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The Reliability of the Current Perception Threshold in Volunteers and Its Applicability in a Clinical Setting

Gaudreault, François BSc, PhD; Drolet, Pierre MD; Fallaha, Michel MD; Varin, France BPharm, PhD

doi: 10.1213/ANE.0000000000000575
Regional Anesthesia: Research Report

BACKGROUND: Even though current perception threshold (CPT) has been used for evaluating the effectiveness of sensory block in patients before surgery, its reliability under controlled conditions has not been investigated. Two independent investigations were performed. The primary objective of the first study was to determine the test-retest reliability of CPT measures after repeated stimulations in a group of healthy volunteers. The primary objective of the second study was to evaluate the clinical applicability of this technique to assess the sensory onset of a femoral nerve block in patients undergoing knee surgery.

METHODS: Thirty healthy subjects participated in 2 identical sessions, separated by at least 24 hours, in which CPTs were measured after 5 consecutive stimulations over the anteromedial aspect of the thigh. Similar measures were obtained in 15 orthopedic patients receiving a femoral nerve block with 20 mL of ropivacaine 0.5%. Test-retest reliability was assessed using intraclass correlation (ICC) and standard error of measurement (expressed as coefficient of variation [CVSEM]), whereas Student t test (P < 0.05) compared the increase in CPTs over baseline.

RESULTS: Within-day ICC values ranged (% confidence interval [CI]) from 0.66 to 0.95 with a CVSEM of approximately 39% (% CI: 17%–58%). Between-day ICC values, ranging from 0.57 to 0.94 (CVSEM: approximately 45%, % CI: 13%–71%), indicated that day-to-day CPT measurements are also variable. The current intensity needed for sensory perception in orthopedic patients significantly increased, varying from a mean CPT value of 82.5 ± 66.5 μA (SD) at time zero to an average of 481 ± 338 μA, 22 ± 8 minutes after the administration of the local anesthetic.

CONCLUSIONS: CPT proved to be a reliable assessment tool for within-day sensory perception in healthy volunteers. Our study also suggests that CPT can be applied to characterize, in a quantitative manner, the sensory onset of a peripheral nerve block in a clinical setting, thereby supporting its use in future studies comparing different regional anesthetic modalities or approaches.

Published ahead of print January 14, 2015.

From the *Faculty of Pharmacy, Université de Montréal, Montreal, Canada; Department of Anesthesiology, Faculty of Medicine, Université de Montréal, Montreal, Canada; and Department of Orthopedic Surgery, Maisonneuve-Rosemont Hospital, Montreal, Canada.

Published ahead of print January 14, 2015.

Accepted for publication October 22, 2014.

Funding: This research program was funded by the Canadian Institutes for Heath Research (MOP-84519) and by the Fonds de la Recherche en Santé du Québec (F. Gaudreault’s studentship).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to France Varin, BPharm, PhD, Faculty of Pharmacy, Université de Montréal, P.O. 6128, Succursale Centre-Ville, Montreal, Quebec, Canada H3C 3J7. Address e-mail to france.varin@umontreal.ca.

Sensory assessment of regional analgesia is routine practice in anesthesia and also plays an important role in pain research.1 The effectiveness of a regional block is currently measured by the elicited response to a simple stimulus such as touch, pinprick, or cold applied near the site of surgery. These qualitative methods, however, do not enable a precise description of the intensity and time-course of the sensory block.2,3 There is also evidence that insensibility to these stimuli does not necessarily imply blockade of nociception during regional analgesia.4

Technological progress has provided us with potentially more accurate and quantitative ways of predicting the effectiveness and time-course of a regional analgesia technique in individual patients. The current perception threshold (CPT)5 is a quantitative measurement that can be used for assessment of sensory blockade. CPT evaluation is performed using a neuroselective diagnostic stimulator (Neurometer® CPT/C, Neurotron, Inc., Baltimore, MD), which uses a microprocessor-controlled constant current sine wave stimulus. The constant current feature compensates for alterations in skin resistance and standardizes the stimulus between skin thickness and degree of skin moisture. Although the device has been used for quantifying the onset of sensory block after epidural administration of lidocaine,6 little has been done to study its reliability.

