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Skin impedance correlates to sedation grade, plasma propofol concentrations and bispectral index during a target-controlled infusion of propofol

Winterhaltera, Michael; Münted, Sinikka; Taschenbreckerc, Peter; Heckerb, Hartmut; Weilbachc, Christian; Osthausc, Alexander W; Grossc, Matthias; Piepenbrockc, Siegfried; Rahe-Meyerc, Niels

European Journal of Anaesthesiology (EJA): July 2009 - Volume 26 - Issue 7 - p 589–596
doi: 10.1097/EJA.0b013e328329b149
Original Articles – Neuro and Monitoring

Background and objective Sympathetic activity, measured as changes in electrical skin impedance, may be used to assess the adequacy of general anaesthesia. The aim of this prospective study was to evaluate electrical skin impedance in comparison with bispectral index values and the Observer's Assessment of Alertness and Sedation (OAAS) scale during propofol infusion.

Methods Electrical skin impedance was measured with an electrosympathicograph. In 22 patients and eight healthy volunteers, anaesthesia was induced and maintained with propofol that was administered via a target-controlled infusion pump at increasing plasma concentrations. Bispectral index, electrosympathicograph and OAAS values were compared at six successive predicted target plasma concentrations (T 1–6: 0, 1.3, 1.7, 2.0, 2.4 and 2.8 μg ml−1).

Results The changes in the electrical skin impedance measured with the assistance of the electrosympathicograph correlated with the changes in bispectral index values at each measurement time point and during the whole course (P < 0.0001), with the target plasma propofol concentrations (P < 0.0001), and with the OAAS scale (P < 0.0001).

Conclusion The observed correlations between electrical skin impedance, predicted plasma concentrations of propofol and OAAS scale appear to justify further investigation of skin impedance as a depth of anaesthesia monitor.

aDepartment of Anaesthesiology, University of Duesseldorf, Duesseldorf, Germany

bDepartment of Biometry, Germany

cDepartment of Anaesthesiology, Hannover Medical School, Hannover, Germany

dDepartment of Anaesthesiology, Helsinki University Clinics, Children's Hospital, Helsinki, Finland

Correspondence to Dr Michael Winterhalter, MD, Consultant, University of Duesseldorf, Department of Anaesthesiology, Moorenstrasse 5, Germany Tel: +49 211 81 17828; fax: +49 211 81 16253; e-mail:

The results of this study have been presented in part at the 7th International Symposium on Memory and Awareness in Anesthesia, Munich, 2008.

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The most common approach to the management of general anaesthesia includes monitoring clinical parameters such as blood pressure (BP) and heart rate (HR). A validated clinical test method for evaluating the degree of sedation in patients is the Observer's Assessment of Alertness and Sedation (OAAS) scale [1]. Previous findings have demonstrated that there is a close correlation between the bispectral index (BIS; Aspect Medical Systems, Newton, Massachusetts, USA) and OAAS values [2].

BIS monitoring helps to assess the depth of hypnosis during general anaesthesia. It provides a useful tool for titrating anaesthetic agents in order to achieve a desired sedation level. In addition, it has been shown to decrease the incidence of awareness in high-risk patients during general anaesthesia [3]. However, BIS, along with other electroencephalogram (EEG)-based depth-of-anaesthesia monitors, only allows the depth of hypnosis to be determined. A method that allows measurement of other endpoints of anaesthesia such as analgesia and suppression of vegetative responses (for determining the depth of anaesthesia, which includes hypnosis, analgesia and suppression of vegetative reactions or reflexes) has not yet been established. A new approach for assessing the depth of anaesthesia is to determine the sympathetic activity. Measuring the skin resistance level and the changes in the resistance of the skin is a simple and noninvasive method for evaluating the sympathetic nerve activity. Sympathetic sudomotor nerves stimulate the eccrine sweat glands to activity, which results in changes in skin potential and resistance.

The present study looks at skin impedance variations in skin areas innervated by sympathetic fibres only. Up to now, skin impedance measurements have predominantly been performed for psychophysiological purposes. Apart from isolated cases, this method has not been employed in general anaesthesia [4] but was widely used for regional anaesthesia [5–7].

Narcotics and sedative agents, as well as analgesic agents, have a central action, inducing an attenuation of the sympathetic nervous system activity, thus also influencing the results of skin conductance measurements [8]. The present prospective study investigated how far measurements of skin impedance can help determine the adequacy of anaesthesia.

To this end, we measured the changes in skin impedance in direct comparison with BIS values, while simultaneously scoring sedation using the OAAS scale during a target-controlled infusion (TCI) of propofol. Skin impedance was measured with the assistance of an electrosympathicograph (ESG).

