WO2008028572A1

WO2008028572A1 - Device for and method of determining a muscle activity

Info

Publication number: WO2008028572A1
Application number: PCT/EP2007/007450
Authority: WO
Inventors: Ashraf Dahaba; Helmar Bornemann
Original assignee: Medizinische Universität Graz
Priority date: 2006-09-05
Filing date: 2007-08-24
Publication date: 2008-03-13

Abstract

A device (100) for determining a muscle activity of a physiological object, the device (100) comprising a pneumatic mechanism (101 to 105) adapted for pneumatically determining the muscle activity of the physiological object.

Description

DEVICE FOR AND METHOD OF DETERMINING MUSCLE ACTIVITY

The invention relates to a device for determining a muscle activity of a physiological object.

The invention further relates to a method of determining a muscle activity of a physiological object. Moreover, the invention relates to a program element.

Furthermore, the invention relates to a computer-readable medium.

Beyond this, the invention relates to a method of using a device for determining a medication induced muscle relaxation of the physiological object.

Myography may be denoted as the science of describing muscles, including the study of muscular contraction.

Mechanomyography (MMG) is disclosed in Viby-Mogensen J, Engbaek J, Eriksson LI, et al., "Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents", Acta Anaesthesiol Scand 1996, 40:59-74, and is based on the measurement of a force generated by a stimulated muscle.

Electromyography (EMG) devices are available (for instance M-NMT module, Datex Ohmeda, Finland) and are based on the measurement of an electric voltage which is generated by a stimulation in a muscle.

Acceleromyography (AMG) is disclosed in Loan PB, Paxton LD, Mirakhur RK, et al., "The TOF-Guard neuromuscular transmission monitor. A comparison with the Myograph 2000", Anaesthesia 1995, 50:699-702, and is based on the measurement of an acceleration of a thumb of a patient.

Furthermore, the bending of a piezo strip arranged between two fingers of a patient may be used, generating an electric signal indicative of the degree of bending (see Dahaba AA, Klobucar F, Rehak PH, List WF, "Comparison of a new piezoelectric train-of-four neuromuscular monitor, the ParaGraph, and the Relaxometer mechanomyograph", Br J Anaesthesia, 1999, 82:780-2).

However, known myographs may be complicated in manufacture and in use and/or may lack sufficient flexibility in operation. It is an object of the invention to enable an efficient myography. In order to achieve the object defined above, a device for determining a muscle activity of a physiological object, a method of determining a muscle activity of a physiological object, a program element, a computer-readable medium, and a method of using a device for determining a medication induced muscle relaxation of the physiological object according to the independent claims are provided.

According to an exemplary embodiment of the invention, a device for determining a muscle activity of a physiological object is provided, the device comprising a pneumatic mechanism adapted for pneumatically determining (or monitoring) the muscle activity of the physiological object.

According to another exemplary embodiment of the invention, a method of determining a muscle activity of a physiological object is provided, the method comprising pneumatically determining (or monitoring) the muscle activity of the physiological object.

According to yet another exemplary embodiment of the invention, a computer-readable medium is provided, in which a computer program of determining a muscle activity of a physiological object is stored which, when being executed by a processor, is adapted to control or carry out a method having the above mentioned features.

According to still another exemplary embodiment of the invention, a program element of determining a muscle activity of a physiological object is provided, which program element, when being executed by a processor, is adapted to control or carry out a method having the above mentioned features. According to yet another exemplary embodiment of the invention, a device having the above mentioned features is used for determining a medication induced muscle relaxation of the physiological object.

Device control, signal generation and signal processing which may be performed according to embodiments of the invention can be realized by a computer program, that is by software, or by using one or more special electronic optimization circuits, that is in hardware, or in hybrid form, that is by means of software components and hardware components.

In the context of this application, the term "pneumatic mechanism" may particularly denote a system being operated, operable, powered or inflated by a hydraulic (liquid) pressure or by a compressed gas, like air. The term "pneumatic mechanism" may relate to or may use a medium like a fluid, a liquid, a gas (under pressure), a gel, a semisolid (like mercury); or a solid (for instance a powder or a granulate material).

The term "physiological object" may particularly denote a human being (child or adult, woman or man), or an animal (for instance a monkey).

The term "balloon" (or cuff) may particularly denote a physical structure which may be selected, for instance, from the following list:

1. A reusable form or

2. A single use form (disposable) 3. Simply using the cuff of a readily available endotracheal tube.

According to an exemplary embodiment, a myograph may be provided in which an inflated balloon is fixed in a palm of a hand of a human being or an animal. Upon a, for instance, electrical stimulation of specific muscles of the hand, when the physiological object (that is to say the human being or the animal) shows muscle activity, the stimulation may result in a muscle contraction in the hand of the physiological object, thereby modulating or modifying the pressure in the balloon. Such a pressure response may be measured and may be taken as a basis for a decision whether the muscle relaxation of the physiological object has occurred or not. For example, under the influence of a medication which may be administered during an anesthetic treatment, the muscle relaxation characteristics may be monitored or adjusted based on the measurement of the (remaining) muscle activity of a patient, for instance for a surgical operation or the like. Therefore, a simple muscle stimulation in combination with a pneumatic measurement of the degree of muscle activity or muscle relaxation may be carried out according to embodiments of - A -

the invention in a very simple manner. Therefore, according to an exemplary embodiment, a pneumatic myograph (PMG) may be provided.

In the field of anesthesia, a medication induced muscle relaxation may be employed in order to simplify for a surgeon to perform a surgical work with a patient, by a reduction or an elimination of muscle tension. On the other hand, it may happen that a patient has to be brought in a specific position during surgery. Embodiments of the invention may enable an accurate monitoring of the muscle relaxation and simultaneously a high degree of flexibility in positioning the patient without disturbing the measurement of the muscle activity. For this purpose, for monitoring the muscle relaxation, a specific nerve (for instance the ulnar nerve) may be electrically stimulated using one or more (typically two) electrodes positioned proximal of the wrist. For instance, a rectangular signal with a duration of 200 ms and a frequency of 2 Hz may be applied for 2 seconds ("train-of-four", TOF). When the patient is in a non-relaxed muscle state (i.e., there is a remaining muscle activity), this treatment may result in a stimulation of the adductor pollicis muscle, resulting in an adduction of the thumb. With increasing relaxation (i.e., loss of muscle activity), this motion is increasingly suppressed, and at a sudden state completely eliminated.

