Although the intensity of neurostimulation (i.e., charge) is a product of current intensity and pulse duration, the effects of the latter on the amplitude of evoked response and subjective discomfort are unknown. Therefore, the authors investigated the effects of current intensity and pulse width, and their interaction with electrode placement and polarity, on force translation (FTR), accelerography (ACG), and electromyography (EMG) at the adductor pollics muscle.
Ulnar stimulating electrodes were applied in one of two configurations: over the distal forearm and olecranon groove ("A") or 5 cm apart on the distal forearm ("B"). Stimuli for FTR and EMG with current intensities of 20, 40, 60, and 70 mA and pulse widths of 0.05, 0.1, 0.2, and 0.4 msec resulted in 16 different charges. These combinations were delivered in each of four orientations: "A-" ("A" configuration with negative electrode distal); "A+", "B-", and "B+" (n = 64 stimuli). Eight stimulus combinations (n = 32 stimuli) were used for ACG. For each monitoring technique, the effects of current intensity, pulse width, electrode polarity, and placement were analyzed with repeated measures ANOVA. Pain responses were scored on a 0-100-mm verbal analog scale and analyzed with ANOVA and Fisher's exact test.
The evoked response amplitude varied directly with current intensity and pulse width. In both electrode placement configurations, the response was greater when the negative electrode was distal. The electrode positioning ("A" vs. "B") had less of an impact on evoked responses than did polarity, regardless of monitoring technique. The evoked pain varied directly with the amplitude of evoked neuromuscular response in all electrode position-polarity combinations.
The total current charge required for evoking a supramaximal neuromuscular response is much higher than previously appreciated, and electrode polarity is important in attaining a supramaximal plateau. Failure to attain (and maintain) a supramaximal stimulus allows changes in the effectiveness of neurostimulation, thus influencing the magnitude of the evoked neuromuscular response and confounding measurements of neuromuscular block.
Methods: Ulnar stimulating electrodes were applied in one of two configurations: over the distal forearm and olecranon groove ("A") or 5 cm apart on the distal forearm ("B"). Stimuli for FTR and EMG with current intensities of 20, 40, 60, and 70 mA and pulse widths of 0.05, 0.1, 0.2, and 0.4 msec resulted in 16 different charges. These combinations were delivered in each of four orientations: "A-" ("A" configuration with negative electrode distal); "A+", "B-", and "B+" (n = 64 stimuli). Eight stimulus combinations (n = 32 stimuli) were used for ACG. For each monitoring technique, the effects of current intensity, pulse width, electrode polarity, and placement were analyzed with repeated measures ANOVA. Pain responses were scored on a 0-100-mm verbal analog scale and analyzed with ANOVA and Fisher's exact test.
Results: The evoked response amplitude varied directly with current intensity and pulse width. In both electrode placement configurations, the response was greater when the negative electrode was distal. The electrode positioning ("A" vs. "B") had less of an impact on evoked responses than did polarity, regardless of monitoring technique. The evoked pain varied directly with the amplitude of evoked neuromuscular response in all electrode position-polarity combinations.
Conclusions: The total current charge required for evoking a supramaximal neuromuscular response is much higher than previously appreciated, and electrode polarity is important in attaining a supramaximal plateau. Failure to attain (and maintain) a supramaximal stimulus allows changes in the effectiveness of neurostimulation, thus influencing the magnitude of the evoked neuromuscular response and confounding measurements of neuromuscular block.
Key words: Monitoring, equipment: surface electrodes, polarity. Monitoring, techniques: accelerography; electromyography; force translation; mechanomyography. Neurostimulation: amplitude; discomfort; electrode placement; electrode polarity; pulse width; supramaximal stimulation.
THE effective current intensity (I) generated by a nerve stimulator is directly related to the emitted voltage (V) and inversely related to the impedance (R) (I = V/R). In contrast to the original "constant-voltage" devices for neurostimulation, many newer nerve stimulators are "constant-current", i.e., they can automatically vary the generated voltage to maintain delivery of a constant current over a range of impedances. It should be noted, however, that current intensity is not the only factor that influences stimulus strength. The charge (in coulombs, Q) is the product of current intensity (in amperes, A) and stimulus pulse width (in seconds).