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Patients and methods


The present study, which was approved by the local ethics committee, represents a prospective investigation in 22 patients, ASA I or II, who had to undergo surgical treatment, and in eight healthy volunteers. All participants gave their written informed consent at least 24 h before beginning the study.

Participants who were younger than 18 years were excluded, as were those with neurological or psychiatric diseases, head trauma, hearing impairment, drug or alcohol abuse or psychoactive medication. The day before, all participants were carefully examined and asked to provide details of their medical history, and they were asked to fast from midnight on. During the study, all participants laid in a supine position on an operating table in an anaesthesia induction room.

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Electrosympathicograph measurement and bispectral index recording

Skin impedance measurements were performed with the assistance of an ESG (ESG 1001 Monitor-System, Dr Janitzki Consulting Engineers, Altenbeken, Germany) in order to prove activity of the sympathetic nervous system. The measurements were made in the constant direct current mode with the help of two Ag/AgCl electrodes that were applied to a small skin area at a current density of less than 2 μA cm−2. Every 200 ms (5 Hz), the impedance data were periodically recorded in real time [9], underwent analogue signal processing and filtering, and were then transmitted to an analogue-to-digital converter.

While the measurements were being made, the measurement data appeared graphically on the monitor screen in the form of a tonic ESG in a time function as ESG measurement curve expressed in kilo ohm (1000 ohms). These measurement values appeared on the monitor screen as a diagram without having undergone additional preprocessing and while the measurements were being made. The measurement value of the tonic ESG in kilo ohm was updated every 5 s and was shown as a numeric display.

For ESG monitoring, two ECG electrodes were attached to the palm side (second and third finger) of the nondominating hand. For determination of bispectral analysis, we used an A-2000 BIS monitor (software version 3.3, Aspect Medical Systems). The BIS sensor (BIS Sensor XP) was attached to the forehead according to the manufacturer's information. The BIS monitor and ESG timers were synchronized prior to beginning the measurements. A serial cable was connected to both the BIS monitor and a computer in order to enable continuous recording of BIS values; the computer stored the data in a text file with the help of the Microsoft HyperTerminal program. The ESG used a continuous real-time automatic online process to store the measured skin impedance data in a computer file over the entire period of time. After connecting all monitoring devices, a 10 min rest break was given to participants in order that they adapt to the test situation.

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No premedication was given before the operation. Prior to induction of anaesthesia, intravenous access and standard anaesthesia monitoring were established. All study participants received a continuous supply of oxygen via a facemask. Propofol 1% was administered via a TCI infusion pump (Graseby 3500, Graseby Medical Limited, Watford, UK) with the assistance of the Diprifusor Target Controlled Infusion Module (Astra Zeneca, Alderley Park, Cheshire, UK). This system operates based on the pharmacokinetic model proposed by Gepts et al. [10] that was modified by Marsh et al. [11] and McMurray et al. [12]. Instead of a fixed administration dose calculated by the formula of milligrams per kilogram per hour, a target plasma concentration was chosen on the basis of body weight. For the purpose of this study, six successive target plasma concentrations of propofol [T1 (0 μg ml−1), T2 (1.3 μg ml−1), T3 (1.7 μg ml−1), T4 (2.0 μg ml−1), T5 (2.4 μg ml−1) and T6 (2.8 μg ml−1)] were employed. Until the steady states were achieved, the participants were left undisturbed; they were neither touched nor spoken to. As soon as no more changes in the BIS values were seen, HR, BP and OAAS were measured in the respective steady-state concentrations (T 1–6), in addition to the continuous recording of BIS and ESG values. At the end of the observation time, all 22 patients received additional fentanyl and atracurium for tracheal intubation. Thereafter, surgical operations were performed as planned. As for the eight volunteers, the administration of propofol was stopped at the end of the observation period, and the volunteers were monitored until they had recovered completely.

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Statistical analysis

Statistical analysis of the ESG data was carried out to identify possible correlations with time, plasma propofol levels, OAAS score and BIS values. The skin impedance monitor (ESG) delivers five measurement values per second. Hence, more than 10 000 skin impedance values per patient were used in the calculations. Every 5 s, the Aspect 2000 BIS monitor supplies a new bispectral analysis, which is calculated retroactively from the previous 15 s. In order to allow a meaningful statistical comparison, a moving average value was calculated from the ESG values (MESG) that included the average value of the last 50 measurements, which corresponds to a measurement interval of 10 s. In other words, the measurement interval was displaced by 5 s each in synchronity with the BIS values. This allowed the respective BIS measurement value to be exactly assigned to a moving average value (MESG). To investigate the dependencies of the parameters within the courses independently of the average values of the individual patients, the mixed model analysis of variance (ANOVA) for analysing value patterns was carried out for the individual measurement time points. In this analysis, the dependent variable includes the patient as an accidental factor, whereas time, BIS values and OAAS and plasma level values are the time-dependent covariables.

