Effects of increasing sevoflurane MAC levels on mid-latency auditory evoked potentials in infants, schoolchildren, and the elderly

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1 British Journal of Anaesthesia 17 (5): (11) Advance Access publication 31 July 11. doi:1.193/bja/aer226 NEUROSCIENCES AND NEUROANAESTHESIA Effects of increasing sevoflurane MAC levels on mid-latency auditory evoked potentials in infants, schoolchildren, and the elderly M. Feuerecker 1, M. Lenk 1, G. Flake 1,. Edelmann-Gahr 1, D. Wiepcke 1, C. Hornuss 1, M. Daunderer 1, H.-H. Müller 2 and G. E. Kuhnle 1,3 1 Department of Anaesthesiology, Klinikum Großhadern and 2 Institute of Medical Informatics, Biometry and Epidemiology, University of Munich, Marchioninistrasse 15, Munich, Germany 3 Clinic of Anaesthesiology, SRH Wald-Klinikum Gera GmbH, Straße des Friedens 122, 7548 Gera, Germany Corresponding author. matthias.feuerecker@med.uni-muenchen.de Editor s key points Age effects in a cohort of young and old people on alterations of mid-latency auditory evoked potential (MLAEP) peak latencies in the awake state and under the influence of sevoflurane were studied. MLAEP latencies increase at the influence of sevoflurane in a dose-dependent manner and in relation to age. These results imply that MLAEP detection is a reasonable tool for monitoring hypnotic effects at all ages. Background. Detection of mid-latency auditory evoked potentials (MLAEPs) is a technology to monitor central nervous structures. As seen in adults and children, general anaesthesia influences the MLAEP latencies. MLAEP detection seems to be a promising tool to assess different levels of anaesthesia depth in adults and children. Methods. MLAEPs were recorded in 1 infants (2 months 3 yr), 12 schoolchildren (6 14 yr), and 1 elderly (75 89 yr) under general anaesthesia with increasing concentrations of sevoflurane at steady state. In addition, MLAEPs were detected before and after the application of sufentanil. Results. At all different ages, MLAEP latencies increased significantly with higher volume percentages of sevoflurane. These results were also detectable when MAC values of sevoflurane were compared with MLAEP peaks. An age-dependent effect could be displayed as elderly people need lower absolute sevoflurane concentrations to achieve the same MLAEP peak increase. Overall, the application of sufentanil under steady-state sevoflurane application at 1 MAC did not importantly affect the MLAEP latencies. Conclusions. MLAEP latencies increase at the influence of sevoflurane in a dose-dependent manner and in relation to age. These results imply that MLAEP detection is a reasonable tool for monitoring hypnotic effects at all ages. Further studies are required to standardize MLAEP alterations related to effects of medication used for general anaesthesia at all different ages. Keywords: evoked potentials; opioids; paediatric anaesthesia; sevoflurane Accepted for publication: 13 May 11 Auditory evoked potentials (AEPs) represent besides cerebral activity also brain stem and cortical responses. 1 Especially, the peaks of the mid-latency auditory evoked potentials (MLAEPs) are sensitive to the influence of centrally acting medications, 2 4 in particular sevoflurane. 5 8 Almost all these studies analysed changes of MLAEP during anaesthesia in adult patients, but very little data are available on the use of MLAEP in children. 9 1 In one of our earlier studies, we were able to demonstrate that MLAEP in children aged 2 1 yr are sensitive to general anaesthesia using volatile anaesthetics 1 and can help to identify states of inadequate anaesthesia. 11 The objective of the present study was: (i) to analyse the effects of increasing doses of sevoflurane on MLAEP latencies in infants, schoolchildren, and elderly people; (ii) to verify changes of MLAEP latencies after the application of sufentanil in each age group during sevoflurane administration. Methods Thirty-two patients aged from 2 months to 89 yr [1 infants (2 months 3 yr); 12 schoolchildren (6 14 yr); 1 elderly (75 89 yr)] undergoing elective surgery participated in this study between November 6 and August 7. Ethics committee approval was obtained before study start and the informed written consent was obtained from the parents or patients themselves. Only patients classified ASA I or II were enrolled into this study. Study exclusion took place if patients had a history of neurological or hearing These authors contributed equally to this work. & The Author [11]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Effects of increasing sevoflurane MAC levels on MLAEP disorders, surgery at the cranium, or the use or abuse of centrally acting substances. Also patients with a history of alcohol or drug abuse were not accepted. Standard clinical monitoring (ECG, pulse oximetry, oscillometric arterial pressure monitoring) was applied from the beginning of the patients arrival at the operating theatre. After skin preparation with acetone, the Ag/AgCl adhesive electrodes (Neuroline 7 -S, Ambu/Medicotest, Denmark) for the measurement of AEPs were applied on A1, A2, Fp1, Fp2, Fpz, and Cz according to the international 1/ system and adjustable headphones were placed at the ears. Interelectrode impedances were kept below 5 k. All electrodes were connected to a special preamplifier (POD, Siemens Medical, Erlangen, Germany) wired to feed four recording channels (A1/Fp1, A2/Fp2, A1/Cz, and A2/Cz with Fpz as the common ground). The signals were amplified and digitized (sensitivity.17 m, sampling rate 4 khz) within the preamplifier and