We performed 2 independent investigations. The first was performed in a group of healthy volunteers with a working hypothesis that CPT measurements would be reliable within and between sessions; the primary objective was to test the reliability of the device under controlled conditions. The second study was performed in patients with a working hypothesis that CPT measurements could be used to quantitatively assess the onset of a peripheral nerve block; the corresponding objective was to explore the possibility of using this device to characterize the onset of sensory blockade after a femoral nerve block in patients undergoing knee surgery.

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METHODS

Subjects

Two institutional research ethics committees (Comité d’éthique de la recherche des sciences de la santé de l’Université de Montréal and Comité d’éthique de la recherche de l’Hôpital Maisonneuve-Rosemont) approved the studies in healthy volunteers (n = 30) and patients (n = 15), respectively.

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Instrumentation and Procedure

A commercially available neurostimulator (Neurometer CPT/T, Neurotron, Inc.) was used to quantitatively assess CPT. The device uses a constant electrical sine wave stimulus at different frequencies (5, 250, and 2000 Hz) that have been reported to primarily stimulate small (C), medium (Aδ), and large (Aβ) fibers, respectively.5 Mostly because of its possible association with the pain-conducting C fibers,7 the 5-Hz frequency (pulse duration: 100 milliseconds) was used throughout the study. The equipment was tested and calibrated according to the manufacturer’s guidelines with prior data collection on each subject.

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Volunteer Study

After arrival in a quiet room, healthy subjects were first seated semirecumbently on a long chair to ensure that postural change would not influence CPTs.8 After adoption of the standardized position, the current was delivered to the middle anteromedial aspect of both thighs9 by a pair of 1-cm diameter gold-plated surface electrodes provided by the manufacturer. The skin site was cleaned and prepared for testing using a skin preparation paste. The stimulating surface of each electrode was covered by a small amount of hypoallergenic electrode gel and maintained in place with soft foam adhesive strips. The intensity of the nonpainful stimulus was increased in steps of 20 μA at 3-second intervals. Subjects were instructed to say “stop” when they perceived any change in sensation (itching, burning, and/or tickling) at or near the electrodes. At this time, the current was turned off by the operator, decreased by 40%, and then reapplied in steps of 10 μA at 3-second intervals. The CPT was defined as the minimal stimulus intensity required to elicit the sensation after the 2 tests. Subjects were familiarized with this procedure before the beginning of the testing sessions.

Each volunteer participated in 2 sessions (referred to below as day 1 and day 2) separated by at least 24 hours. Each trial included 6 repeated CPT measurements separated by an interval of 5 minutes. This testing sequence was undertaken for both thighs (left and right) on an alternating basis. To prevent a possible “order-effect,” the side to be tested first was randomly (flip-coin test) selected by the operator. Two operators took part in the study.

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Application in Patients

Thirty healthy subjects aged 18 to 65 years and 15 ASA physical status I-II patients participated after giving written informed consent. Patients were scheduled to receive a femoral nerve block before undergoing unilateral primary total knee arthroplasty under spinal anesthesia. Exclusion criteria were as follows: body mass index over 40 kg/m2, diabetes, open skin lesion or scars over the testing site (above the knees), and any significant cardiovascular disease. In addition, patients were excluded if they had any of the following: age >75 years, revision surgery, and contraindication to either femoral nerve block or spinal anesthesia.

After arrival in the operating room, each patient was positioned supine, and standard noninvasive monitoring equipment (electrocardiogram, noninvasive arterial blood pressure, pulse oximeter) was applied. An IV catheter was placed at the upper limb for drug(s) and fluid administration. If deemed necessary by the anesthesiologist, light sedation using IV fentanyl (0.75 μg/kg) was given before the procedure. Femoral nerve block was performed by the anterior approach using both ultrasonic guidance and neurostimulation. A linear array ultrasound transducer (L10-5, Zonare Medical System, Mountain View, CA) was used to identify the neurovascular structures. After skin infiltration with 1% lidocaine, a short bevel 50-mm, 22-gauge, Teflon-coated neurostimulation needle (Stimuplex, B Braun, Bethlehem, PA) was advanced toward the femoral nerve to elicit an ipsilateral quadriceps contraction at <0.5 mA (1–2 Hz, 0.1–1.0 milliseconds). At this point, after negative aspiration, 20 mL ropivacaine 0.5% (100 mg) was slowly (5 mL every 10 seconds) injected.