One can deliberately increase the total charge delivered by the stimulator to maximize muscle fiber recruitment or, conversely, one can decrease the charge to minimize patient discomfort. In the clinical setting, changes in total charge are accomplished solely by adjusting voltage (and, hence, current intensity), while pulse width remains constant. Although comparable changes in total charge also should be attainable by adjusting pulse width, this has not been investigated.
Electrode placement and polarity orientation also may affect the magnitude of the evoked response. [1-3]However, the relative effects of these factors have not been explored over the range of current intensities and pulse widths that may be used clinically, and their effects on subjective responses (pain) have not been evaluated. Such information is important in both clinical and investigative settings. Neurostimulation is increasingly used in nonoperative settings in unanesthetized patients or volunteers (postoperative care and intensive care units and clinical research centers), where the effects of neurostimulation intensity and efficiency may directly impact patient comfort. Also, pharmacodynamic studies of new muscle relaxant agents (and their comparison with established agents) rely on measurements of evoked responses that are very sensitive to even minor fluctuations in stimulus intensity. Therefore, the current investigation was undertaken to evaluate the effects of varying the stimulating current intensity, pulse width, electrode placement, and electrode polarity on evoked neuromuscular responses and pain. Our goals were: 1) to determine which, if any, current intensity/pulse width combinations and electrode placement/polarity orientations are superior for eliciting neuromuscular responses with reduced pain; 2) to identify which combinations and orientations reliably achieve supramaximal stimulation; and 3) to define what information is necessary when neuromuscular monitoring techniques are described during evaluations of muscle relaxant agents.
Materials and Methods
The current study was approved by the institutional review board and oral informed consent was obtained from healthy, unmedicated volunteers and from participating surgical patients. All measurements were obtained in the absence of neuromuscular blocking drugs.
In all cases, neurostimulation was delivered as single-twitch square-wave impulses every 30 s via surface stimulating electrodes (20-mm diameter, Cleartrace 1700-005 multipurpose ECG electrodes, Medtronic Andover Medical, Haverhill, MA) that were placed (20 min before the study period) in two different electrode configurations on skin along the ulnar nerve of the nondominant arm: over the olecranon groove and on the distal volar forearm ("A" in Figure 1) and with both electrodes 5 cm apart on the distal volar forearm ("B" in Figure 1). This provided four possible electrode placement/polarity orientations: "A" configuration with the negative electrode distal (A-); "A" configuration with the positive electrode distal (A+); "B" configuration with the negative electrode distal (B-); and "B" configuration with the positive electrode distal (B+).
Evoked Neuromuscular Responses
The interactions among current intensity, pulse width, electrode positioning, and electrode polarity were determined for evoked responses measured by force translation (FTR), accelerography (ACG), and electromyography (EMG). For FTR and ACG, neurostimulation was delivered to anesthetized patients to avoid the effects of inadvertent muscle movement on the amplitude of evoked contraction. Alternatively, for EMG monitoring, neurostimulation was delivered to awake volunteers to enable simultaneous measurement of stimulus-induced pain and EMG amplitude.
Force translation was used in five anesthetized patients. The thumb ipsilateral to the stimulating electrodes was placed in the ring of a force transducer monitor (APM-L, Professional Instruments, Houston, TX) with a preload of 300 gm. Neurostimulation was delivered by the stimulating channel of a Quantum 84 multichannel EMG monitor (Cadwell Laboratories, Inc., Kennewick, WA). The amplitude of the evoked contractile response (measured in millimeters) was displayed and recorded on an interfaced monitor (Datascope 2000 A/RS, Datascope Corp, Paramus, NJ) in which the force of thumb adduction (mmHg) was proportional to the deflection of the recording pen (1 mmHg = 1 mm deflection). Each of four different current intensities (20, 40, 60, and 70 mA) was paired with each of four different pulse widths (0.05, 0.1, 0.2, and 0.4 ms) to deliver 16 different stimuli, ranging in charge from 1 to 28 micro Q. Each charge was delivered at each of the four possible placement/polarity orientations, resulting in a total of 64 different stimulus patterns. These were delivered in random order, and the amplitudes of the evoked responses were recorded.
