WO2018141850A1

WO2018141850A1 - Method and apparatus of assessing or monitoring an effectiveness of a neural block in a living subject

Info

Publication number: WO2018141850A1
Application number: PCT/EP2018/052524
Authority: WO
Inventors: Hanne Storm; Semih GUNGOR
Original assignee: Neural Block Technology As; New York Society For The Ruptured And Crippled Maintaining The Hospital For Special Surgery
Priority date: 2017-02-01
Filing date: 2018-02-01
Publication date: 2018-08-09

Abstract

A method of assessing or monitoring an effectiveness of a neural block in a living subject, the subject having a skin, comprises assessing or measuring electrodermal activity, wherein the electrodermal activity is skin conductance, galvanic skin response, electrodermal response, psychogalvanic reflex, skin conductance response, sympathetic skin response or skin conductance level. Skin conductance may be assessed by calculating skin conductance fluctuation peaks per time unit, and when the skin conductance fluctuations peaks disappear in an analyzing window with a length of about 15 to 60 seconds, the neural block is assessed as being obtained or successful. Alternatively, the skin conductance may be assessed by calculating rise time of skin conductance fluctuation, size on amplitude of the skin conductance fluctuation peaks, or area under the curve of skin conductance fluctuation peaks.

Description

METHOD AND APPARATUS OF ASSESSING OR MONITORING AN EFFECTIVENESS OF A NEURAL BLOCK IN A LIVING SUBJECT

FIELD OF THE INVENTION

The invention relates to a method of assessing or monitoring an effectiveness of a neural block in a living subject. The invention also relates to an associated apparatus.

BACKGROUND OF THE INVENTION

In current clinical practice, commonly used monitoring methods to assess the success of a neural block are observation of clinical signs of sympathetic blockade, skin temperature monitoring pulse amplitude monitoring in pulse oximetry plethysmography, and combinations of such monitoring methods. These methods in the background art often demonstrate an unpredictable or delayed response and other disadvantages. Therefore, it is a clinical desire to develop an objective monitoring method which is reliable, has a rapid response, and which is not affected by other disadvantages of background art. Hence, there is a need for an improved method and apparatus of assessing or monitoring an effectiveness of a neural block in a subject, e.g. a human patient.

SUMMARY OF THE INVENTION

An object of the invention is to provide an improved method and apparatus of assessing or monitoring an effectiveness of a neural block in a living subject.

The invention is set forth in the appended claims.

The present disclosure relates to a method of assessing or monitoring an

effectiveness of a neural block in a living subject, the subject having a skin. In an advantageous aspect, the subject is a human, e.g. a human patient. In an alternative aspect, the subject may be an animal.

Assessing or monitoring an effectiveness of a neural block in the subject, e.g. the human patient, may include determining the successful achievement of sympathetic block in a clinical setting.

An advantageous aspect relates to a method of monitoring an effectiveness of the neural block in the subject. An alternative aspect, relates to a method of assessing an effectiveness of the neural block in the subject. The method comprises assessing or measuring electrodermal activity, wherein the electrodermal activity is chosen from the group consisting of: Skin conductance, galvanic skin response, electrodermal response, psychogalvanic reflex, skin conductance response, sympathetic skin response and skin conductance level.

In an advantageous aspect, electrodermal activity is measured. In an alternative aspect, electrodermal activity is assessed.

Advantageously, the electrodermal activity assessed or measured is skin

conductance. Advantageously, the skin conductance is assessed or measured by calculating skin conductance fluctuation peaks per time unit, and when the skin conductance fluctuations peaks disappear in an analyzing window with a length of about 15 to 60 seconds, the neural block is assessed as being obtained or successful. Particularly advantageous, the length of the analyzing window is about 15 seconds.

The skin conductance may be assessed or measured by calculating rise time of skin conductance fluctuation. In this case, when the rise time decreases in an analyzing window with a length of about 15 to 60 seconds, the neural block is assessed as being obtained or successful. The length of the analyzing window is advantageously about 15 to 30 seconds.

The skin conductance may be assessed or measured by calculating size on amplitude of the skin conductance fluctuation peaks. When the size on the amplitude decrease or disappear in an analyzing window with a length of about 15 to 60 seconds, the neural block is assessed as being obtained or successful. Particularly

advantageously, the length of the analyzing window is about 15 seconds.

The skin conductance may be assessed or measured by calculating area under the curve of skin conductance fluctuation peaks. When the area under the curve of skin conductance fluctuations peaks decrease or disappear an analyzing window with a length of about 15 to 60 seconds, the neural block is assessed as being obtained or successful. Particularly advantageously, the length of the analyzing window is about 15 seconds.

The skin conductance may be in the entire body of the subject.

In any of the above-mentioned methods and aspects, neural block may be for a sympathetic nerve. However, the neural block may be for a mixed nerve block chosen from the group consisting of motor+sympathetic, sensory+sympathetic, and motor+ sen sory+symp athetic . In any of the above-mentioned methods, the neural block may be obtained by local analgesia or local anesthesia.

In any of the above-mentioned methods, the neural block may be assessed or measured at the skin level.

In any of the above-mentioned methods, the neural block may be assessed or measured in the limbs including but not limted to the palmar side of the wrist, the palm, the ankle area, dorsum of the knee or the plantar part of the foot.

Any of the above-mentioned methods may further comprise the use of additional methods to assess or measure a neural block. Such additional methods may be chosen from the group consisting of unilateral thermometry monitoring, bilateral comparative thermometry monitoring, change in waveform amplitude in pulse oximetry plethysmography, and any combination thereof.

In any of the discloses methods, the electrodermal activity at two or more extremities may be assessed or measured, wherein in the electrodermal activity of one extremity with neural block and one extremity or more extremities without neural block are compared.

Any of the disclosed methods may further comprise stimulating electrodermal activity that disappears when the nerve block is assessed or measured to have been obtained or successful.

The invention also relates to an apparatus configured to performing the disclosed method.

The apparatus may comprise a wireless sensor with bluetooth connection to a computer or cell phone wherein a signal is processed through a computer software application and wherein the apparatus can send wireless information through a wireless technology to other computers, or mobile devices or tablets with computer software program. The apparatus may comprise a measuring box with electrodes and computer software display on any computer tablets.

The apparatus may be used together with an accelerometer which will inform about movements to and give information about movement artefacts.

The apparatus can be connected to other methods which can assess neural block, wherein additional methods are chosen from the group consisting of unilateral thermometry monitoring, bilateral comparative thermometry monitoring, change in waveform amplitude in pulse oximetry plethysmography, and any combination thereof. The apparatus can be used to assess electrodermal activity at two or more extremities to compare the extremity with neural block to extremity(ies) without neural block.