transmitted to the recording system via broadband glass fibre cables. Data were stored on the measuring computer unit. In an offline analysis with a special program (Mo v. 8., Toennies/iasys, Hoechberg, Germany), 1 successive EEG epochs of 1 ms duration after each stimulus were extracted. To obtain one single high-quality AEP for each channel, 1 EEG epochs were recorded during 18 s of anaesthesia. In some cases, single EEG epochs of the 1 were rejected due to fact that the amplitudes were above the cutting point. This occurred, for example, during the application of electric devices (e.g. heating mattress, electrocauter). This is the reason why only an approximate time of one AEP collection in our study 18 s can be given. Every AEP signal was inspected visually and the channel with the best recordings was selected for each patient. Furthermore, visual analyses with quality control were revised by two investigators (M.F. and G.F.) aware of the order of recordings but blinded to the patient s age and further clinical data such as sevoflurane concentration. The quality of every signal was classified as excellent, acceptable, or insufficient for interpretation. AEP signals evaluated as distorted or insufficient for interpretation were excluded from further analysis. The nomenclature of Picton and colleagues 1 for AEP was applied; the negative and positive peaks of the MLAEP were identified and marked as,,, and. In addition, peak of the BAEP was identified and marked as a control of adequate AEP detection (data not shown). A first AEP recording was started during the premedicated state while the patients were awake and calm with eyes open. Anaesthetic regime in infants and schoolchildren Except two infants, everyone received.3 mg kg 21 midazolam orally or rectally min before general anaesthesia (Table 1). In all 22 children, anaesthesia was induced via a face mask using 8 vol% sevoflurane and 1% oxygen with a high fresh gas flow; thereafter, an i.v. cannula was placed. Anaesthetic regime in elderly people The elderly were premedicated with.6 mg kg 21 midazolam orally min before induction of general anaesthesia. Anaesthesia was induced in this group by initial i.v. application of etomidate (.3 mg kg 21 ) and subsequently anaesthesia was deepened by assisted mask ventilation using 4 6 vol% sevoflurane. Tracheal intubation was performed in all groups after the single i.v. application of.3.5 mg kg 21 atracurium. Subsequently, sevoflurane was applied continuously. The study protocol included the maintenance of three different end-tidal sevoflurane concentrations (.5, 1., 1.5 MAC) using the age calculation for MAC sevoflurane by Mapleson 12 [MAC¼a 1 bx, x, difference in age (yr) from ; b¼.269; a, MAC at age yr] over a time period of 3 min for the MLAEP measurement after a steady state was reached. Steady state was defined as the stable concentration of a constant end-tidal concentration of sevoflurane with unchanged settings of fresh gas flow and vapour for 5 min before MLAEP detection. For each MAC value, AEP were recorded and documented in the study computer. After completion of the sevoflurane titration and before incision,.3 mg kg 21 sufentanil were given, meanwhile the MAC was kept at 1.. AEP were recorded 2 min after the Table 1 tient characteristics and anaesthetic details: n¼32, values are median (SD) (range) Infants, 2 months 3 yr Schoolchildren, 6 14 yr Elderly, yr tient characteristics Number of patients (n) (1.41) ( ) 1.46 (2.71) ( ) (3.2) ( ) Weight (kg) 9.5 (3.15) (6. 15.) 33.8 (17.21) (. 71.) 65. (9.17) (. 88.) Height (cm) 74. (15.76) ( ) 145. (15.79) (122, 171.) 1. (8.1) (1. 18.) Gender: male/female (n) 7/3 5/7 1/9 Details of anaesthetic procedure [mean (SD)] Duration of anaesthesia (min) 176. (76.23) (86 244) 119. (77.49) (98 271) 162. (86.65) (7 251) Premedication: n¼ Dosage midazolam (mg kg 21 ).55 (.9) (.27.73) (rectally).35 (.14) (.11.56) (orally).6 (.1) (.4.9) (orally) No premedication (n) 2 727

3 Feuerecker et al. opioid application. Further anaesthetic management, for example, further opioid application, was based on clinical judgement during the surgical procedure. During the entire AEP recording, the anaesthetist was blinded to the AEP signals. Statistical analysis To test differences in the MLAEP between the age groups and also between defined comparable consciousness states, one-way analysis of variance (ANOA) was planned, followed by closed testing pairwise comparisons. On behalf of the experience of our previous studies, group size was calculated to be 1 participants in the three age groups each (desired power.8, minimum detectable difference in means 15 for peak latency, expected standard deviation of residuals 1). 1 Closed testing the three pairwise comparisons needs no adjustments. To search for statistical differences in the MLAEP in the age groups at different MAC levels, one-way repeatedmeasures (RM) ANOA was applied in extension. Deviation from normal distribution of sample data was detected by the Kolmogorov Smirnov test. Hence, the Kruskal Wallis test and the Wilcoxon Mann Whitney test were applied in addition for verification, and further analysis preferred non-parametric methods. A non-parametric Wilcoxon s signed-rank test was performed to look for differences in MLAEP values between anaesthesia with and without sufentanil application. A linear regression analysis and analysis were performed for all MLAEP latencies with respect to different sevoflurane concentrations and MAC levels. Regression curves, R 2 values, and correlation coefficients are presented for linear modelling, and