CPT measurements were used to describe the time-course of sensory block. For this purpose, the stimulus was applied above the site of surgery (standardized at approximately 15 cm over the knee), as well as the contralateral limb (control site) before the administration of the local anesthetic (baseline measurement) and at approximately 5, 10, 15, 20, and 25 minutes thereafter. The assumption was that inhibition of nerve conduction at the femoral area would cause an increase in the current intensity required for perception of the electrical stimulus. To confirm the effectiveness of the regional block, sensory evaluation, using an ice cube, was also assessed up to 30 minutes after the administration of ropivacaine. Loss of cold sensation was determined by the patient’s verbal response to the stimulus applied to the middle anteromedial aspect of the thigh. The response was noted as follows: 0 = normal sensation, 1 = no perception.

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Data Analysis

Descriptive statistics were used to summarize clinical and demographic characteristics of the participants. Results obtained in healthy volunteers are presented in whisker plot (box plot). CPT values in patients were expressed as mean ± SD, except for the response to cold ice testing where an empirical Kaplan-Meier survival analysis was used for plotting the time-course of loss of cold sensation.

Within- and between-day reliability of CPT measurements was evaluated using intraclass coefficient (ICC2,1; 2-way random effects model) with 95% confidence intervals (CIs)10:

CV

CV

where MSb and MSw are the between- and within-subject variance and k is the number of measurements. Within-day reliability was determined by comparing CPT measurements obtained at different times for a given subject. Between-day reliability was assessed by comparing the first measurement taken on each day. The standard error of measurement,11 expressed as coefficient of variation or standard error relative to baseline (CVSEM), was also calculated within each subject to determine the absolute reliability of the measure. The estimated parameters were summarized via descriptive statistics, and nonparametric bootstrap was used to estimate the CI of the mean values. Finally, CPT measurements in patients were compared with baseline using a Student t test.

Sample size calculation was based on the expectation of an ICC value of 0.90 with a minimal acceptable value of 0.75. According to the literature,12 at α = 5% and 1 − β = 80%, the inclusion of at least 25 healthy subjects was necessary. The objective of the second study was to explore whether CPT measurements could be used for monitoring the onset of block in patients. These data are meant to be descriptive and, therefore, no sample size calculation is required. Statistical analyses were performed using SPSS® version 20.0 (SPSS, Inc., Chicago, IL). Figures were generated using Sigma Plot (Systat Software Inc., San Jose, CA) and S-Plus (TIBCO Software Inc., Palo Alto, CA).

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RESULTS

Table 1 presents demographic characteristics of the 2 groups of subjects studied. Thirty healthy volunteers and 15 orthopedic patients were enrolled in the study from whom 5 (volunteers) dropped out after day 1 for logistic reasons. Femoral nerve block was successful in 12 patients (12/15), as confirmed by cold ice testing. Intravenous sedation (fentanyl 0.75 μg/kg) was given to all patients except 1 (who experienced a successful nerve block). No adverse effects occurred throughout the studies.

Table 1

Table 1

Whisker plots displaying CPT measurements obtained in healthy volunteers are shown in Figure 1. Values varied between 4.0 and 525 μA with an overall mean CPT value of 100 ± 101 μA. Table 2 shows ICC and CVSEM values for CPT measurements calculated at day 1 and day 2. Within-day mean ICC values ranged (% CI) from 0.66 to 0.95 with an overall mean CVSEM of approximately 39% (% CI: 17%–58%). Between-day mean ICC values were 0.78 (0.57–0.90) and 0.87 (0.72–0.94) for the right and left thigh, respectively, with an overall mean CVSEM of approximately 45% (% CI: 13%–71%) indicating that day-to-day CPT measurements are also variable.

Table 2

Table 2

Figure 1

Figure 1

In orthopedic patients, the effect of ropivacaine on loss of cold sensation and CPT measurements at different time points on the control and treated thighs after a femoral nerve block is presented in Figure 2. There was a wide range in the observed maximal intensity for CPT (481 ± 338 μA, n = 12) measurements, with an increase (P = 0.014) approximately 6-fold from baseline (82.5 ± 66.5 μA, n = 12). The maximal ropivacaine response was observed within 22 ± 8 minutes of dosing. The increase in CPT values paralleled the time-course of loss of cold sensation in patients.