In conventional mechanomyography (MMG), the force may be measured which is generated by the stimulated muscle. Due to the direct measurement of the clinically relevant parameter (force), the performance of such a system may be satisfactory. However, using such a device, an accurate positioning of the patient is necessary for the mechanomyography measurement, so that no positional variations are possible and the MMG is only suitable for specific applications in research. According to conventional electromyography (EMG), an electric voltage is measured which results from a stimulation in the muscle. The electric voltage may allow to derive relaxation information, however with insufficient accuracy.

In conventional acceleromyography (AMG), the acceleration of the thumb upon stimulation of the muscles may be measured. However, also acceleromyography does not provide sufficient accuracy in specific applications. A conventional measurement of the bending of a piezo strip positioned between forefinger and thumb may allow to derive an electric signal generated depending on the degree of bending. Although a flexibility with regard to positioning the patient may be possible with such a method, the accuracy may be insufficient. According to an exemplary embodiment of the invention, a balloon may be filled with a medium (for instance a gas and/or a liquid), for instance can be filled with 20 ml of air, and may be put on the palm of the patient. Optionally, a plate can be placed or positioned along the forefingers of the open hand and/or along the thumb. Such force transmission elements may allow to efficiently transmit a pressure or force from the thumb onto the balloon, thereby increasing accuracy of the measurement. Then, the hand of the patient may be closed and may be fixed with an elastic bandage. The balloon may be connected to a pressure sensor. The pressure in the balloon without relaxation can be calibrated as a reference value (for instance value "100"). Then, a stimulation of the ulnar nerve may be performed using a conventional nerve stimulator. With increasing muscle relaxation (for instance promoted by a medication administered during anesthesia), the force with which the thumb compresses the balloon is reduced, therefore the pressure in the balloon is reduced. The resulting measurement data may then be interpreted to derive a degree of muscle relaxation. Therefore, according to an exemplary embodiment, the clinically interesting target parameter may be directly measured, namely the pressure and/or the force which can (still) be generated by the patient (for instance being subject of an anesthetic treatment). On the other hand, due to the design of the sensor system, a very large flexibility with regard to the (intra-)operative positional opportunities is maintained. Such an embodiment may be used as a module in an anesthesia monitor or as a (separate) stand-alone module for neuromuscular monitoring.

According to an exemplary embodiment, the muscle relaxation (for instance under the influence of anesthesia) based on a pressure generated by a patient's muscle force and acting on a balloon in a patient's hand may be measured, wherein the muscle activity may be initiated by a (for instance electric) muscle stimulation. Therefore, a neuromuscular transmission monitor may be provided, which may be denoted as a pneumatomyograph (PMG), and which may be used for neuromuscular monitoring.

Next, further exemplary embodiments of the device will be explained.

However, these embodiments also apply to the method of determining a muscle activity of a physiological object, to the computer-readable medium, to the program element, and to the method of using such a device for determining a medication induced muscle relaxation of the physiological object. The pneumatic mechanism may comprise a balloon being inflatable with a medium. The term "pneumatic" may particularly denote that a pressure of a compressible fluid may be measured which a patient exerts on a balloon or the like. Such a balloon may have an essentially spherical shape. Other geometries are possible, like a flattened elliptic configuration, a cuboid configuration or the like. The shape may be adjusted to an anatomy of a human or animal patient. Such a balloon may be made of a plastic material which may be flexible so as to allow a patient to considerably modify the shape of the balloon when applying a pressure on the balloon. The balloon may be inflatable, that is to say may be pumped up, or the fluid may also be removed from the balloon. The balloon may be adapted to be accommodated in a hand of the physiological object. Therefore, shape, material, and pressure response characteristics may be adjusted to values which are suitable for use with a specific physiological object.

The pneumatic mechanism may comprise a medium conduit (like a plastic tube) being in fluid communication with the balloon. Such a medium conduit may be a hollow tube, for instance made of a plastics material, and connecting the balloon with an inflation unit adapted for inflating the balloon. Such an inflation unit may be a pressure reservoir like a gas bottle, a pump, a pressure air connection in a lab, etc. Therefore, by coupling the balloon with the inflating unit via the fluid conduit (which may be made of an essentially rigid material and which may have a small inner diameter to reduce "dead volume"), the balloon can selectively be brought in an extended/inflated state or in a loose state. A valve mechanism or the like may be provided between inflation unit and balloon, so that a selective opening or closing of such a valve may allow to adjust the default pressure of the balloon. Beyond this, the device may comprise a fastening element which may be adapted to fasten the balloon in a hand of the physiological object. By fastening the balloon in a hand of the patient, the reliability of the system may be significantly increased since a proper force transmission from the hand to the balloon may be ensured. An example for such a fastening element may be an elastic tape binding or bandage which may be wound around a hand of a patient enclosing the balloon, and which may have a fastening mechanism like a click connection, a snap-in connection, or a Velcro fastener.

The device may comprise a stimulator unit adapted for stimulating a nerve, particularly the ulnar nerve of the physiological object. The ulnar nerve may be denoted as a nerve that in humans runs down the arm and forearm, and into the hand.

Such a stimulator unit may comprise electrodes to be connected to the physiological object for electrically stimulating the physiological object. For instance, two electrodes may be placed on a specific portion of the skin of a patient, and a stimulating electric signal may be applied to the patient, resulting in an activation of a muscle of the thumb. Such a stimulator unit may be programmable by a human user so as to define a stimulation procedure like a time sequence, electric amplitudes, etc.

A pressure sensor may be provided to measure a pressure in the balloon (or in the conduit), particularly when being at least partially inflated. The pressure sensor/manometer may be any kind of pressure sensor (for example a MEMS, a pressure gauge, an air speed indicator, a piezo based sensor, a membrane based force sensor, a spring based sensor, or a flow meter) and may be connected in a medium conduit and connected to the balloon. The pressure sensor may detect the time dependence of the pressure in the balloon which may be modified when a muscle is activated in response to a stimulation of a nerve of the physiological object. Therefore, the muscle activity or the muscle relaxation may be measured by the pressure sensor. The conduit connecting the balloon and the pressure sensor may be essentially incompressible so as to prevent that pressure changes in the balloon due to a muscle activity of the patient is manipulated by a compression or expansion of such a conduit. Therefore, the accuracy of the system may be significantly improved.