Although this investigation considered each value pattern individually, the results are formed over all value patterns. This allowed detailed conclusions to be drawn regarding possible dependencies.

In addition to this, evaluations by regression analyses were carried out concerning the relative changes in ESG values in comparison with the baseline value (instead of absolute ESG values). The following formula was used:

where RESG(tx) is the relative change in ESG at the time of measurement; MESG(tX) is the moving average of ESG at the time of measurement (10 s interval); and MESG(t0) is the moving average of the ESG at baseline time (10 s interval).

This enabled us to look at the course of the ESG values alone and independently of different absolute values. The ANOVA has always looked at both courses (RESG and MESG). A P value of less than 0.05 was determined to be the significance level. Evaluation was carried out with the assistance of the PROC MIXED program from SAS v. 9 and SPSS v. 11.0 (SPSS Inc., Chicago, Illinois, USA).

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All participants finished the study procedures, and, during the observation period, there was no case of apnoea or relevant change in haemodynamics (Table 1). The individual baseline skin impedances differed greatly from participant to participant. This can be seen from the large SDs of the ESG values (Table 2). In general, skin impedances increased with increased doses of propofol, whereas BIS values dropped. Awakening stimuli applied during the process of measuring the level of alertness with the help of the OAAS scale led, depending on the depth of sedation, to short-term drops in skin impedances (Fig. 1).

Table 1

Table 1

Table 2

Table 2

Fig. 1

Fig. 1

As explained above, in light of the interdependencies among the measurement values, it is not reasonable to base the calculations upon the average values of all measurements. That is why the mixed model ANOVA was given preference. As already mentioned above, another approach included calculations of the relative changes in the ESG values RESG(tx) independently of different baseline and absolute values. The changes in ESG values showed a highly significant correlation with the changes in BIS values at the individual time points and over the entire course (MESG regression coefficient −4.3724, P < 0.0001; RESG regression coefficient −0.02159, P < 0.0001), with the target plasma concentrations of propofol (MESG regression coefficient 79.2168, P < 0.0001; RESG regression coefficient 0.4075, P < 0.0001) and with the OAAS scale (MESG regression coefficient −48.6111, P < 0.0001; RESG regression coefficient −0.2652, P < 0.0001). Another highly significant correlation appeared between BIS values and target plasma concentrations of propofol (regression coefficient −17.6003, P < 0.0001).

Considering time as a covariable in the ‘mixed model’ provides the possibility of investigating whether the course analysis reveals relationships between ESG and BIS, OAAS scale, the plasma level of propofol or all, which cannot be explained by a linear time trend that underlies the parameters (adjusted for linear time trend).

The changes in ESG values continued to show a highly significant correlation with the changes in BIS values both at the individual time points and over the entire course, and a significant correlation with the target plasma concentrations of propofol (MESG regression coefficient 25.1193, P = 0.0363; RESG regression coefficient 0.1235, P = 0.0399) and the OAAS scale (MESG regression coefficient −6.3903, P = 0.3246; RESG regression coefficient −0.09720, P = 0.0026) even after time was considered as a covariable (MESG regression coefficient −3.1143, P < 0.0001; RESG regression coefficient −0.01136, P < 0.0001).

In the negative case (regression coefficient < 0), a selective increase in the ESG value beyond the ESG trend over time was associated with a selective decrease in the BIS value beyond the BIS trend over time. In the positive case (regression coefficient > 0), a selective increase in the target plasma concentration of propofol beyond the propofol target plasma concentration trend over time was also associated with a selective increase in the ESG value beyond the ESG trend over time.

Furthermore, a receiver operator characteristic (ROC) curve for MESG was calculated for a cutoff point at BIS 60. With a sensitivity of 77% and a specificity of 63%, the relative change in baseline MESG by the factor 0.4274 corresponded to a BIS value of 60. The area under the curve (AUC) value was 0.716, the P value was equal to 0.0001 and the 95% confidence interval lower bound was 0.706 and the upper bound was 0.725 (Fig. 2).