The apparatus can be used together with an electrodermal activity stimulator which can be used to give information about when the neural block starts to work and/or a successful block.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments, aspects and principles of the invention will now be described in more detail with reference to the attached drawings, in which figure 1 is a schematic flow chart illustrating a method of assessing or monitoring aneural block in a subject, in a first aspect; figure 2 is a schematic flow chart illustrating a method of assessing or monitoring aneural block in a subject, in a second aspect; figure 3 is a schematic flow chart illustrating a method of assessing or monitoring aneural block in a subject, in a third aspect; figure 4 is a schematic block diagram illustrating an apparatus; figure 5 is a schematic block diagram illustrating further possible aspects of the method and apparatus; figure 6 is a schematic block diagram illustrating further possible aspects of the method and apparatus, figure 7 is an illustration of aspects of a measurement arrangement. figure 8 is a schematic block diagram illustrating further aspects of the apparatus, figure 9 is a graph illustrating recorded skin conductance measurements, shown with two different time scales, and figure 10 is a graph illustrating comparison between an assessment tool based on skin conductance monitoring and other assessment tools available in the background art.

DETAILED DESCRIPTION

There are three types of nerves that are bundled together within the same neural element. These nerves are sympathetic nerves, sensory nerves and motor nerves. Local anesthetic application to neural structures in the living body, e.g. the human body, creates a differential nerve blockade depending on the dose of the local anesthetic. In general, small fibers are blocked faster than those of large ones because of the time course of drug diffusion into the nerves. Also, some fibers maybe slightly more subjective to impulse blockade by the local anesthetic than others because of anatomic features, such as the presence of myelin. Third, axons of the nerves may be differentially sensitive to local anesthetic block depending on the presence of voltage-gated potassium channels; due to difference of sodium channel types, or the difference in the membrane lipids.

When a local anesthetic block is applied to the nerve, the first nerve fibers to be blocked are C- fibers including the postganglionic sympathetic fibers. C-fibers are also involved in the slow pain transmission. Myelinated fibers are blocked later than unmyelinated fibers. The smallest diameter myelinated fibers are B -fibers, also known as preganglionic sympathetic fibers are blocked next.

Therefore, the first nerve fibers to be blocked by a local anesthetic nerve block are mainly sympathetic fibers including small diameter unmyelinated C-fibers postganglionic sympathetic fibers), and lightly myelinated mid sized B- fibers (preganglionic sympathetic fibers), along with C fibers for slow transmission of pain.

The blockade of the densely myelinated and larger diameter fibers comes next in the order of: A-delta fibers for fast transmission of pain, then A-fibers for motor the muscle spindles. Then, A-Fibers for touch and pressure are blocked. The last fibers to the blocked are A- delta fibers for somatic motor block and for proprioception of the muscle spindles and golgi tendon organ. The reason that these fibers are blocked last is that these A-delta fibers are the largest in diameter and they are densely myelinated.

Based on such knowledge, the inventors have found that it is possible to monitor the sympathetic activity at the skin level by the use of a skin conductance monitor, thereby to directly monitor the cessation of sympathetic activity in the distribution of the blocked nerves. As the sympathetic nerves are the first nerves to be blocked, the cessation of the sympathetic activity in the distribution of the nerves that are attempted to be blocked would be the first objective measurement that the local anesthetic block was successful and starting to work. Although C-fibers for slow transmission of pain are also smaller in diameter and unmyelinated, therefore expected to be blocked early after the local anesthetic injection, and as A-delta fibers for fast transmission of pain are not yet blocked as they are myelinated and larger in diameter, the patients will still feel the pain sensation even if the C- fibers are blocked as A- delta fibers will still unblocked early after the local anesthetic injection. This may have some important clinical applications when nerve block by local anesthetics is considered in the clinical practice. First of all, the clinician will immediately note that the block was appropriately performed, and the block is starting to set in within seconds after the local anesthetic is given just by monitoring the sympathetic activity with the use of a monitor that monitors electro -dermal activity. As the block for sensory and motor is delayed after the local anesthetic block due to the reasons mentioned above, this will provide sense of security to the clinicians that the sensory and motor block will take place within the next approximately 5-30 minutes. If in case of a failed block that did not start any changes in the skin conductance activity within seconds after the application of the local anesthetic block, this will inform the clinician for the failure of the block within seconds so that the block technique may be modified immediately in order to avoid negative consequences.

Diffusion of anesthetic molecules from the nerve and absorption into the vascular bed determines to duration of the blockade. The nerve fibers that are blocked the first, should be the nerve fibers that recover the last. This means that the

sympathetic fibers will recover last from the block. The inventors have found that electrodermal activity and skin conductance monitoring may be used to monitor, and document the complete resolution of the nerve block.

Potential use of electrodermal activity to monitor neuromodulation techniques. Neuromodulation techniques including spinal cord stimulator with various stimulation modes, including but not limited to, DRG stimulation meaning dorsal root ganglion stimulation, high density stimulation, high frequency stimulation, peripheral nerve stimulation, and any other stimulation techniques used in the clinical practice and also in experiment models. One of the mechanisms that these neuromodulation techniques provide is the sympathectomy in the limbs. There is potential use of monitoring electric -dermal activity to find out whether sympathetic block or changes in sympathetic activity in the body is achieved. Figure 1 is a schematic flow chart illustrating a method of monitoring an

effectiveness of a neural block in a subject in a first aspect.

In this example, the subject is a human patient. Alternatively, the subject may be a human non-patient or an animal. In the context of this example, monitoring an effectiveness of a neural block in the human patient includes determining the successful achievement of sympathetic block in a clinical setting.

The method starts at the initiating step 1 10.

The method includes the measuring step 120 of measuring electrodermal activity. Advantageously, the measured electrodermal activity is skin conductance. In alternative aspects, the electrodermal activity may be galvanic skin response, electrodermal response, psychogalvanic reflex, skin conductance response, sympathetic skin response or skin conductance level.

The method further proceeds to a calculating step 130, wherin the skin conductance measurement data are processed by calculating skin conductance fluctuation peaks per time unit.

The method further proceeds to the determining step 140. In the determining step 140, when the skin conductance fluctuations peaks are determined to disappear in an analyzing window, the method proceeds to the establishing step 150. In establishing step 150, the neural block is established as being obtained or successful.

Advantageous, the analysis window has a length in time of about 15 to 60 seconds. Particularly advantageous, the the length of the analyzing window is about 15 seconds.

When the neural block has been established to be successful in step 150, the method may be terminated at terminating step 160, or alternatively, repeated from the initiating step 110. In the determining step 140, if the skin conductance fluctuations peaks are determined not to disappear in the analyzing window, the measurement step 120, calculating step 130 and determining step 140 may be repeated.

Figure 2 is a schematic flow chart illustrating a method of monitoring an

effectiveness of a neural block in a subject in a second aspect. The subject is a human patient also in this example. Alternatively, the subject may be a human non- patient or an animal. In the context of this example, monitoring an effectiveness of a neural block in the human patient includes determining the successful achievement of sympathetic block in a clinical setting.