A force transmitting element may be provided and adapted for promoting a transmission of a force from a hand of the physiological object to the balloon. Such a force transmitting element may be any physical element or component which improves the force coupling between the balloon and the hand. For example, a first rigid element (like a plastic strip) may be provided to be positioned along a finger row (including the forefingers of the hand, i.e. the fingers with exception of the thumb) of a palm of the physiological object. A second rigid element may be located along a thumb of a palm of the physiological object and may be a plastic strip as well. The two plastic strips may functionally cooperate and may serve as two legs of a lever action unit. Therefore, even small muscle forces may be converted into a significant compression of the balloon in case of an intact muscle activity of the patient.

The pneumatic mechanism may be adapted for pneumatically monitoring a muscle relaxation of the physiological object. Such a muscle relaxation may be a partial reduction or a complete elimination of muscle activity, for instance caused by a muscle relaxants or inhalational anesthetics for example administered to the patient.

The device may comprise a user interface unit adapted for enabling a user a control of the device, an operation of the device, and/or an inspection of the muscle activity of the physiological object. Such a user interface may comprise a display unit (for instance an LCD display, a cathode ray tube, a plasma display device or the like) and may therefore be a graphical user interface (GUI). The user interface may further include input elements like buttons, a keypad, a joystick, a trackball, or even a microphone of a voice recognition system. Such a user interface unit may be a computer or a handheld device assisting a user of the device for convenience. The user interface unit may communicate with a control unit for centrally controlling cooperation of components of the device so as to improve the degree of automation of the system.

Systems according to exemplary embodiment of the invention may be used for determining a medication induced muscle relaxation of the physiological object, particularly for determining a dose of a medication to be administered to the physiological object to maintain a muscle relaxation of the physiological object at a desired level. Therefore, during a surgical procedure, an anesthetist may monitor continuously or from time to time the muscle relaxation state of a patient being subj ect of a surgical operation.

The aspects defined above and further aspects of the invention are apparent from the examples of embodiment to be described hereinafter and are explained with reference to these examples of embodiment.

The invention will be described in more detail hereinafter with reference to examples of embodiment but to which the invention is not limited.

Fig. 1 illustrates a device for determining a muscle activity of a physiological object according to an exemplary embodiment of the invention.

Fig. 2 to Fig. 11 show components of a device for determining a muscle activity of a physiological object and illustrate a method of using such a device according to an exemplary embodiment of the invention.

Fig. 12 illustrates a Bland and Airman scatterplot of the pneumatomyograph and a mechanomyograph.

Fig. 13 illustrates a regression plot of the pneumatomyograph against the mechanomyograph. Fig. 14 illustrates a Bland and Altaian scatterplot of the pneumatomyograph and the mechanomyograph.

Fig. 15 illustrates a regression plot of the pneumatomyograph against the mechanomyograph.

Fig. 16 illustrates a mean Tl% and TOF measured by a pneumatomyograph (PMG) and a mechanomyograph (MMG) during muscle relaxation with rocuronium in six patients.

Fig. 17 shows a sequence of response signals of a hand of a patient after being excited before and after administering a muscle relaxing agent to the patient.

Fig. 18 illustrates geometrical shapes of plate-like rigid elements for a device for determining a muscle activity of a physiological object according to an exemplary embodiment of the invention.

The illustration in the drawing is schematically. In different drawings, similar or identical elements are provided with the same reference signs. In the following, referring to Fig. 1, a device 100 for determining a muscle activity of a patient according to an exemplary embodiment of the invention will be described.

The device 100 comprises a pneumatic mechanism adapted for pneumatically monitoring the muscle activity of the physiological object, as will be explained in the following in more detail.

The pneumatic mechanism comprises a compressible plastic balloon 101 having a volume of, for instance, 20 ml in an inflated state, thereby being dimensioned to be accommodated in the hand of an average adult human being as the physiological object. The balloon 101 is made of a flexible plastic material and is inflatable with air. A conduit 102 is foreseen as a hollow tubular component which is essentially incompressible and couples the inflatable balloon 101 for fluid communication with a three-way valve 120. The three-way valve 120 may selectively couple the balloon 101 to a pressure sensor 103 or, via an optional further valve 104, with a gas container 105 or a pump.

When the three-way valve 120 couples the balloon 101 to the gas container 105 or pump, the balloon 101 may be pumped with a gas to be inflated. When the three-way valve 120 couples the balloon 101 to the pressure sensor 103, the pressure in the balloon 101 may be measured (once, from time to time, or continuously). Furthermore, a bandage 106 is provided which is adapted for fastening the balloon 101 when received or accommodated in a hand of a human patient. The bandage 106 is made of a flexible fabric 107 having an oblong rectangular shape and having a VeI cro fastener element 108 for fastening the bandage 106 when wound around a hand of the patient holding the balloon 101. As can further be taken from Fig. 1 , a muscle stimulator unit 109 is provided which is adapted for stimulating a nerve, particularly a ulnar nerve, of the patient. The stimulator unit 109 comprises a control unit 110 controlling operation of the stimulator unit 109, application of electric potentials, etc. and comprises two electrodes 111 connected via cables 112 with the control unit 110. When activating the stimulator unit 109, and when the electrodes 1 11 are positioned on an appropriate skin portion of the human patient, then the stimulator unit may stimulate the ulnar nerve which may trigger a motion in the hand of the human, when the muscles of the human patient are in an active state.

The pressure sensor 103 is adapted to measure a pressure in the balloon 101 when being at least partially inflated. This pressure may change in the balloon 101 in response to a stimulation of a nerve of the human patient, since this stimulation may result in a muscle motion in the hand.

Further shown in Fig. 1 is a plate-like rigid element 113 which is shaped and dimensioned to be properly positionable along a thumb of a palm of the human patient. Furthermore, a plate-like rigid element 114 is provided as to a second force transmitting element and is adapted and shaped to be positioned along a finger row of a palm of the human patient.