Fig. 2

Fig. 2

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In this study, we investigated the relationships between propofol concentrations, BIS values, clinical assessment of sedation and skin impedance measurements. The results show that skin impedance values obtained with the ESG, as well as the BIS values of the EEG, can be used as pharmacodynamic indicators of the sedative effects of propofol. The changes in ESG data show a highly significant correlation with the changes in BIS results at the individual Ts and over the entire course, with the OAAS scale and with the plasma propofol concentration. BIS values lower than 60 are suggested to be consistent with loss of consciousness and BIS values higher than 60 with intraoperative awareness (manufacturer's recommendation). Interestingly, a relative rise in the ESG values by a factor of 0.4274 from the patient's individual baseline value could be seen with a BIS value of 60.

A great number of parameters and different afferent nerves trigger changes in the skin impedance that are measured as an indicator of sympathetic activity [13]. Several studies among patients with circumscribed lesions of the central nervous system (CNS), with direct stimulation of single areas of the brain or both, reported that several regions of the CNS are involved in generating the skin resistance response. The changes in skin impedance are induced in the subcortical and cortical regions of the CNS with the hypothalamus, limbic system and the basal ganglia being involved in this induction process [14]. Sympathetic efferent pathways descending from the hypothalamus run through the brain stem, synapsing with preganglionic neurons in the nucleus intermediolaterales of the lateral horn. The second synapse is in the sympathetic trunk. The postganglionic neurons take their path as sympathetic–sudomotor fibres, together with the remaining portions of the peripheral nerves, up to the neuroglandular junctions. The involvement of cortical structures is certainly a factor that contributes to the high level of agreement between BIS and skin impedance values. Skin conductivity measurements using the MEDSTORM AS 2005 monitor (Medstorm Innovations, Oslo, Norway) also revealed a high level of agreement with the BIS values.

The current approach assumes that two parameters [number of skin conductance fluctuations (NSCF) and amplitude of skin conductance fluctuations (ASCF)], which are derived from skin conductance measurements, allow determination of the analgesic components during general anaesthesia [15]. On the basis of Ohm's law, devices that measure sympathetic activity via sudomotor pathways make use of different measuring principles [16]. Available methods include the constant voltage technique (skin conductance) that allows determination of the conductance G in a measurement range of 1–50 μΩ (μSiemens) and the constant current technique (skin resistance) that relies on feeding a constant current through the skin site and measuring the voltage drop that is proportional to the skin impedance (Z). The usual measurement ranges vary from 10 to 500 kΩ [17–19]. The values for resistance and conductance can be merged into each other. In general measurement, results obtained by using constant direct current voltage can be considered equivalent [20]. But one thing that must be kept in mind is that the parameters of the skin display a nonlinear behaviour, in particular, if current, voltage limit or both values are exceeded in the measurements. The reason is that the skin impedance (Z) is equal to 1 per admittance (Y) [21]. Measurements involving high stimulus intensities therefore yielded different responses to skin resistance and skin conductance measuring methods [22].

The difference between this study and studies investigating the skin conductance response [23] and older applications [24–26] is that we focused on evaluating the relationships between increasing sedation (repeatedly assessed with the help of the OAAS scale) and skin impedance values with a direct reference to both plasma propofol concentration and BIS monitoring. Electrical responses, that is, skin impedance and skin conductance, result from the sympathetic stimulation of the eccrine sweat glands. Sympathetic activation by cortical and subcortical areas [27,28] produces changes in the potential and resistance of the target organ, the eccrine sweat glands, which are exclusively innervated by the sympathetic nervous system. There is a direct correlation between the activity of the eccrine sweat glands and the resistance of the skin [29]. Relying on the constant current technique, Lidberg and Wallin [30] and Wallin et al. [31] have proved that there is a direct dependency between the discharge rate during sympathetic intraneural stimulation and the amplitude of simultaneously recorded skin impedance changes.

The high level of individual variability of the measurement values constitutes a problem in the interpretation of skin resistance measurements. Skin resistance variations occur depending on the place of recording, the condition of the skin, the measurement electrodes, the temperature and the neuronal function. Thus, a broad spread of measurement values in the present data up to the factor 10 was to be expected from the outset. Consequently, for the purposes of a reasonable statistical evaluation, the course of the change of skin impedance, and not a single value, had to be considered. In the context of comparability of skin impedance measurements, this means that a value measured after an event must, in any case, be seen in relation to a value measured before the respective event. Because of the high recording rate of the ESG (5 Hz), it was also important to evaluate measurement intervals. For the purposes of this study, we adjusted the measurement interval to the BIS measurement interval, thus enabling a direct comparison of the obtained data in terms of time. In each measurement interval, a moving average over 10 s was obtained, and all data were evaluated using the above formula. These measurement intervals corresponded almost exactly with those used for measuring skin conductance. A change in the ‘number of fluctuations in the skin conductance’ (NFSC) of more than 0.1 s−1 during a period of 15 s was considered a significant change [32].