Accelerography was performed in a second group of five anesthetized patients. The hand ipsilateral to the stimulating electrodes was immobilized on an arm-board while the thumb was allowed to move freely. An accelerographic piezoelectric wafer (Biometer INMB Monitor, Biometer, Odense, Denmark) was taped to the thumb, with its longitudinal axis along the plane of thumb adduction. The amplitude of the evoked response was displayed by the built-in monitor. Each of four current intensities (20, 40, 50, and the maximum current available, 60 mA) was paired with each of the two different pulse widths available with this device (0.2 and 0.3 ms), at each of the four electrode placement/polarity orientations. These combinations resulted in a total of 32 different stimulus patterns that were delivered in random order while the amplitudes of the evoked responses were recorded.
Electromyography was performed in two groups of subjects. The EMG recording electrodes were placed on the skin over the belly of the adductor pollicis muscle (active electrode), over the muscle tendon of the adductor pollicis (reference), and on the dorsum of the hand (ground). In one group of five volunteers, the EMG monitor delivered stimulating currents of 20, 40, 60, and 70 mA, with pulse widths of 0.05, O. 1, 0.2, and 0.4 ms. This provided the same 16 current intensity/pulse width combinations used for FTR. Each charge was delivered with each of the four possible electrode placement/polarity orientations, for a total of 64 different stimulus patterns. The evoked EMG responses (in micro Volt) were displayed on the built-in monitor and were quantified as maximal amplitude deflections, measured from isoelectric line (baseline) to peak deflection. To more precisely delineate the effect of polarity on the charge required for attainment of supra-maximal response, a second group of five volunteers underwent EMG monitoring with 24 combinations of current intensity (20, 40, 60, and 70 mA) and pulse width (0.05, 0.1, 0.15, 0.2, 0.3, and 0.4 ms) in the "A" electrode configuration.
In addition to undergoing EMG testing for recording of amplitude of evoked neuromuscular responses, the first group of five volunteers also rated the discomfort associated with each stimulus on a verbal analog scoring (VAS) scale ranging from 0 (no discomfort) to 100 (worst pain ever experienced). The first stimulus was always repeated later in the sequence, to minimize the impact of surprise on VAS scores. The median VAS value in response to neurostimulation was determined for each current intensity/pulse width combination.
To determine whether any of the electrode placement/polarity orientations would be superior for testing awake subjects (i.e., maximizing evoked response while minimizing discomfort), the ratio of the VAS score to the EMG amplitude (VAS/EMG ratio) was determined for each stimulus in the four different orientations. To determine the relative effects of current intensity and pulse width on subjective discomfort, stimuli of high current intensity/brief pulse width were paired with stimuli of low current intensity/long pulse width, such that the total stimulus charges were within 15% of each other.
For each electrode placement/polarity orientation, the evoked responses at each of the stimulating current intensity/pulse width settings were expressed as mean plus/minus SD. The values were analyzed with respect to the effects of current, pulse width, positioning, and polarity using repeated-measures ANOVA (rm-ANOVA) and rm-ANOVA with Dunnett's test for multiple comparisons. The relative effects on the VAS/EMG ratio of different current intensity/pulse width combinations were assessed using Fisher's exact test. For all analyses, statistical significance was defined at the P < 0.05 level.