Beyond this, a control unit (for instance a computer, a CPU, a microprocessor or the like) 115 is provided which centrally controls operation of the device 100. The control unit 115 may communicate bidirectionally particularly with an input/output unit 116, with the pressure sensor 103, with the valve 104, with the inflation unit 105 and with the muscle stimulator unit 109. Therefore, the control unit 115 may provide each of these and other components of the system 100 with control commands or may receive information from these components. The input/output device 116 may be a user interface which may enable a user to control operation of the device 100 and inspect muscle activity of the human patient. Each of the communication channels 117 may be wired or wireless, hi a wired configuration, the connections 117 may comprise cables, and in a wireless configuration a Bluetooth, infrared or other wireless communication scheme may be implemented.

According to a further exemplary embodiment of the invention, the balloon 101 and both plates 113 and 114 may be integrally formed, that is to say particularly formed as a single piece. Optionally, also the bandage 106 may be fixedly connected to the balloon 101 and/or both plates 113 and 114 to form an integrally formed configuration. This may improve user convenience when operating the device 100. It is also possible to omit the plates 113 and 114. In such a scenario, it may be possible to substitute the plates 113 and 114 by correspondingly positioned hardened portions of the balloon, improving or promoting force transmission. Thus, it is possible that the force transmitting components 113, 114 are integrally formed with the balloon 101.

In the following, referring to Fig. 2 to Fig. 11 , operation of a device 100 for determining a muscle activity of a physiological object according to an exemplary embodiment of the invention will be explained. hi Fig. 2 to Fig. 1 1, an inflatable balloon 101 is realized using an endotracheal tube (as available, for instance, as a product called Hi-Contour from the company Mallinckrodt). In such a tracheal tube, only the inflatable balloon 101 and a corresponding conduit 102 are used, wherein other tube components may remain unused, according to exemplary embodiments of then invention. Particularly, a tube component 1102 is shown which is not used in the described embodiment. An interior of the inflatable balloon 101 is coupled for fluid communication with the conduit 102 via an opening 200. An end 201 of the conduit 102 is closed.

Fig. 2 illustrates the inflatable balloon 101 together with the tube component 1102. The balloon 101 is dimensioned, shaped and foreseen of such a material that it can be inflated or pumped up with 20 ml of air. Fig. 3 shows a hand 300 of a patient comprising a palm 301 , a thumb 302 and a finger row 303. In the operation state of Fig. 3, the inflatable balloon 101 is positioned on the palm 301 of the patient.

As can be taken from Fig. 4, the plates 113, 114 are positioned in order to improve the capability of transmitting a thumb 302 motion accurately onto the balloon 101. Such a thumb motion is indicated schematically with reference numeral 400. The plate 113 is positioned to extend essentially along the thumb 302 up to the palm 301 of the hand 300. The plate 114 is positioned along the finger row 303, in a direction essentially perpendicular to an extension of the fingers 303.

As shown in Fig. 5, the bandage 106 is positioned around the hand 300 to ensure the positioning of the balloon 101 and/or of the plates 113, 114 and simultaneously provides a counter pressure to the force of the inflated balloon 101.

Fig. 6 shows the bandage 106 in an operation state in which it is wound around the hand 300 of the human being, and is fastened.

Therefore, the system is properly fixed, and the hand 300 of the patient can be freely moved.

Fig. 7 shows a further view of the hand 300 of the patient when the bandage 106 is wound around the hand 300.

Fig. 8 shows a nerve stimulator unit 110 which may serve for transmitting pulses through electrodes to the ulnar nerve of the human patient. The stimulator unit 110 comprises an LCD display 700 and control buttons 701.

Now referring to Fig. 9, electrodes 111 of the stimulator unit 110 stimulate the ulnar nerve via surface electrodes on the skin or needle electrodes subcutaneous placed through the skin of the arm of the human being.

As illustrated schematically in Fig. 9, when the ulnar nerve is stimulated, the thumb 302 is adducted.

In an operation state, in which the nerves and the muscles of the human are active (for instance in normal life or before an anesthesia for preparing a surgical procedure has started), the adduction 400 of the thumb 302 will compress the balloon 101 and will make the pressure sensor 103 to measure a modified pressure in the balloon 101. This information may be transmitted via the connection 117 to the control unit 115 which will output a corresponding information at a display element of the I/O device 116. However, when muscle relaxation has occurred in the body of the patient (for instance since a medication has been administered to the patient for anesthesia), no adduction 400 (or only a reduced or delayed adduction) occurs, as indicated schematically in Fig. 10. Therefore, no pressure modification is measured in the balloon 101, and the surgeon can be sure that the patient has no remaining muscle relaxation.

As illustrated in Fig. 11, the conduction of the pressure modification in the balloon 101 occurs via an uncompressible tube 102 to a pressure sensor 103 (not shown). A three-way valve 120 may be foreseen to provide the fluid (or more generally media) communication paths as shown in Fig. 1. In this application, a neuromuscular transmission monitor is disclosed which may be denoted as a Pneumatomyograph (PMG). A study was carried out to validate the neuromuscular monitor by comparing the neuromuscular block of 0.6 mg kg^"1 rocuronium (2 x 95% effective dose, EDc_>5) monitored by the PMG to that monitored by the Relaxometer^® mechanomyo graph (MMG). The two monitors were alternately allocated to the left or right hands of 20 patients. Ti, the first twitch of the train-of- four (TOF) expressed as percentage of control response and the TOF ratio (T₄: Ti) were used for evaluating the neuromuscular block. The PMG monitor exhibited no pre-relaxation Ti exceeding 100%. There was no significant difference in the mean (min) ±SD onset time, time to 25% Ti recovery, or time to 0.8 TOF ratio recovery measured by the PMG (1.5+0.3, 21.7±3.3, 40.3±9.9) compared to MMG (1.8+0.6, 22.9+3.1, 40.1+9.6) respectively. According to a Bland and Altaian analysis, during recovery from neuromuscular block, the difference in Ti % between the two monitors showed a bias of -0.16%. The limits of agreement were -8% and +8%. The bias for the TOF ratio was -0.009, and the limits of agreement were -0.04 and +0.04. The PMG monitor exhibited no drift phenomenon at recovery. In conclusion, the PMG could precisely indicate the time to tracheal intubation, time to repeat dose administration, as well as full recovery from neuromuscular block at least as efficaciously as the MMG. The PMG has also the advantage of having a simple, small, quick fit sensor, which does not require time to set up or a rigid support of the arm. Thus, the PMG is a reliable clinical monitor for the daily anesthesia practice. Compared to mechanomyography, the neuromuscular transmission monitor Pneumatomyograph (PMG) according to an exemplary embodiment of the invention can efficaciously indicate time to tracheal intubation, time to rocuronium repeat dose administration and full recovery from 0.6 mg kg^"1 rocuronium neuromuscular block. Mechanomyography (MMG) has been regarded for many years as the standard method for precise quantification of neuromuscular block (Viby-Mogensen J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996;40:59-74). The conventional MMG measures the exact force of muscle contraction in response to electric stimulation of a motor nerve. It quantifies the neuromuscular function by measurement of the force displacement. However the equipment is rather bulky, takes time to set up, requires a rigid support of the arm in an often crowded operating room. All this limits its clinical use in the daily anesthesia practice. On the other hand several versatile and small, stand-alone neuromuscular monitoring devices such as the ParaGraph, TOF-Guard and TOF- Watch or the integrated neuromuscular monitoring module M-NMT are all based on either bending of a piezo-strip or correlating the acceleration of a piezo-electrode to the force of the thumb movement. However versatility and mobility comes at the expense of accuracy as all these monitors were shown not to accurately correlate to mechanomyography, due to the simple fact that all these monitors are based on a different physiological phenomenon.