In our study, depth of anaesthesia was assessed using the OAAS scale, which is an established and widely used instrument [33]. Utilizing a TCI to achieve certain plasma propofol levels has become widespread clinical practice. In order to achieve different sedation depths by using preset plasma propofol concentrations, we took as our basis the results obtained by Casati et al. [34], who, with the chosen concentrations, found a good gradation and a good correlation with the OAAS scale. Several authors were able to show a good agreement between the propofol concentration calculated with the assistance of the ‘Diprifusor’ TCI systems and the propofol concentration measured in the blood [35,36].

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We have measured skin impedance with the aim of determining anaesthetic depth in a small group of patients. In this study, we tested only propofol. In further studies, this technique should be evaluated against many different anaesthetic and analgesic agents before a final judgement can be made. But on the basis of the results from this study, this seemed to be a promising approach in the future. In addition to visual, acoustic and mechanical stimuli, and depending on the patient's vigilance, emotions may also influence skin impedance [37].

This means that, if skin impedance data are analysed in order to judge the depth of anaesthesia, such values should immediately be correlated to the ambient conditions and to the patient's individual baseline values. Furthermore, it also means that one single absolute value is not representative at all; it is essential to look at the course of the values. Other points that need to be taken into consideration are that the measuring electrodes have a manifold influence upon skin impedance measurements. Making measurements using hydrogel electrodes can induce hydration of the stratum corneum, causing it to swell. As a result, an increase in skin conductance takes places. Also, a closure of the sweat gland ducts may take place, which, in turn, would lead to a decrease in skin conductance [38]. Finally, solid gel electrodes may cause sweat accumulation provided a strong transpiration is present. Factors resulting from the measurement electrodes and having an influence upon skin conductance include, in addition to the hydration effect, the electrodes’ electrolyte composition [39,40].

Another important point is that the function of the human eccrine sweat glands could be influenced by the administration of atropine and other drugs [41]. This fact must be taken into consideration when interpreting skin impedance data for the purpose of assessing the depth of anaesthesia.

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ESG measurements reveal that changes in skin impedance under propofol infusion show a correlation with clinically evaluated sedation depths (OAAS scale) as well as with the BIS values and calculated plasma propofol levels. Within the frame of general anaesthesia, it seems to be possible to measure the sympathetic nerve activity and thus the adequacy of anaesthesia with the assistance of the ESG. In future, the measurement of the skin impedance may prove to be a valuable tool for assessment and management of general anaesthesia. It appears that further investigations into this technique should be conducted.

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Skin impedance measurements were performed with the assistance of an ESG (ESG 1001 Monitor-System, Dr Janitzki Consulting Engineers). We published the method recently [42]. The impedance values ranged from 0 to 1 MΩ and were recorded with a sampling rate of 5 Hz. The current was applied with the help of two Ag–AgCl electrodes that were connected to the volar surface of the second and third finger of the nondominant hand.

The very large measurement range demanded that an analogue-to-digital converter having a resolution of 18 bits plus sign be used. In order to not leave the measurement data susceptible to failure, digitization was done as soon as possible. Optocouplers then transferred the digital data to the internal memory of the ESG computer. This system computer predominantly fulfils three tasks: first, it organizes and controls the recording of the measurement data (likewise via optocouplers); second, it performs the digital processing of the recorded measurement data and displays them on a monitor screen; and third, the computer performs a quasicontinuous recording (every 200 ms) of all digital measurement data in a nonvolatile storage medium (storage space requirements, approximately 100 kB h−1 and channel). The data so stored can be exactly assigned to each single measurement and to a specific time, which allows them to be used by other computers and programs in later processing.

The system's measurement range spans from 5000 to 2 000 000 Ω. It is of course possible to also perform measurements below 5000 Ω, but then the measurement sensitivity is strongly reduced, and the temperature dependence of the sensors increases. Changes of up to 100 Ω are in the normal sensitivity range. The baseline impedance values on the palms of the hands vary greatly from person to person, being in the range from 10 000 Ω up to several 100 000 Ω.

Available recording electrodes included standard ECG solid gel electrodes having a recording surface of 2.2 cm2 and consisting of a 5% KCl conductive adhesive gel (Conmed – 1700 Cleartrace; Conmed Deutschland GmbH, Gross-Gerau, Germany).

42 Winterhalter M, Schiller J, Münte S, et al. Prospective investigation into the influence of various stressors on skin impedance. J Clin Monit Comput 2008; 22:67–74.

bispectral index; OAAS scale; propofol; skin impedance

© 2009 European Society of Anaesthesiology