The method starts at the initiating step 210.

The method includes the measuring step 220 of measuring electrodermal activity, wherein the measured electrodermal activity is skin conductance. In alternative aspects, the electrodermal activity could have been galvanic skin response, electrodermal response, psychogalvanic reflex, skin conductance response, sympathetic skin response or skin conductance level.

The method further proceeds to a calculating step 230, wherein a rise time of skin conductance fluctuations is calculated.

The method further proceeds to the determining step 240. In the determining step 240, when the rise time decreases in an analyzing window, the method proceeds to the establishing step 250.

In establishing step 250, the neural block is established as being obtained or successful.

Advantageous, the analysis window has a length in time of about 15 to 60 seconds. Particularly advantageous, the the length of the analyzing window is about 15 to 30 seconds.

When the neural block has been established to be successful in step 250, the method may be terminated at terminating step 260, or alternatively, repeated from the initiating step 210.

In the determining step 240, if the rise time of fluctuations does not decrease in the analyzing window, the measurement step 220, calculating step 230 and determining step 240 may be repeated (not illustrated).

Figure 3 is a schematic flow chart illustrating a method of monitoring an

effectiveness of a neural block in a subject in a third aspect.

Also in this example, the subject is a human patient. Alternatively, the subject may be a human non-patient or an animal. In the context of this example, monitoring an effectiveness of a neural block in the human patient includes determining the successful achievement of sympathetic block in a clinical setting. The method starts at the initiating step 310.

The method includes the measuring step 320 of measuring electrodermal activity, wherein the measured electrodermal activity is skin conductance. In alternative aspects, the electrodermal activity could have been galvanic skin response, electrodermal response, psychogalvanic reflex, skin conductance response, sympathetic skin response or skin conductance level. The method further proceeds to a calculating step 330, wherein an area under the curve of skin conductance fluctuation peaks in an analyzing window is calculated.

The method further proceeds to the determining step 240. In the determining step 340, when the area under the curve of skin conductance fluctuations peaks decreases or disappears in the analyzing window, the method proceeds to the establishing step 350.

In establishing step 350, the neural block is established as being obtained or successful.

Advantageous, the analysis window has a length in time of about 15 to 60 seconds. Particularly advantageous, the length of the analyzing window is about 15 seconds.

When the neural block has been established to be successful in step 350, the method may be terminated at terminating step 260, or alternatively, repeated from the initiating step 310.

In the determining step 340, if the area under the curve of skin conductance fluctuations peaks does not decrease or disappear in the analyzing window, the measurement step 220, calculating step 230 and determining step 240 may be repeated.

The step of calculating area under the curve of skin conductance fluctiation peaks may also be combined with the step of calculating skin conductance fluctutation peaks per time unit, as has been described above with reference to figure 1.

In any of the methods and aspects described above with reference to figures 1, 2 and/or 3, the skin conductance may be in the entire body of the subject.

In any of the methods and aspects described above with reference to figures 1 , 2 and/or 3, neural block may be for a sympathetic nerve. However, the neural block may be for a mixed nerve block chosen from the group consisting of

motor+sympathetic, sensory+sympathetic, and

motor+ sen sory+symp athetic . In any of the methods described above with reference to figures 1, 2 and/or 3, the neural block may be obtained by local analgesia or local anesthesia. Local analgesia or local anesthesia may have been given to the subject, e.g., the human patient, in advance, i.e., not as a part of the method of assessing or monitoring the

effectiveness of the neural block. Alternatively, local analgesia or local anesthesia may have been given to the subject, e.g., the human patient, as part of the method.

In any of the methods described above with reference to figures 1, 2 and/or 3, the neural block may be assessed or measured at the skin level. In any of the methods described above with reference to figures 1, 2 and/or 3, the neural block may be assessed or measured in the different location of limbs including but not limited to the palmar side of the wrist, the palm, the ankle area, dorsum of the knee, or the plantar part of the foot. Any of the methods described above with reference to figures 1 , 2 and/or 3 may further comprise the use of additional methods to assess or measure a neural block. Such additional methods may be chosen from the group consisting of unilateral thermometry monitoring, bilateral comparative thermometry monitoring, change in waveform amplitude in pulse oximetry plethysmography, and any combination thereof.

In any of the methods described above with reference to figures 1, 2 and/or 3, the electrodermal activity, e.g, the skin conductance, at two or more extremities may be assessed or measured. In this case, the electrodermal activity, e.g. skin conductance, of one extremity with neural block and one extremity or more extremities without neural block may be compared.

Any of the disclosed methods may further comprise stimulating electrodermal activity that disappears when the nerve block is assessed or measured to have been obtained or successful. Alternatively, such stimulating of electrodermal activity may be made separately from the method, e.g., before the method is performed. In the latter case, stimulating electrodermal activity is not part of the method of assessing or monitoring the effectiveness of a neural block in the subject. Figure 4 is a schematic block diagram illustrating an apparatus that may be used for the purpose of assessing or monitoring of the effectiveness of a neural block in a subject. The apparatus includes an internal bus, which is interconnected to a processor, a memory, a first and a second I/O device, and optionally to a communication adapter. The communication adapter may e.g. enable communication between the apparatus and an external computer, network or system. The first I/O device is interconnected to a user interface, which enables the operation of the apparatus by a user, including providing input data to the apparatus via input devices such as a keyboard, and/or keys, switches, etc. The second I/O device is interconnected to a measurement device, which is adapted to measure electrodermal activity of a subject, in particular to measure skin conductance of an area of a human patient's skin.

The method of assessing or monitoring the effectiveness of a neural block in the subject, e.g. the human patient, as has been disclosed in the present specification, an in particular as described above with reference to figures 1, 2 and 3 above, may advantageously be implemented as a sequence of processing instructions, i.e., a computer program, that may be stored in the memory that is interconnected to the bus in the apparatus. Hence, when the processing instructions are executed by the processor in the apparatus, the apparatus will perform a method of assessing and monitoring the effectiveness of a neural block according to the present disclosure.

Figure 5 is a schematic block diagram illustrating further possible aspects of the method and apparatus. As shown in figure 5, the apparatus may be interconnected to a PC with a display, for instance via a communication cable. The apparatus may also be connected to electrodes and stimulating devices via connections illustrated as electrode cable. As illustrated, the interconnected stimulating devices may include audio equipment, providing sound stimulation to the subject, and/or electrodes providing electrical stimulation to the subject. Electrodes to be attached to the subject (patient) for measuring electrodermal activity, e.g., skin conductance, have also been illustrated.