According to an exemplary embodiment of the invention, a neuromuscular transmission monitor is provided, the Pneumatomyograph (PMG) that quantifies the neuromuscular function by measurement of the signal generated from the squeezing of a small balloon between two small plastic strips held by a simple strap in the patient's hand. Thus the two monitors MMG and PMG quantify the neuromuscular function based upon the principle of force transduction. The described study analyzed the PMG by comparing the neuromuscular block of 0.6 mg kg^"1 rocuronium (2 x 95% effective dose 2 x EDg₅) monitored by the PMG with that monitored by the Relaxometer^® mechanomyograph (Groningen University, Holland, Rowaan CJ, Vandenbrom RHG, Wierda JMKH. The Relaxometer: a complete and comprehensive computer-controlled neuromuscular transmission measurement system developed for clinical research on muscle relaxants. J Clin Monit 1993;9:38- 44.). A prospective controlled clinical consecutive study was planned and conducted in accordance with the guidelines of "Good Clinical Research Practice (GCRP) in Pharmacodynamic Studies of Neuromuscular Blocking Agents" (Viby- Mogensen J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996;40:59-74.). After approval of Graz Medical University ethics committee, potential participants with a history of neuromuscular disease, small joint arthritis or patients on treatment with drugs thought to interfere with neuromuscular transmission were excluded. A convenience sample size of 20 consecutive patients aged 18-59 yr, American Society of Anesthesiologists classification I-II, undergoing short elective surgical procedures expected to last for approximately 1 h in the supine position were included in the study.

Midazolam, 7.5 mg p. o. was administered for premedication 1 h preoperatively. Anesthesia was induced with propofol 2-3 mg kg^"1 and fentanyl 1.5 μg kg^"1 until the eyelash reflex was obtunded. Anesthesia was maintained with propofol 100-150 μg kg^"1 min^"1 and remifentanil 0.1-0.2 μg kg^"1 min^"1 infusions. A ProSeal Laryngeal Mask Airway (LMA) was inserted and after capnographic confirmation of correct positioning of the LMA, the lungs were ventilated mechanically with 40% oxygen in air. Ventilation was adjusted to maintain 30-40 mm Hg end-tidal carbon dioxide. Patients were warmed using a forced-hot-air- blanket to maintain core temperature >37°C and skin temperature >32°C.

Both arms were comfortably positioned on arm boards. The area above the ulnar nerve at the wrist was cleaned to ensure adequate electrodes contact. To level out the effect of dominance of one hand, the two monitors were alternately allocated to the left or right hands. The force transducer of the Relaxometer (MMG) was attached to one hand, and the preload on the thumb was maintained within 200-400 g throughout the whole procedure. The PMG balloon was placed between the 2 small plastic strips in the patient's other hand and held by a special strap for simultaneous monitoring, as shown in Fig. 2 to Fig. 11. The Pneumatomyograph (PMG) quantifies the neuromuscular function by measurement of the signal generated from the squeezing of a small balloon between two small plastic strips held by a simple strap in the patient's hand.

The balloon was then inflated with 20 ml air. hi response to evoked stimulation of the ulnar nerve, the patient squeezed the PMG balloon. This generated a pressure motion that was directly measured by the PMG pressure transducer. The pressure in the PMG line was calibrated to 100%. The area under the positive voltage wave curve over time was calculated and quantified. The signal was then filtered, amplified, displayed and recorded.

After supramaximal current determination by both monitors, the ulnar nerves were stimulated by train-of-four (TOF) stimuli (2-Hz, pulse width 200 μs, square wave for 2 s) at 12-s intervals. T₁, first twitch of the TOF expressed as percentage of control response and the TOF ratio (T₄: T₁) were used for evaluating the neuromuscular block.

After a stable control response for both monitors was achieved, defined as variation of less than ±2% T₁ for the last 3 min (Viby-Mogensen J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996;40:59-74.), 0.6 mg kg^"1 rocuronium (2x 95% effective dose, ED₉₅) was administered. After the 2 time clocks of both monitors were exactly synchronizing, the MMG and PMG data were simultaneously collected and stored on two lap top computers using the "AZG- Relaxometer 5.0 program" and the "PMG data collection software". Patients were allowed to recover spontaneously from the neuromuscular block and onset time (time from beginning of rocuronium administration until maximal neuromuscular block), Dur₂₅ (time from beginning of rocuronium administration until 25% Tj recovery), Dur₂₅_₇₅ (time from 25% to 75% Ti recovery), Dur₂₅_o_.8 (time from 25% Ti to 0.8 TOF ratio recovery) and Dur_{0 8} (time from beginning of rocuronium administration until 0.8 TOF ratio recovery) time-course-of-action variables were calculated (Viby- Mogensen J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996;40:59-74.).

A statistical analysis of the data was carried out.