Figure 2

Figure 2

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DISCUSSION

In this study, we evaluated the reliability of CPT measures in a group of healthy volunteers before exploring the possibility of using this technique to characterize, in a quantitative manner, the sensory onset of a peripheral nerve block in orthopedic patients. An overall good reliability (ICC > 0.75)13 was shown for within-day CPT measurements in healthy subjects (ICC approximately 0.84, % CI: 0.66–0.95), with a coefficient of variation no larger than 58%. This result is in agreement with Kim et al.,14 who reported similar reliability statistics (ICC: 0.76–0.89) for measures taken at the infraorbital and inferior alveolar areas in healthy volunteers (n = 200, 23.6 ± 3.2 years). This finding suggests that the dermatome area being tested is not likely to influence the reliability of the measure.

In conjunction with ICC, we used the CVSEM to evaluate the reliability of CPT measurements. The CVSEM can be interpreted as the percentage of deviation from the average threshold below which 68% of the differences between measurements may be expected to lie.15 In contrast to other measurements of absolute reliability (such as standard error of measurement), the CV is dimensionless (i.e., without unit) and thus very useful when comparing the reliability of different methodologies.16 In the present study, we found a trend for a relatively higher CVSEM (approximately 39%, % CI: 17.1%–58.3%) compared with the one previously reported (approximately 28%) in a group of healthy subjects (n = 28, 52.1 ± 13.0 years).17 Although substantial, this CVSEM is approximately 10 times lower than the percentage increase in CPT measurements (approximately 480%) observed after the administration of ropivacaine in orthopedic patients (Fig. 1), thereby allowing a good discrimination between sensory response to ropivacaine and baseline noise.

A possible explanation for the differences with previous publications may be the larger incremental step (10–20 μA) used in our study to obtain CPT measurements. In previous studies,6,8,14,17 CPTs were obtained using the standardized double-blind methodology that consists of 2 basic steps (the intensity alignment and the forced true and false testing cycles) repeated several times until consistency of response within a range of ± 2 μA is observed. Although very precise, this testing procedure requires approximately 4 to 5 minutes per site, which would be clinically unreasonable in many institutions, and was excluded at the very beginning because of the relatively fast onset of sensory blockade expected to occur after a femoral nerve block and spinal anesthesia.7 The manual testing method used in our study not only provides faster CPT measurements (<30 seconds) without compromising reliability (ICC > 0.75) but also the possibility of characterizing, in a quantitative manner, the sensory onset of a peripheral nerve block.

The maximal value of CPT associated with nerve blockade showed, however, a high interindividual variability most probably because of differences in spatial distribution of anesthesia after a femoral nerve block.9 Indeed, standardized positioning of electrodes may have prevented us from capturing the full magnitude of the anesthetic effect in some of our patients.

When designing this pharmacodynamic study, CPT measurements were chosen to monitor the time-course of sensory blockade because they produce a continuous quantitative response that was reported to be more precise than qualitative methods (cold ice testing).2,3 Indeed, the category “no cold sensation” inevitably will include different degrees of sensory block during cold ice testing. Therefore, to confirm the effectiveness of the sensory block in our patients, we also used the cold ice test. According to cold ice testing, a block failure rate of 20% was observed in our patients (3/15). This was higher than expected. Still, the literature shows a significant margin in the success rate of femoral blocks, depending on how failure is defined.18,19 Also, Marhofer et al.20 showed that the mean onset time for sensory blockade for a femoral block guided by neurostimulation was 27 ± 16 minutes. It is then possible that we might have obtained more success had the observation period been extended beyond 30 minutes.

Of the 12 patients for whom femoral nerve block was confirmed successful by cold ice testing, 9 patients also showed complete sensory nerve block, as judged by a plateauing of CPTs before surgery. Examination of CPT measurements obtained on the untreated leg showed almost unchanged CPTs, thereby confirming that the sedative effect of opioids does not appear to interfere at 5 Hz. This finding is in agreement with Liu et al.21 who reported that the perception threshold to 5 Hz was not changed at dermatome L2 by either epidural or IV fentanyl administration in 8 healthy volunteers.