Evoked Neuromuscular Responses
Stimulating Current Intensity and Pulse Width. The data for the current intensity/pulse width combinations used for the FTR, ACG, and EMG assessments are summarized for each electrode placement/polarity orientation in Table 1, Table 2and Table 3. For each means of monitoring, the amplitude of the evoked response increased significantly as the stimulating current or pulse width (i.e., total charge) increased in each of the electrode placement/polarity orientations. When the current was constant at each of the four prescribed current settings (i.e., at 20, 40, 60, or 70 mA), there was a consistent increase in the amplitude of the evoked neuromuscular responses as pulse width increased. Likewise, when the pulse width was constant (at 0.05, 0.1, 0.2, and 0.4 ms), there was a consistent increase in the evoked responses as current intensity increased.
Electrode Polarity and Placement. In the "A" electrode configuration, the evoked neuromuscular responses were greater when the negative electrode was distal for FTR, ACG, and EMG (P < 0.05). In the "B" electrode configuration, the responses also were greater when the negative electrode was distal, reaching statistical significance during FTR at lower total charges. The effect of polarity on EMG is clearly evident in Figure 2: the plateau phase (i.e., maximal response) was approached at a charge of approximately 12 micro Q when the negative electrode was distal ("A-" configuration), but required a charge of 21 micro Q when the negative electrode was proximal ("A+" configuration).
The effects of changing electrode placement at a given polarity orientation were less pronounced and less consistent than the effects of changing polarity at a given electrode position (described above). When the negative electrode was distal, mechanomyographic responses (FTR and ACG) were greater when electrodes were placed in the "A-" configuration than in the "B-" configuration, but no difference between "A-" and "B-" was noted during EMG. When the positive electrode was distal, the impact of electrode positioning on the amplitude of evoked responses was minimal for each means of assessment.
Subjective Discomfort (VAS Pain Scores)
Similar to the amplitude of evoked responses, VAS scores varied directly with both current intensity and pulse width (i.e., with the total stimulating charge; Table 4).
No electrode placement or polarity orientation proved to be consistently superior for increasing the amplitude of the evoked EMG response while decreasing the perceived discomfort; i.e., the VAS/EMG ratios were comparable among the four polarity/placement orientations. When a given polarity caused a lesser subjective score (Table 4), it also caused a lower amplitude of the evoked neuromuscular response (Table 3). When the 16 charges shown in Table 3and Table 4were matched to provide five pairs of comparable current intensity/pulse width combinations (Table 5), the high current intensity/brief pulse width combination caused relatively more pain (i.e., a higher ratio) in all five pairs in the "A-" configuration and in four of the five pairs in the "A+" configuration. Overall, the VAS/EMG ratio was higher in the high current/brief pulse width combination than in the low current/long pulse width combination in nine of the ten equal-charge matched pairs in the "A" configuration (P = 0.14). In the "B" configuration ("B-" and "B+"), five of the ten pairs caused relatively more pain at high current intensity/brief pulse width, while five caused less pain.
Although both current intensity and pulse width contribute to the strength (intensity) of neurostimulation, anesthesiologists have focused almost exclusively on the former as a means of varying total stimulus charge. Virtually all neurostimulating devices that are designed for perioperative monitoring of neuromuscular function allow the delivery of a prescribed charge by adjusting voltage output, while maintaining a fixed pulse width (typically 0.2 ms).
An unexpected finding of the current investigation is that the charges routinely delivered in the clinical setting do not ensure maximum recruitment of nerve fibers. Prior investigations indicated that, in most cases, supramaximal neuromuscular responses were achieved with a current intensity of 30 mA (with a stimulator which delivered a fixed pulse width of 0.2 ms, for a charge of 6 micro Q). [5,6]The current findings in response to charges as great as 28 micro Q indicate that far greater charges are required for supramaximal stimulation. The progressive and persistent increase in the amplitude of the evoked responses was especially evident with EMG, and may be primarily caused by the greater sensitivity of the EMG monitoring technique. The failure to achieve supramaximal stimulation is most apparent when pulse widths less than 0.2 ms are used. In the current investigation, briefer pulse widths failed to elicit maximal responses, even at currents commonly regarded as supramaximal (60 mA); pulse widths of 0.05 (or 0.1) ms would necessitate currents of 240 (or 120) mA to deliver a 12 micro Q total charge.