Because the PMG monitor was newly developed, to date no data on PMG monitoring of neuromuscular block exists to enable an a-priori sample size to be calculated, thus a convenience sample size of 20 patients was chosen. Paired t test was used for the parametric data analysis. Data was expressed as mean ±SD. P <0.05 was considered statistically significant. Data collected during recovery from neuromuscular block as well as the time-course-of-action variables were further analyzed based on the statistical method of Bland and Airman (Bland JM, Altaian DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1 :307-10.). Although mechanomyography might be regarded as the standard method for quantification of neuromuscular block (Viby- Mogensen J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996;40:59-74) still it is subject to experimental error. The Bland and Airman analysis considers that both techniques are subject to experimental error and thus uses the average of the two measurements as an estimate of the true value rather than assuming that the MMG is a true standard. The bias defines the mean of the difference between the two monitors. The limits of agreement define the bias ±1.96 SD in which 95% of the differences between the two monitors are expected to lie. In the following, results of the study will be described.

Patients' demographics are presented in Table 1.

Table 1. Patients' demographics.

Age (yr) 54.3±16.7 Weight (kg) 75±14

Height (cm) 172+8

Male/Female 6/6

Mean ±SD, n = 20.

Next, the stabilization phase will be explained.

During the stabilization period, before rocuronium administration, T₁ monitored by MMG exceeded 100% (111.9 ±7.1). MMG required 4.9 ±1.5 min to establish a stable control response. T₁ monitored by PMG did not exceed 100%. The mean pre-relaxation TOF ratios monitored by the PMG (0.98 ±0.02) or by the MMG (0.97 ±0.02) did not exceed 1.0. hi the following, the onset phase will be described.

Following rocuronium administration, the T_\% and the TOF ratio of both monitors started to decrease simultaneously. There was no significant difference in the lag and onset times measured by the two monitors, see Table 2. Full block was reached in all patients independent of the monitoring technique. Table 2. Rocuronium time variables (min).

Limits of agreement

Mean +SD, P <0.05, n =20, MMG = Relaxometer Mechanomyograph, PMG = Pneumatomyograph, Bias = the mean of the difference between the two monitors (Bland and Altaian analysis), Limits of agreement = bias ±1.96 SD, Lag time = first measurable effect of neuromuscular block, onset time = time from beginning of rocuronium administration until first response of train-of-four (T₁) maximum suppression, Dm₂₅ = time from beginning of rocuronium administration until 25% T₁ recovery, Dur₂₅_₇₅ = time from 25% to 75% T₁ recovery, Dur_o.g = time from beginning of rocuronium administration until 0.8 train-of-four ratio recovery, Dur₂₅_ o.₈ = time from 25% T) to 0.8 train-of-four ratio recovery. Tl% Correlation coefficient r = 0.9928, PO.0001 95% Confidence interval for r = +0.9920 - 0.9936 TOF Correlation coefficient r = 0.9896, PO.0001 95% Confidence interval for r = +0.9881 - 0.9910

Next, the recovery phase will be described. Both monitors detected the start of recovery from neuromuscular block as well as 0.8 TOF ratio full recovery with very narrow limits of agreement. Furthermore there was almost identical agreement between the two monitors in measuring time for repeated dose administration Dur₂s (see Table 2). During recovery from neuromuscular block, the difference in Ti % between the two monitors showed a bias of —0.16%. The limits of agreement were -8% and +8%, see Fig. 13.

Fig. 12 shows a Bland and Airman scatterplot of the difference between the first twitch (Ti %) of the Pneumatomyograph (PMG) and the mechanomyograph

(MMG) against the mean of the two measurements, during recovery from neuromuscular block. The middle dotted line represents the bias. The upper and lower dotted lines represent the limits of agreement between the two monitors.

The Ti% regression plot showed a linear relationship between the two monitors (see Fig. 13).

Fig. 13 illustrates a regression plot of the first twitch (T i%) of the Pneumatomyograph (PMG) against the mechanomyograph (MMG), during recovery from neuromuscular block. The middle dotted line represents the line of identity.

The bias for the TOF ratio was -0.009, and the limits of agreement were -0.04 and +0.04, see Fig. 14.

Fig. 14 shows a Bland and Altman scatterplot of the difference between the train-of-four (TOF) ratio of the Pneumatomyograph (PMG) and the mechanomyograph (MMG) against the mean of the two measurements, during recovery from neuromuscular block. The middle dotted line represents the bias. The upper and lower dotted lines represent the limits of agreement between the two monitors.

Similarly the regression plot demonstrated a close relationship between the two monitors, see Fig. 15.

Fig. 15 shows a regression plot of the train-of-four (TOF) ratio of the Pneumatomyograph (PMG) against the mechanomyograph (MMG), during recovery from neuromuscular block. The middle dotted line represents the line of identity.

After full recovery from neuromuscular block, Ti % monitored by MMG, exceeded the control response (120.6%±12.8), whereas the Ti% monitored by the PMG did not exceed 100% (99 ±0.1). The TOF ratios monitored by MMG was 0.88±0.08 and by PMG was 0.90 ±0.03. The two monitors quantified the neuromuscular function based upon the same principle, namely the force displacement of the thumb detected by the force transducer of the MMG and the squeezing motion of the hand detected by the pressure transducer of the PMG. In the following, a stabilization phase will be described.

In the study T₁ monitored by the MMG exceeded 100% before the administration of neuromuscular blocking drugs. This was similarly reported in 50% of the patients monitored by the ParaGraph piezoelectric motion sensor (Dahaba AA, Klobucar F, Rehak PH, List WF. Comparison of a new piezoelectric train-of-four neuromuscular monitor, the ParaGraph, and the Relaxometer mechanomyograph. Br J Anaesthesia. 1999;82:780-2), and with piezoelectric acceleromyographic TOF- Guard monitor (Loan PB, Paxton LD, Mirakhur RK, et al. The TOF-Guard neuromuscular transmission monitor. A comparison with the Myograph 2000. Anaesthesia 1995;50:699-702.). A possible explanation is that, despite the period of stabilization before neuromuscular blocking drugs administration, the nonrelaxed free-moving thumb might not return to exactly the same position after each stimulus (Loan PB, Paxton LD, Mirakhur RK, et al. The TOF-Guard neuromuscular transmission monitor. A comparison with the Myograph 2000. Anaesthesia 1995;50:699-702.). Because the PMG measures the pressure in a closed calibrated line, this might explain the absence of the phenomenon of the MMG exceeding

100%. This could be due to the design of the PMG monitor that restricts the hand in a strap. This allows the thumb and the hand as a whole to only squeeze the balloon held in the hand during stimulation, and would not allow the thumb or the hand from gliding from the original position after each stimulus. Such design provides greater flexibility in the positioning of the patients arms as the strap allows frequent and greater freedom of movement as well as diverse positioning of the monitoring hand, which is often the case in an operating room. Next, the onset phase will be explained. The results of the study demonstrated that the two monitors simultaneously detected full neuromuscular block. This suggests that if tracheal intubation is attempted at full neuromuscular block (Agoston S. Onset time and evaluation of intubating conditions: rocuronium in perspective. Eur J Anaesthesiol 1995; 12 (Suppl. 11):31-7.), PMG is equally effective in indicating the time to tracheal intubation.