The stimulating devices may be arranged to stimulate electrodermal activity in the subject (e.g., the patient). When neural block is given and electrodermal activity is assessed, a stimulator to secure electrodermal responses may be used as an additional option. This stimulating device should be a sensor stimulator of a certain strength which gives rise to one or several electrodermal response(s) in the subject. It could be e.g sound, pressure, electrical, light, or smell stimulus/stimuli.

Figure 6 is a schematic block diagram illustrating further possible aspects of the method and apparatus. As shown in figure 6, the apparatus is used in an arrangement to assess or monitor the effectiveness of a neural block in a subject (illustrated as the nervous system of a human), using electrodermal activity measured from a plurality of extremities. More specifically, the features of figure 6 enables the assessment or measurement of electrodermal activity, e.g., skin conductance, at two or more extremities, wherein in the electrodermal activity of one extremity with neural block and one or more extremities without neural block are compared. As indicated in figure 6, separate electrodes are arranged to measure electrodermal activity, e.g. skin conductance, at the human's two hands. Optionally, as illustrated by dotted lines, electrodes may also be arranged to measure electrodermal activity, e.g. skin conductance, at the human's two feet. The electrodes are connected to the apparatus. The apparatus is further connected to a PC and display via a

communication cable.

The arrangement illustrated in figure 6 provides additional features for

assessment/monitoring of the effect of neural block in one extremity. The extremity or extremities which not will be blocked, will work as control extremity or extremities for the extremity which will be blocked.

Figure 7 is an illustration of aspects of a measurement arrangement.

Figure 7 illustrates an extremity of a subject, namely, a foot of a human patient. Three electrodes are attached to the plantar skin of the patient's foot. The electrodes are a current (C) electrode, a reference (R) electrode, and a measurement (M) electrode, respectively. The electrodes may be self-adhesive electrodes. They are interconnected by means of electrode cables to an apparatus that may be configured to perform the method of assessing or monitoring the effectiveness of a neural block in the patient, as disclosed herein.

Although a three electrode arrangement has been shown in figure 7, it should be noted that a two electrode arrangement for measuring electrodermal activity such as electrodermal response, galvanic skin response, skin resistance or skin conductance.

Figure 8 is a schematic block diagram illustrating further aspects of the apparatus.

Figure 8 is an overview of the apparatus and its interconnected devices during use. The apparatus 1 is interconnected with electrodes to measure electrodermal activity in the subject (e.g., patient), via electrode cable 2. The indicated arrangement of three electrodes is appropriate for measuring skin conductance on a portion of the patient's skin. The apparatus powered by a power supply 4 with a mains cable 6. A communication cable 3 interconnects the apparatus 1 with a PC 7 with a display and a stand 10. The PC may be powered by a power supply 8 with a mains cable 9.

Figure 9 is a graph illustrating recorded skin conductance measurements, shown with two different time scales.

Figure 9 shows results of skin conductance measurements recorded at a portion of a human skin. The graph to the right shows the progress of the skin conductance measurements before and after a sympathetic nerve block was given to the patient . The left graph in figure 9 shows the grey area of the right graph in closer detail.

Figure 10 is a graph illustrating comparison between an assessment tool based on skin conductance monitoring and other assessment tools available in the background art.

The observational real time skin conductance monitor (SCM) , i.e., an apparatus configured to perform the disclosed method of assessing or monitoring the effectiveness of a neural block in a living subject, has been compared with traditional assessment tools for sympathetic nerve blocks when assessed each minute or each 5 min. All traditional methods of determining the achievement of sympathetic block had substantially smaller odds of indicating successful block in the next moment, compared to the observational skin conductance responses tested by the SCM in real time (P < 0.001). When analysing the skin conductance responses in real time each minute, all patients had successful sympathetic block (defined as the skin conductance responses per sec were 0.00 in a real time 15 sec window) within 10 minutes that was statistically different than the traditional sympathetic block assessment tools (P < 0.001).

The following discloses a further study of changes in the skin conductance monitor as an endpoint for sympathetic nerve blocks. The present study substantiates and verifies the advantageousness of the disclosed method and apparatus for assessing or monitoring the effectiveness of a neural block in a subject, e.g. a human patient.

In the background art there is a lack of satisfactory, objective methods for determining the achievement of sympathetic block. This study validated skin conductance monitoring (SCM) as an endpoint indicator of successful sympathetic blockade as compared to traditional monitors.

Methods: This interventional study included 13 patients undergoing 25 lumbar sympathetic blocks to compare time to indication of successful blockade between the SCM indices and traditional measures; clinically visible hyperemia, clinically visible engorgement of veins, subjective skin temperature difference, unilateral thermometry monitoring, bilateral comparative thermometry monitoring and change in waveform amplitude in pulse oximetry plethysmography, within a 30-minute observation period. Differences in the SCM indices were studied pre and post block to validate the SCM.

Results: SCM showed substantially greater odds of indicating achievement of sympathetic block in the next moment (i.e., hazard rate) compared to all traditional measures (clinically visible hyperemia, clinically visible engorgement of veins, subjective temperature difference, unilateral thermometry monitoring, bilateral comparative thermometry monitoring and change in waveform amplitude in pulse oximetry plethysmography (P<0.011). SCM indicated successful block for all (100%) procedures, while the traditional measures failed to indicate successful blocks in 16-84% of procedures. The SCM indices were significantly higher pre- block compared to post-block measurements (P < 0.005).

Conclusion: This preliminary study suggests SCM is a more reliable and rapid response indicator of a successful sympathetic blockade when compared to traditional monitors.

Sympathetic blocks are clinically used for both diagnosis and treatment of sympathetically mediated pain in variety of neuropathic pain conditions including complex regional pain syndrome. Sympathetic nerve block has been found successful in about 40% of the patients with neuropathic pain to improve their pain conditions [1, 2] . A sympathetic blockade refers to an injection of a local anesthetic around the sympathetic nerves to alter their functions [2] . The local anesthetic block, often repeated with intervals, may reduce the activity of spontaneous discharges in hyperactive neurons [2] . Reducing the sympathetic nerve activity in the painful region by blocking sympathetic nerve ganglia with a series of local anesthetic nerve blocks may therefore break the cycle of sympathetically mediated pain, and provide pain relief [2] . Despite the frequent use of these blocks, there is still a lack of objective methods for determining the successful achievement if sympathetic block in the clinical setting.

In current clinical practice, the most commonly used monitoring methods to assess the success of a sympathetic block are observation of clinical signs of sympathetic blockade, skin temperature monitoring [3-6] , pulse amplitude monitoring in pulse oximetry plethysmography [7] and any combination of these monitoring methods. The skin temperature and pulse amplitude in pulse oximetry plethysmography may increase after sympathetic block [3, 8] . However, observation of clinical signs of sympathetic blockade, monitorization of skin temperature and pulse amplitude often demonstrate an unpredictable or delayed response. Furthermore, confounding variables, such as ambient temperature, coexisting vascular disease, use of other vasoactive medications, may contribute to inconsistencies in the temperature measurements, or pulse amplitude responses. Therefore, it is a clinical necessity to develop an objective monitoring method that is reliable, rapid response, and also not affected by the other confounders.

