOF stimulation at the end of the operation, this probability rose to as high as 72% [18]. Neither DBS nor tetanic stimulation were able to achieve comparable values [17, 18].

o

Even when pre -calibration is omitted and TOF only measured byacceleromyography at the end of the operation, this method is still better suited to detect residual blockade than subjectively assessed fade after DBSor tetanus.

Conversely, if acceleromyographic monitoring is carried out continuously right from the beginning of surgery, the probability of this method actually detecting incomplete neuromuscular recovery goes up to 97%. However, previous calibration of the device is a prerequisite for this [19]. Thus, acceleromyography can help to reliably detect patients who do not need to be reversed at the end of the operation. When the device is used properly, even low levels of residual blockade can be diagnosed with certainty. This is a feat that subjective neuromuscular monitoring cannot achieve.

4

187

4.7 · FAQS

a Tab. 4.3. Isolated AMG, lOG-Hztetanus or DBSfor detecting residual blockade (mod ified after (17)) Patient

MMGTOF

AMGTOF ratio

lOG-Hz tetanus,

D8S

rano

>0.9

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

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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.

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Chapter 4 · Acceleromyography

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.

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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

Chapter 4 . Acceleromyography

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.

Stimulation electrodes

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

Chapter 4 . Acceleromyography

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

Chapter 4 · Acceleromyography

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

Chapter 4 . Acceleromyography

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