Next, the recovery phase will be described. Discrepancies between the two monitors were minimal at the start, along the course, and at full recovery. This indicates that the PMG is effective in detecting the time to repeat rocuronium administration as well as identifying full recovery from neuromuscular block, as the mean 0.8 TOF ratio measured by the MMG in the study corresponded to 0.79 TOF ratio when measured by the PMG (see Fig. 16). hi the current study it was demonstrated that the TOF ratio limits of agreement of -0.04 and +0.04 are considerably narrower than those of piezoelectric sensor monitors compared to mechanomyography (Dahaba AA, Klobucar F, Rehak PH, List WF. Comparison of a new piezoelectric train-of-four neuromuscular monitor, the ParaGraph, and the Relaxometer mechanomyograph. Br J Anaesthesia. 1999;82:780-2; Kern SE, Johnson JO, Westenskow DR, Orr JA. An effectiveness study of a new piezoelectric sensor for train-of-four measurement. Anesth Analg 1994;78:978-82.). The limits of agreement for the ParaGraph were as wide as -0.28 and +0.21 (Dahaba AA, Klobucar F, Rehak PH, List WF. Comparison of a new piezoelectric train-of-four neuromuscular monitor, the ParaGraph, and the Relaxometer mechanomyograph. Br J Anaesthesia. 1999;82:780-2), whereas those for the piezoelectric sensor were -0.24 and +0.275 (Kern SE, Johnson JO, Westenskow DR, Orr JA. An effectiveness study of a new piezoelectric sensor for train-of-four measurement. Anesth Analg 1994;78:978-82.). This suggests that the discrepancies of the ParaGraph (Dahaba AA, Klobucar F, Rehak PH, List WF. Comparison of a new piezoelectric train-of-four neuromuscular monitor, the ParaGraph, and the Relaxometer mechanomyograph. Br J Anaesthesia. 1999;82:780- 2) and piezoelectric sensor (Kern SE, Johnson JO, Westenskow DR, Orr JA. An effectiveness study of a new piezoelectric sensor for train-of-four measurement. Anesth Analg 1994;78:978-82.) compared to mechanomyography are largely due to an inherent difference in the fade characteristics between the two phenomena. On the other hand the considerably narrow limits of agreement between the PMG and MMG would allow the values given by these two monitors to be used interchangeably for individual patients.

Hand temperature <32°C could be a contributing factor in the "drift" from baseline (Ti >100%) after full recovery from neuromuscular block (Viby-Mogensen J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996;40:59-74). Although the hand temperature of all the study patients was kept constant >34°C the results revealed that MMG was still prone to drift. One possible explanation of this manifestation is that MMG requires frequent preload adjustments in response to even minor repositioning of the patient's hand on its rigid armboard to maintain it within 200-400 g. This might not necessarily bring the thumb back to the original prerelaxation position. On the other hand the design of the PMG monitor that restricts the hand in a strap, allows the thumb and the hand as a whole to only squeeze the balloon held in the hand during stimulation and would restrict the thumb and the hand from sliding from the original position after each stimulus, hence the PMG was not prone to drift.

In conclusion the PMG monitor exhibited no pre-relaxation Ti exceeding 100%, no drift phenomenon at recovery, and could precisely indicate the time to tracheal intubation, time to repeat dose administration, as well as full recovery from neuromuscular block as efficaciously as the MMG. The PMG has also the advantage of having a simple, small, quick fit sensor, which does not require time to set up or a rigid support of the arm. Thus, the PMG may be a reliable clinical monitor in the daily anesthesia practice. Fig. 16 illustrates a mean Tl% and TOF measured by a pneumatomyograph

(PMG) and a mechanomyograph (MMG) during muscle relaxation with rocuronium in six patients.

Reference numeral 1600 illustrates a point of time of an injection, reference numeral 1601 illustrates a point of time of a state of recovery. Reference numeral 1602 indicates a lag time, and reference numeral 1603 indicates an onset time. Fig. 17 shows a sequence of response signals of a hand of a patient after being excited four times, respectively, before and after administering a muscle relaxing agent (during anesthesia) to the patient.

More particularly, Fig. 17 shows a diagram 1700 having an abscissa 1701 along which the time is plotted, and having an ordinate 1702 along which the intensity of a muscle contraction as measured by a pressure sensor in a pneumatic system (as depicted in Fig. 1) is plotted.

A first sequence of four equidistant signals 1703 is measured by applying a muscle stimulation pulse to a patient after having mounted the apparatus of Fig. 1 at a hand of the patient. Then, a muscle relaxing substance is administered to the patient at a point of time indicated with reference numeral 1704. After that, a second sequence of four equidistant signals 1705 is measured by applying a muscle stimulation pulse to a patient in an operation state in which the apparatus of Fig. 1 is still mounted at the hand of the patient. As a result of the administration of the muscle relaxing substance, the muscle activity becomes slower and slower.

Meaningful parameters indicative of whether the anesthesia has already deactivated muscle activity of the patient are the values of the ratios TVT₀ and T₄:Ti. However, other activation schemes or evaluation schemes may be implemented according to exemplary embodiments of the invention. Fig. 18 illustrates alternative geometrical shapes of plate-like rigid elements

1800 and 1810 which may be used in a similar manner as the above-described plate- like rigid elements 113 and 114.