One potential method is the examination of sympathetic nerve activity via a skin conductance monitor (SCM). Normal skin sympathetic nerve activity stimulates muscarinic receptors that subsequently stimulate the sweat glands to secrete and fill with sweat containing sodium and other electrolytes [9] . The electrolytes present in the sweat increase the electrical conductance while decreasing the electrical resistance at the skin level. The real-time changes in SCM indices can be monitored at the skin level, by use of non-invasive electrodes attached to the skin [9] (cf.

figuere 7). This is best monitored in the areas with relatively dense sweat glands, such as palm and plantar skin. A computer program analyzes the data and produces a real-time graphic and numeric data demonstrating the skin conductance response [9] (Figures 8 and 9). The initiation of successful sympathetic blockade can cause rapid cessation of the skin sympathetic nerve activity that leads to a decrease in skin conductance responses within seconds [10] (Figure 9). Currently, there is no rapid- response monitor with easy clinical applicability to assess the achievement of a successful sympathetic blockade. Such a monitor could increase procedural accuracy and efficiency, thereby improve patient care. This is especially important to evaluate the response to the sympathetic blocks as they are important for diagnostic purposes to differentiate neuropathic pain types as the sympathetically mediated/maintained pain (SMP), or sympathetically independent pain (SIP). The patients with neuropathic pain presenting with similar symptoms can be classified into two groups depending on their negative or positive response to selective sympathetic blockade. If the pain is relieved by the selective sympathetic block it is considered as SMP. Sympathetically mediated pain is defined as a symptom in a subset of patients with neuropathic pain. The significance of differentiating between SMP or SIP is that, SMP has a greater chance of responding favorably to

sympatholytic blockade. Therefore, a prospective therapy plan of performing repeated sympatholytic blocks may be considered as these blocks are more efficacious in SMP. On the contrary, as the chance of responding favorably to sympathetic blocks is less likely in SIP, alternative therapies must be considered in this group of patients. In order to plan the prospective treatment options, objective confirmation of sympathectomy created by the attempted sympathetic block is important to differentiate SMP versus SIP [1 1] . In this context, utilization of a monitor with a rapid response and easy clinical applicability which can demonstrate effective sympathetic block would serve to function as an objective endpoint for the evaluation of sympathetic blockade both clinically and for future research. We hypothesize that the SCM is, on average, a more reliable and rapid response indicator of a successful sympathetic blockade than traditional monitors such as clinical assessment, monitoring changes in the skin temperature and pulse amplitude. Methods - subjects

After Institutional Review Board (IRB) approval, Total of 25 recordings were included in the analysis from 13 patients recruited for this study after written informed consent was obtained. The patients were selected among patients who were scheduled for lumbar sympathetic block of the lower extremity. The inclusion criteria were that they were scheduled for lumbar sympathetic block at one of the lower extremities, and the other lower extremity was healthy. Inclusion ages were 18-99 years. The exclusion criteria were; patients with pacemakers, cardiac defibrillators and spinal cord stimulators, intravenous sedation for anxiety or analgesia, or patients with dermatological conditions in the plantar aspect of the foot where SCM electrodes to be attached, history of allergic reaction to adhesive tape, patients with diagnosis of dysautonomia, sympathetic dysfunction (such as Raynaud disease or Buerger disease), disorders of sweating (such as acquired idiopathic generalized anhidrosis) as well as patients on vasoactive drugs

of which the mechanism of action is directly on the vascular tone. All the procedures were performed under fluoroscopy by the same practitioner by using the same technique. The patients were positioned prone on the fluoroscopy table. After the monitors were placed, including the research monitors, the entry site was marked at the Lumbar 3 vertebral body level in 30 degrees oblique view ipsilateral to the affected extremity under fluoroscopy. 2 mL of lidocaine 1 % was used for local anesthesia of the skin and subcutaneous tissues at the needle entry site. Then by using the 20-gauge 3.5-inch introducer needle, and 25-gauge 6-inch spinal needle, the needle was advanced to the anterolateral aspect of the Lumbar 3 vertebral body on the affected side. After negative aspiration, 4 mL of lohexol 180 mg/mL (Omnipaque 180) contrast was injected under live fluoroscopy, and the needle tip location with the spread of the contrast anterolateral to the Lumbar 3 vertebral body were confirmed, and intravascular uptake was ruled out. The contrast distribution was confirmed on anteroposterior, oblique and lateral views. After negative aspiration, initially 3 mL of lidocaine 2% was given as a test dose, followed by 7 mL of bupivacaine 0.5% in all patients. Clinicaltrial.gov number was NCT02390323. Methods

Monitoring temperature as a measure for Sympathetic block assessment Temperatures in the affected (Tl) and unaffected limb (T2) were continuously measured and recorded prior to the procedure which constituted baseline, and at 1 minute intervals thereafter, until 10 minutes post-procedure. To determine the success of the sympathetic block, a thermometry score of 0-3 was assigned based on the recorded values (Table 1). Specifically, a bilateral (temperature difference between bilateral limbs) [4-6], or unilateral (temperature difference within measurements of the affected limb) [5] temperature score> 3 (i.e. an increase in temperature>2°C) was used to indicate a successful sympathetic block. The temperature was assessed with dual channel monitor from Puritan-Bennett

Corporation PB240, USA.

Monitoring Pulse Amplitude in pulse oximetry plethysmography as a measure for Sympathetic block assessment

Pulse amplitude [6, 7] of the affected extremity was measured at baseline and then at 1 minute intervals until 10 minutes after completion of procedure by using plethysmography (Table 2). To determine the success of the sympathetic block, a plethysmography score of 0-4 was assigned based on the recorded values (Table 2). Specifically, a score that is >3 (i.e. a waveform amplitude reading of 20) was used to indicate a successful sympathetic block. The pulse pressure amplitude was assessed with plethysmography-monitoring equipment from Puritan-Bennett Corporation PB240, USA.

Skin conductance activity to assess sympathetic block The skin conductance measurement [12] was performed using three self-adhesive noninvasive electrodes attached to the participants' plantar skin surface of the affected lower extremity [13] (Figure 1). The skin conductance responses were assessed using the SCM equipment provided by Med-Storm Innovation, Oslo, Norway, software 1.0.6.33 [14], The SCM is a device that primarily measures changes in skin conductance real time (Figure 2, Figure 3). A skin conductance response is defined as a minimum followed by a maximum in conductance values (mS). The measurement is performed using three self-adhesive electrodes, denoted C (current), R (reference) and M (measurement) attached to plantar skin (Figure 1). The measurement unit uses the C and R electrodes in a feedback configuration to apply an exact and constant alternating voltage between the Rand M electrodes. The return current from the M electrode is recorded, as its value provides direct information on the skin conductance. The recorded alternating current signal is subjected to advanced filtering which removes noise and interference before the signal is sent on to the display computer (Figure 8).