The overall agreement observed between the time-course of sensory block onset measured by CPTs and that measured by loss of cold sensation is an interesting finding although direct comparison of both tests was not the objective of this study. We used CPT measurements to quantitatively assess the time-course of sensory blockade, with the long-term goal of using neurostimulation in future pharmacodynamic studies. Biologically, the relationship between the biomarker and the clinical end point may be explained by the possible selectivity of the 5-Hz frequency toward C fibers,7 which are assumed to mediate thermal sensation in humans.22 If true, this neuroselectivity may offer an additional advantage of this quantitative end point over traditional methods when comparing the efficacy of different local anesthetics or their mechanisms of action. However, to our knowledge, there is still no direct evidence of a selective activation of C fibers by the aforementioned frequency. In fact, these unmyelinated axons have a relatively high activation threshold compared with pain-conducting Aδ fibers.23 Therefore, it cannot be excluded that C-fiber activation after current stimulation at 5 Hz may also be associated with low-threshold Aδ-fiber excitation.1 More studies using multimodal test procedures are needed to assess sensory function after a peripheral nerve block in a fiber-selective manner.

CPTs were chosen instead of pain perception threshold (PPT) mostly because a relatively fast onset of sensory blockade was expected to occur after a femoral nerve block. Indeed, the intensity at which the stimulus begins to evoke pain (PPT) will not only take a longer time to be reached but is also expected to yield more censored measurements than CPTs at ropivacaine maximal effect, resulting in the loss of clinically important information. In addition, PPTs are influenced by the sedative effect of opioids,24 which, again, does not appear to be the case with CPT measurements at 5 Hz.

Our study has some limitations. First, interrater reliability, which is useful to assess the consistency of different operators in rating a given subject, was not evaluated in the present study. We felt that repetitive observations would lead to fatigue and undesirable learning or aversion effects,12 and thereby limited the number of raters to 1 per subject. Second, reliability statistics were assessed on a relatively young population compared with the one investigated for testing the applicability of the method in a clinical setting (Table 1). It cannot be excluded that an age-related increase in skin sensory threshold, as previously reported in a relatively large healthy population (N = 1,632),25 could lead to different reliability statistics. The effect of repeated stimulations on perception levels, or modulation, may also have influenced the reliability of the measure. The clinical implication, if any, would be an overestimation of the true pharmacological effect of the local anesthetic in patients.

In conclusion, this report suggests that CPT measurements have overall good within-day reliability when applied to the middle anteromedial aspect of the thigh in volunteers. Our findings also support the possibility of using CPT measurements to precisely define the onset of sensory block after a femoral nerve block in patients. This quantitative test may be applied in future studies comparing different regional analgesic or anesthetic modalities or approaches.

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ACKNOWLEDGMENTS

The authors are grateful to Johanne Couture and Isabelle Beaudoin from Université de Montréal and Nadia Godin from Hôpital Maisonneuve-Rosemont for their technical support. We also want to thank Dr. Louis-Philippe Fortier, Dr. Issam Tanoubi, and Dr. Bruno Petit at Hôpital Maisonneuve-Rosemont for their precious collaboration.

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DISCLOSURES

Name: François Gaudreault, BSc, PhD.

Contribution: This author made substantial contributions to study conception and design, acquisition of data, and analysis and interpretation of data; drafting the article and revising it critically for important intellectual content; and final approval of the version to be published.

Attestation: François Gaudreault attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Pierre Drolet, MD.

Contribution: This author made substantial contributions to study conception and design, acquisition of data, and analysis and interpretation of data; drafting the article and revising it critically for important intellectual content; and final approval of the version to be published.

Attestation: Pierre Drolet attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Michel Fallaha, MD.

Contribution: This author made substantial contributions to study conception and design, acquisition of data, and analysis and interpretation of data; drafting the article and revising it critically for important intellectual content; and final approval of the version to be published.

Attestation: Michel Fallaha attests to the integrity of the original data and the analysis reported in this manuscript.

Name: France Varin, BPharm, PhD.

Contribution: This author made substantial contributions to study conception and design, acquisition of data, and analysis and interpretation of data; drafting the article and revising it critically for important intellectual content; and final approval of the version to be published.

Attestation: France Varin attests to the integrity of the original data and the analysis reported in this manuscript, approved the final manuscript, and is the archival author.

This manuscript was handled by: Terese T. Horlocker, MD.

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