The plate-like rigid element 1800 is functionally shaped and dimensioned to be properly positionable along a thumb (indicated schematically with reference numeral 1801 ) of a palm of the human patient. A closed main portion of the hand is indicated schematically with reference numeral 1802. The plate-like rigid element 1800 is designed to match with a human hand's anatomy and allows a patient to carry the plate 1800 without pain or inconvenient feeling. For this purpose, the plate- like rigid element 1800 comprises a thickened portion 1803 having a mechanically stabilizing effect. Beyond this, the plate-like rigid element 1800 comprises a thinner elongated portion 1804 to extend along a palm of the patient in a convenient manner.

Corners 1805 of the plate-like rigid element 1800 are rounded for convenience. The essentially rectangular plate-like rigid element 1800 is therefore adapted to fit to a human's hand anatomy. The plate-like rigid element 1810 is functionally shaped and dimensioned to be positioned along a finger row of a palm of the human patient of the human patient.

The plate-like rigid element 1810 is designed to match with a human hand's anatomy and allows a patient to carry the plate 1810 without pain or inconvenient feeling. For this purpose, the plate-like rigid element 1800 has a straight geometry and comprises an essentially rectangular plate, wherein corners 1811 of the plate-like rigid element

1800 are rounded for convenience. A flattened portion is adapted to fit to a human's hand anatomy.

Consequently, a force transmitting element may be provided comprising components 1800, 1810 being designed to match to an anatomy of a human being's hand.

It should be noted that the term "comprising" does not exclude other elements or steps and the "a" or "an" does not exclude a plurality. Also elements described in association with different embodiments may be combined.

It should also be noted that reference signs in the claims shall not be construed as limiting the scope of the claims.

Claims

C L A I M S

1. A device (100) for determining a muscle activity of a physiological object, the device (100) comprising a pneumatic mechanism (101 to 105) adapted for pneumatically determining the muscle activity of the physiological object.

2. The device (100) of claim 1, wherein the pneumatic mechanism (101 to 105) comprises a balloon (101) being inflatable with a medium, particularly with a fluid.

3. The device (100) of claim 2, wherein the balloon (101) is shaped and sized to be accommodated in a hand (300) of a human being.

4. The device (100) of claim 2 or 3, wherein the pneumatic mechanism (101 to 105) comprises conduit (102) being in fluid communication with the balloon (101).

5. The device (100) of any one of claims 2 to 4, wherein the pneumatic mechanism (101 to 105) comprises an inflation unit (104, 105) adapted for selectively inflating the balloon (101).

6. The device (100) of claim 5, wherein the inflation unit (104, 105) is coupled with the balloon (101) for fluid communication between the inflation unit (104, 105) and the balloon (101) via the fluid conduit (102).

7. The device (100) of any one of claims 2 to 6, comprising a fastening element (106) adapted to fasten the balloon (101) in a hand (300) of the physiological object.

8. The device (100) of claim 7, wherein the fastening element (106) comprises an elastic bandage.

9. The device (100) of any one of claims 1 to 8, comprising a stimulator unit (109) adapted for stimulating a nerve of the physiological object.

10. The device ( 100) of claim 9, wherein the stimulator unit (109) is adapted for stimulating an ulnar nerve of the physiological object.

11. The device (100) of claim 9 or 10, wherein the stimulator unit (109) comprises one or more electrodes (111) to be connected to the physiological object for transmitting an electric stimulation signal from the stimulator unit (109) to the physiological object.

12. The device (100) of any one of claims 2 to 11, comprising a pressure sensor (103) adapted to measure a pressure in the balloon.

13. The device (100) of claim 12, wherein the pressure sensor (103) is adapted to measure a pressure change in the balloon (101) in response to a stimulation of a nerve of the physiological object.

14. The device (100) of claim 12 or 13, comprising an essentially incompressible conduit (102) providing a fluid communication between the balloon (101) and the pressure sensor (103).

15. The device (100) of any one of claims 2 to 14, comprising a force transmitting element (113, 114) adapted for promoting a transmission of a force between a hand (300) of the physiological object and the balloon (101).

16. The device (100) of claim 15, wherein the force transmitting element comprises a first rigid element (114) adapted to be positioned along a finger row (303) of the physiological object.

17. The device (100) of claim 15 or 16, wherein the force transmitting element comprises a second rigid element (113) adapted to be positioned along a thumb (302) of the physiological object.

18. The device (100) of claim 16 or 17, wherein at least one of the group consisting of the first rigid element (114) and the second rigid element (113) comprises one of the group consisting of a strip, a plate, and a rod.

19. The device (100) of any one of claims 1 to 18, wherein the pneumatic mechanism (101 to 105) is adapted for pneumatically monitoring a muscle relaxation of the physiological object.

20. The device (100) of any one of claims 1 to 19, comprising a user interface unit (116) adapted for enabling a user to perform at least one of the group consisting of controlling the device (100), operating the device (100), and inspecting of the muscle activity of the physiological object.

21. The device (100) of any one of claims 15 to 20, wherein the force transmitting element (113, 114) is integrally formed with the balloon (101).

22. The device (100) of any one of claims 1 to 21, wherein the force transmitting element comprises one or more components (1800, 1810) being designed to match to an anatomy of a human being's hand.

23. A method of determining a muscle activity of a physiological object, the method comprising pneumatically determining the muscle activity of the physiological object.

24. The method of claim 23, comprising fixing an inflatable balloon (101) at a palm (301) of a hand (300) of the physiological object.

25. The method of claim 24, comprising inflating the balloon (101).

26. The method of any one of claims 23 to 25, comprising stimulating a nerve of the physiological object.

27. The method of claim 26, comprising measuring a pressure change in the balloon (101) in response to the stimulation of the nerve of the physiological object.

28. A computer-readable medium, in which a computer program of determining a muscle activity of a physiological object is stored, which computer program, when being executed by a processor (115), is adapted to carry out or control a method of any one of claims 23 to 27.

29. A program element of determining a muscle activity of a physiological object, which program element, when being executed by a processor (115), is adapted to carry out or control a method of any one of claims 23 to 27.

30. A method of using a device (100) of any one of claims 1 to 22 for determining a medication induced muscle relaxation of the physiological object.

31. The method of claim 30, comprising using the device (100) for controlling a dose of a medication to be administered to the physiological object to maintain the muscle relaxation of the physiological object.