The 3-electrode system used in our study allow us to only assess skin conductance activity underneath the M electrode. The system can measure conductance values in the range l-200mS, with a noise level (1 SD) below 0.002mS. The threshold we used to define a skin conductance response was 0.005 microsiemens.

The measuring unit also has error detection that provides a warning for events caused by a loose electrode, external interference, or the use of electrocoagulation. The skin conductance responses per sec are not influenced from environmental temperature [15] . This device has been issued a European Community declaration of conformity but not FDA approved.

Skin Conductance Visual Observation Scale in real time

Easily recognizable changes on skin conductance graph to determine the successful sympathetic block may have practical advantages (Figure 3). Definite and easily recognizable change in the SCM graph that is usually a sudden decline in the graph (Figure 3) and in this study for research purposes this time point was defined as no observable skin conductance responses that is to imply the skin conductance responses per second were 0.00 in a real-time 15 second time window. The SCM was applied to the affected lower extremity (Figure 7), immediately prior to the procedure to obtain baseline readings. Measurements were recorded at 0 minutes and every 1 minute until 10 minutes after completion of procedure in real time, to compare the data with the other sympathetic block assessment tools. The preset skin conductance analyzing window of 15 second was used on the SCM. A measurement of 0.00 responses per second was taken as an indicator of a successful block (Table 3). The visible/recognizable changes are determined when the skin responses per second reading was 0.00 in a 15 second analyzing window.

Validation of reliability: Offline skin conductance assessment

The skin conductance activity measurements for enrolled patients were saved as distinct registrations reflecting the precise time points when the test dose and the block were administered during the procedure. The purpose of in-depth analysis of 20 registrations after sampling the data was, (a) to study the reliability of the method; and (b) if we can further develop a more effective and accurate way of analyzing skin conductance responses rather than observing the registration curve (Figure 9) each minute in real time. During this analysis, we tested Med Storm Innovation's software in various settings: Analyzing windows of 15 seconds, 30 seconds and 60 seconds were defined, and used from the start of block in order to gauge when the skin conductance responses disappeared, which was the definition of a successful block. We tracked this identical duration in time before the start of block to study what the lowest normal activity was in the affected extremity before the block for each individual. Moreover, the derivate of the skin conductance was obtained for these different time periods with the lowest number of skin

conductance responses, before and after the block, for the different analyzing windows to study how the derivate of the skin conductance curve changed after the block.

Monitoring clinical assessment of signs as a measure of sympathetic block assessment

Clinical assessment of signs included (a) clinically visible hyperemia, (b) clinically visible engorgement of veins, (c) subjective warmth and temperature difference resultant of comparison of the bilateral lower extremities as assessed by inspection and palpation. These clinical evaluations were performed every 5 minutes until 20 minutes post procedure (Table 4). A score of 0-3 was assigned based on the clinical assessment values (Table 4). Specifically, a score>l (i.e. mild difference) for each of the three parameters of clinical assessment, was used as an indicator of successful sympathetic block.

These clinical evaluations were not studied each minute, but every 5 minutes until 20 minutes after the procedure for practical clinical feasibility reasons (Table 4).

The current limited evidence for using these traditional methods is presented (Table 5). Level of evidence was graded based on the reference by Xu J. et al [16] .

Statistics

A clinically meaningful difference in time to indication of successful block between traditional and skin conductance measurement was taken to be 5 minutes (300 seconds). Assuming a standard deviation of 180 seconds, 10 sympathetic blocks and 10 stellate ganglion blocks would provide 80% power to detect a 300 second difference in time to indication of successful block between SCM and each of the 6 traditional measures at a Bonferroni-corrected alpha level of 0.004 (0.05 divided by 12 comparisons). The protocol was subsequently amended to include only lumbar sympathetic blocks to standardize the procedural technique, which allowed for over 99% power to detect the desired effect size at a Bonferroni-corrected alpha level of 0.008 (0.005 divided by 6 comparisons) Continuous variables are presented as means with standard deviations or medians with 1st and 3rd quartiles, depending upon the distribution of the data. Categorical variables are presented as counts and percentages. Kaplan -Meier curves were constructed to show the proportion of patients not yet displaying evidence of sympathetic blockade based on SCM and each of the traditional methods (Figure 10). A Cox proportional hazards model was used to compare each tradition method to SCM using a marginal approach with a working independence assumption to account for the correlation between measurements on the same patient.

The skin conductance responses were assessed on only the affected extremity. Therefore, the values before the block were compared with the values after the block off line in 20 registrations to explore the validity and the reliability of the method. In the same time period before and after the block, the minimum levels of skin conductance responses per second were studied. The length of the time period was defined by the time point at which the block started to work; i.e. the SCM responses per sec were 0.00, for analyzing windows of 15 sec, 30 sec and 60 sec. Regression based on the generalized estimating equations (GEE) approach was used to compare the difference in lowest peak value, and the difference in lowest average rise time before and after block dose administration. GEE was also used to evaluate the difference in time to start of decline in the SCM curve, and difference in time to disappearance of peaks after test dose administration between 15, 30, and 60 second measurement windows. The GEE approach was used to account for lack of independence between measurements obtained from multiple blocks performed on the same patient. All statistical hypothesis tests were two-sided, with Bonferroni- adjusted P < 0.05 defined as statistical significant. Statistical analyses were performed with SAS Version 9.3 (SAS Institute, Cary, NC). Results

The 13 patients included had a mean + SO age of 54 + 13 years, body mass index (8MI) of 26 + 3, and 39% were female. There were 25 blocks in total where 7 patients received 1 block, 3 patients received 2 blocks, and 3 patients received 4 blocks. The SCM (Figure 2) and the temperature with pulse amplitude were displayed at two different monitors. All traditional methods of determining the achievement of sympathetic block had substantially smaller odds of indicating successful block compared to the observational skin conductance responses tested by the SCM in real time (P<0.011) (Table 6 and Figure 10). Further, the

observational SCM was the only method that indicated successful block for all patients within the observation period (Table 6 and Figure 10). Moreover, when the SCM readings were assessed off line on the affected extremity before and after the block using analyzing windows of 15 sec, 30 sec and 60 sec, the differences were statistically significant for all the windows studied (n=20) (p<0.005) (Table 7). The mean of the lowest values before the block was similar for all analyzing windows, 15 sec, 30 sec and 60 sec with respectively 0.07 + 0.08,0.05 + 0.06 and 0.07 + 0.06 skin conductance responses per sec (Table 7). Interestingly, when using the same window, 15 sec, as the observational SCM score, the skin conductance responses per sec were 0.00 after 28.9 + 21.4 sec, which was a statistically significantly shorter time than using 30 sec or 60 sec, which were 74.1 + 46.9 sec and 150.6 + 89.4 sec, respectively, to reach 0.00 skin conductance responses (P < 0.001), (Table 8). Moreover, the derivate of the skin conductance curve changed statistical significance to negative only for the 30 sec and 60 sec analyzing window from before to after the block.