The inability to attain supramaximal total charges means that measurements of absolute twitch height in the assessment of neuromuscular blocking agents may be influenced not only by the depth of neuromuscular block, but also by the changing intensity of neurostimulation. Relatively small changes in stimulator output, electrode efficiency, or tissue conductance may alter the intensity of neural stimulation and, hence, the evoked muscle response. A change in the efficiency of neurostimulation may affect not only baseline amplitude values, but also such key timepoints in the assessment of muscle relaxant effects as the times to 10% and 25% recovery. Such variations may further accentuate the wide variability that has been noted among patients and among studies of muscle relaxants.
In light of the lack of an efficient means of measuring the strength of neurostimulation in clinical settings, we recommend that the consistency of the "baseline" evoked response be confirmed not only by measuring twitch height at the beginning and the end of the study, but also by confirming that there is no fade in the train-of-four (TOF) ratio. In contrast to the importance of supramaximal charges for the assessment of absolute twitch height, failure to deliver a supramaximal charge would have little impact on monitoring the relative heights of the fourth and first TOF responses; a sub-maximal charge would affect the fourth and first responses proportionately. [6-10]Therefore, fade in the TOF ratio would be a more specific indicator of residual neuromuscular block (as opposed to decreased stimulus charge). In fact, for routine TOF monitoring, we recommend that submaximal, rather than supramaximal, charges be employed. Large charges may cause direct muscle stimulation and, by increasing thumb displacement from the original resting baseline, high charges may lead to overestimation of the magnitude of the fourth TOF response during visual or tactile inspection. [11-13]The use of a lower charge, be it the consequence of reduced current intensity or reduced pulse width, will offer the added benefit of causing less pain in awake subjects. 
The current findings indicate a theoretical advantage in attaining a given charge by increasing pulse width rather than exclusively increasing stimulating current intensity. In the "A" configuration, the VAS/EMG ratio was greater for the high current/brief pulse width combination in nine of ten sets of comparisons (Table 5). However, this would be of clinical importance only if one were delivering large total charges to ensure supramaximal stimulation while monitoring single twitch amplitude in awake subjects. A more compelling reason not to use excessively long pulse widths (e.g., greater than 0.3 ms) is that they may result in repetitive nerve and direct muscle stimulation. [1,15,16]
The effects of the four electrode placement/polarity orientations on evoked responses were similar for FTR, ACG, and EMG. The "A-" and "B-" configurations (i.e., negative electrode distal) generally elicited the greatest neuromuscular responses and the most discomfort. As shown in Figure 2, the charge required to deliver a maximal stimulus was almost twice as high in the "A+" as opposed to the "A-" orientation. The greater effectiveness of the "A-" orientation may be attributable to the negative (cathodal) electrode, which generates a dense depolarizing current directly under the electrode (i.e., near the effector site). In contrast, the positive (anodal) electrode delivers a more diffuse stimulus, which may cause nerve depolarization at scattered exit points from the nerve. The effects of electrode placement on evoked responses and subjective discomfort were less pronounced than the effects of polarity, and should have little impact on clinical monitoring.
An obvious conclusion from this investigation is that the charge required to induce supramaximal evoked responses is very much an arbitrary endpoint. Contrary to conventional wisdom, some increment in evoked response can be obtained by increasing the delivered stimulus charge well beyond that used clinically. This is true for EMG, FTR, and ACG recordings. Fortunately, the difficulty in ensuring stimulation with a supramaximal charge is of relatively little consequence in the clinical setting, when TOF monitoring is employed. However, in the investigative settings, researchers commonly measure changes in the absolute twitch height. Thus investigators should be as detailed as possible when describing how they obtained and defined "supramaximal stimulation"; because "absolute supramaximal stimulation" is easier to define than to obtain, a constant delivered stimulus is probably a more achievable goal.