Discussion

All the traditional methods of determining how fast the achievement of sympathetic block occurred had substantially smaller odds of indicating successful block in the next moment compared to the observational skin conductance testing by the SCM when validating these methods at one minute intervals. Further, the observational SCM was the only method that indicated successful block for all patients (100%) within the observation period (i.e., Skin conductance responses disappeared after the block in all patients tested). The reliability was assessed by comparing the minimum skin conductance responses per second, and the rise time of the curve before and after block start time point. Analysis of the offline registrations of SCM to validate the reliability of the SCM, demonstrated that SCR disappeared 28 + 21 sec after, when using the same analyzing window, 15 sec, as used in the

observational SCM test. Furthermore, when the lowest SCM values (skin

conductance responses per second) were studied before the block, it was statistically different from the responses per second after the block. If the observational validation periods had been each 30 sec and not each 1 minute, the sympathetic block probably would have been assessed earlier also according to the observational SCM test.

Interestingly, when clinically observing the skin conductance curve graph, it was obvious that there was a sharp decline after the block (Figure 3). When studying the derivate of the curve for the different analyzing windows before and after the block, only the 30 second and 60 second analyzing windows showed statistically significant decreases. One may speculate that by reducing the Med-Storm software threshold value for defining the derivate of the curve to be negative, also a statistical significant value for the 15 sec analyzing window would be obtained.

It has been questioned whether the patients in need of sympathetic block might have increased skin sympathetic nerve activity in the affected extremity. According to this study, the pre-block skin sympathetic nerve activity that is mirrored by skin conductance responses per sec was within normal range. The lowest levels were about 0.06 responses per sec which according to other studies show normal activity in relaxed patients [13] . The skin conductance responses per sec are assessed plantar in this study. The skin sympathetic nerve activity consists of four nerve types; vasoconstrictor, vasodilator, sudomotor, and pilomotor nerves [ 17] . The skin sympatheric sudomotor nerves have acetylcholine acling on muscarinic receptors which are blocked by aropine. They increase in activity during hyperthermia and lead to release of sweat in the body [17], except palmary and plantar where the skin sympathetic sudomotor activity is released during emotional stress stimuli [15, 18] and not influenced from

environmental temperature [15, 18] . Bini uses micro neurography and monitors changes in skin resistance palmary showing that temperature between 22 °C and 40 °C does not influence the sudomotor activity [15] .

Multiple factors like sweating, status of the epithelium, humidity of the skin will influence the mean skin conductance level, but not the "skin conductance responses per sec" that was used in this study [ 15, 17, 18].

Common mode rejection and differential amplifiers were integrated in the skin conductance monitor used in this study. The threshold we use to define a skin conductance response is 0.005 microsiemens. After going through many hundred recordings manually, we have found that the threshold of 0.005 microsiemens is suitable to define a skin conductance response without any significant influence from noise. The way we performed these analyzes are described for the prototype skin conductance monitor where we used the threshold value of 0.02 microsiemens [19] .

Other possible values for the skin conductance threshold value are within the range of 0.003 to 0.5 microsiemens.

The candidates for diagnostic/therapeutic sympathetic blocks are those patients with presentation of neuropathic pain mainly in the limbs, head and neck. Lumbar sympathetic blocks are performed for lower extremity neuropathic pain conditions, and stellate ganglion blocks are performed for upper extremity, head and neck neuropathic pain conditions. Some of the clinical conditions that may benefit from sympathetic blockade are either for pain relief in clinical conditions such as complex regional pain syndrome (CRPS), phantom limb pain, acute herpes zoster, cancer patients with involvement of the sympathetic nervous system, or to improve blood flow in vasospastic disorders such as Raynaud disease, early frostbite, obliterative arterial disease that is not suitable for vascular surgery [11] . It is recommended that the interdisciplinary approach is the most effective therapy in these patients, including pharmacologic, physical therapy with rehabilitation, psychological support and interventional therapies [16, 20] . Sympathetic blocks are also considered as part of the interventional therapy. The advantage of sympathetic blocks, despite the risks associated with them, they help to differentiate SMP from SIP, and may help to reverse the disease process in subset of patients with neuropathic pain [11] . There are also more invasive alternatives such as

neuromodulation therapy with spinal cord stimulation [20] .

This study examined lumbar sympathetic block for lower extremity. Theoretically, this may also be valid for upper extremity sympathetic blocks, but this needs further exploration. In this study, the SCM is shown to be superior to other traditional ways of monitoring to determine whether a successful sympathetic block is achieved after administration of lumbar sympathetic blocks. As an objective endpoint, SCM has been shown to determine the achievement of successful sympathetic block significantly faster. In this study all methods, except observation of clinical signs sympathectomy, were assessed in real time. Although the numeric values were measured and compared in this study for research purposes, by purely observing the trend of skin sympathetic activity real-time graph on SCM, the practitioner performing the block could easily determine whether a potentially successful sympathetic block is starting to work within seconds (Figure 3). One limitation was that the assessments were each minute and could beneficially be narrowed to 30 second to improve the reaction time for the SCM. Furthermore, the study included only lower extremity sympathetic blocks, and all procedures were performed by only one interventional pain management physician. The study design made it impossible to blind the participants. Another limitation of this study was that traditional measures such as clinically visible hyperemia, clinically visible engorgement of veins, subjective skin temperature difference, unilateral and bilateral comparative thermometry measurements and change in waveform amplitude in pulse oximetry plethysmography were used to validate the skin conductance device. Although it would have been possible to assess

microneurography in the blocked nerve, and compare this method with the skin conductance device, the use microneurography was outside the scope of this study because of the invasiveness and complexity of this method.

Med-Storm Innovation's software was not developed to assess small decreases in the skin conductance curve, when the derivate of the curve turns negative. All the patients studied showed a visual and recognizable decrease in the skin conductance curve when the block started to work (Figure 9). One improvement in the Med- Storm Innovation's software could be to define the decrease in the curve as negative for smaller changes. Then, both the skin conductance responses and the derivate of the curve could be used to define the successful block. Currently, the SCM has the possibility to monitor only one extremity in real time. Hence, it would have been ideal to have a dual-channel SCM equipment to monitor both extremities in real time for comparison purposes, between the affected extremity undergoing the block and the unaffected one as a reference standard.

To conclude, this preliminary study suggests SCM as a more reliable and rapid response indicator of a successful sympathetic blockade when compared to traditional monitors. As a non-invasive monitor with easy clinical applicability, it has a potential to improve procedural accuracy and efficiency during performance of lumbar sympathetic blocks. References

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Table 1. Bilateral Thermometry Score (temperature difference between bilateral limbs), a score of 3 will be taken as an indicator of complete sympathetic block. Unilateral Temperature Score (temperature difference within measurements of the affected limb), a score of 3 will be taken as an indicator of complete sympathetic block.

Table 2. Plethysmography scores will be assigned to each measurement as follow, an increase in the waveform reading score of 2 will be taken as an indicator of improvement in capillary circulation secondary to sympathetic block/vasodilatation. A reading of 3 and above will indicate a successful block.

Table 3. Skin Conductance Graph Visual Observational Scale is assessed to quickly evaluate and determine when the block starts work in real time. A reading of 2 will indicate a successful sympathetic block, when there are 0.00 skin conductance responses, in the 15 sec analyzing window.

Table 4. Clinical Assessment of signs is divided into 3 categories, and was made with left and right comparison, with inspection and palpation. At least 1 (mild) change was considered a complete sympathetic block in all of the modalities.

Table 6. The Skin Conductance Monitor compared to the traditional assessment tools to show sympathetic block. Number of endpoint not observed show the patients who did not receive the successful sympathetic block.

Table 7. Differences in the lowest skin conductance responses (SCR) per second values, before and after the sympathetic block; with different analyzing time windows.

Table 8. The time period from the sympathetic block start time until the skin conductance curve starts to decline. Time period from the sympathetic block start time until the skin conductance responses (SCR) per sec is 0.00, defined as the complete sympathetic block.

The following references serve as background and include: EP- 1191 879; US 6,571, 124; EP-1 519679; PCT/N02003/00148; EP-1 858409; PCT/N02006/000048; EP-1 848 335; PCT/N02006/000049; EP-1 903 940; PCT/N02006/000217; EP- 2094156; PCT/N02007/000394; PCT/N02009/000099; US Appl. 12/922689; EP 10717882.4; and US Appl. 13/637654 as well as Storm 2008 Changes in Skin Conductance as a Tool to Monitor Nociceptive Stimulation and Pain" Current Opinion in Anaesthesiology 21 :796- 804, all herein incorporated by reference in their entirety.

Claims

1. A method of assessing or monitoring an effectiveness of a neural block in a living subject, the subject having a skin,

the method comprising assessing or measuring electrodermal activity,

wherein the electrodermal activity is chosen from the group consisting of skin conductance, galvanic skin response, electrodermal response, psychogalvanic reflex, skin conductance response, sympathetic skin response and skin conductance level.

2. The method of claim 1, wherein the electrodermal activity assessed or measured is skin conductance.

3. The method of claim 2, wherein the skin conductance is assessed or measured by calculating skin conductance fluctuation peaks per time unit and wherein when the skin conductance fluctuations peaks disappear in an analyzing window with a length of about 15 to 60 seconds, the neural block is assessed as being obtained or successful.

4. The method of claim 3, wherein the length of the analyzing window is about 15 seconds.

5. The method of claim 2, wherein the skin conductance is assessed or measured by calculating rise time of skin conductance fluctuation and wherein when the rise time decreases in an analyzing window with a length of about 15 to 60 seconds, the neural block is assessed as being obtained or successful.

6. The method of claim 5, wherein the length of the analyzing window is about 15 to 30 seconds.

7. The method of claim 2, wherein the skin conductance is assessed or measured by calculating size on amplitude of the skin conductance fluctuation peaks are calculated and wherein the size on the amplitude decrease or disappear in an analyzing window with a length of about 15 to 60 seconds, the neural block is assessed as being obtained or successful.

8. The method of claim 7, wherein the length of the analyzing window is about 15 seconds.

9. The method of claim 2, wherein the skin conductance is assessed or measured by calculating area under the curve of skin conductance fluctuation peaks are calculated and wherein the area under the curve of skin conductance fluctuations peaks decrease or disappear an analyzing window with a length of about 15 to 60 seconds, the neural block is assessed as being obtained or successful.

10. The method of claim 9, wherein the length of the analyzing window is about 15 seconds.

1 1. The method of claim 1, wherein the skin conductance is measured

entire body of the subject.

12. The method of claim 1, wherein the subject is an animal.

13. The method of claim 1, wherein the subject is a human.

14. The method of claim 1, wherein the neural block is for a sympathetic nerve.

15. The method of claim 1, wherein the neural block is for a mixed nerve block chosen from the group consisting of motor+sympathetic, sensory+sympathetic, and motor+ sen sory+symp athetic .

16. The method of claim 1 , wherein the neural block is obtained by local analgesia or local anesthesia.

17. The method of claim 1, wherein the neural block is assessed or measured at a skin level of the subject.

18. The method of claim 1, wherein the neural block is assessed or measured in the subject's limbs, a palmar side of the subject's wrist, the subject's palm, the subject's ankle area, or a plantar part of the subject's foot.

19. The method of claim 1, further comprising the use of an additional process to assess or measure a neural block, wherein the additional process is chosen from the group consisting of unilateral thermometry monitoring, bilateral comparative thermometry monitoring, change in waveform amplitude in pulse oximetry plethysmography, and any combination thereof.

20. The method of claim 1, wherein the electrodermal activity at two or more extremities of the subject is assessed or measured, wherein in the electrodermal activity of one extremity with neural block and one or more extremity(ies) without neural block are compared.

21. The method of claim 1, further comprising stimulating electrodermal activity in the subject that disappears when the nerve block is assessed or measured to have been obtained or successful.

22. An apparatus configured to performing the method of any of claims 1 -21.

23. The apparatus of claim 22, wherein the apparatus comprises a wireless sensor with bluetooth connection to a computer or cell phone wherein a signal is processed through a computer software application and wherein the apparatus can send wireless information through a wireless technology to other computers, or mobile devices or tablets with computer software program.

24. The apparatus of claim 22, comprising a measuring box with electrodes and computer software display on any computer tablets.

25. The apparatus of claim 22, wherein the apparatus is configured to be used together with an accelerometer which will inform about movements to and give information about movement artefacts.

26. The apparatus of claim 22, wherein the apparatus is further configured to perform another process which can assess a neural block, wherein the additional process is chosen from the group consisting of unilateral thermometry monitoring, bilateral comparative thermometry monitoring, change in waveform amplitude in pulse oximetry plethysmography, and any combination thereof.

27. The apparatus of claim 22, wherein the apparatus is configured to assess electrodermal activity at two or more extremities to compare the extremity with neural block to one or more extremities without neural block.

28. The apparatus of claim 22, wherein the apparatus further comprises an electrodermal activity stimulator which is configured to give information about when the neural block starts to work and/or a successful block.