P-values for statistical tests. To search for significant differences in the MLAEP in the age groups at different MAC levels, one-way RM ANOA followed by pairwise comparisons using closed testing was applied. This method was also used for comparison of MLAEP values between the age groups and defined comparable consciousness states. A non-parametric Wilcoxon s signed-rank test was performed to look for significant differences in MLAEP values between anaesthesia with and without sufentanil application. The significance level was.5, not adjusted for multiple testing in explorative analyses. Results are expressed as mean (SD), Sigmastat w (Jandel Corp., San Rafael, CA, USA). Results The patient characteristics and also the anaesthetic information are presented in detail in Table 1. All MLAEP data from the 32 patients were enclosed for further analysis. At the awake state, 19 of the 32 individual AEP were rated excellent, 13 were classified as acceptable. The data quality intraoperatively remained overall stable for the selected channel: an average of 25.3 individual AEP were classified excellent whereas 6.7 AEP met the criteria acceptable. For the awake state, every MLAEP peak was detected earlier with increasing age. Under anaesthesia with sevoflurane, this finding was reversed and all peak latencies showed a later appearance in time (Fig. 1 and Table 2). With increasing MAC levels of sevoflurane, the peak latency of the MLAEP was significantly increased. This finding was not specific to one single age class but was demonstrated in all age groups (Table 3). In the data analyses, the two most suitable peaks of the MLAEP in describing the diversity to MAC levels were Peak and (Fig. 2). These results of the increase in latency were also seen with significant differences when the volume percentages of sevoflurane were analysed (Fig. 3). Owing to the study s technical limitations, all latencies were displayed within a time window up to 1 ms. Thus, at the highest sevoflurane concentration peak and in some cases also latency crossed this upper limit. To compare different age groups, comparable states have to be found. In this study, these criteria were achieved at the awake phase, the influence of 1.3 vol% and 2.3 vol% sevoflurane. During the awake phase, no statistical significant differences could be seen between the age groups. Nevertheless, MLAEP peak latencies appeared earlier with increasing age (Table 4). In contrast to this are the states of sevoflurane application. Compared with the infants, an increase in the peak latency of and could already be seen at 1.3 vol% sevoflurane in schoolchildren and in the elderly. This difference remained stable at the influence of 2.3 vol% sevoflurane compared with the infants concerning the peak. was already at the upper measuring limit and so no differences could be further detected (Table 4). The significant differences between age groups could be confirmed by the non-parametric tests. The application of sufentanil had no influence on MLAEP latencies in all different patient groups at the concentration of 1 MAC sevoflurane, as assessed in six infants, six schoolchildren, and four elderly people met the criteria (Table 5). Discussion In continuation of our previous work, 1 we now recorded MLAEP not only in children but also in infants from the youngest age of 2 months during general anaesthesia. Changes of MLAEP latencies under general anaesthesia with volatile anaesthetics are a well-described phenomenon in adults. The dose-dependent alteration of latencies in adult patients was previously reported by Schwender and colleagues. 6 For this reason, we did not investigate the group of adults in our study separately. ery few reports on MLAEP recording in children are available and almost no data can be reviewed for MLAEP in infants so far Taking this together, we investigated age effects in a cohort of young and old people on alterations of MLAEP peak latencies in the awake state and under the influence of sevoflurane. There was a clear 728

4 729 Peak latency (ms) Peak latency (ms) Peak latency (ms) vol% sevoflurane Awake vol% sevoflurane Fig 1 MLAEP latencies in correlation with age; linear regression, all parameters are listed in Table Peak latency (ms) Peak latency (ms) Peak latency (ms) Effects of increasing sevoflurane MAC levels on MLAEP

5 Feuerecker et al. Table 2 Results of linear regression and for MLAEP peaks,,, and due to different states; P,.5 State Peak latency Peak latency Peak latency Peak latency Awake Linear regression equation.6772(.164 age) (.563 age) (.337 age) (.922 age) R 2 of linear regression coefficient , significance vol% sevoflurane Linear regression equation (.533 age) (.18 age) (.8 age) (.119 age) R 2 of linear regression coefficient significance vol% sevoflurane Linear regression equation 21.6+(.19 age) (.143 age) (.125 age) (.183 age) R 2 of linear regression coefficient significance reduction in peak latencies with increasing age during the premedicated, contactable awake phase. A reduction in those peak latencies was also previously reported in children and young adults, whereas an assimilation at the age of 1 yr was described Owing to a dynamic development of the relevant central nervous structures 17 and the few cases in our study, we did not look for such a cut-off age. Under the influence of sevoflurane, peak latencies appeared, in contrast to the awake state, later in the elderly. This matches perfectly with findings on end-tidal sevoflurane concentrations and age-dependency in correlation with the neurophysiological bispectral index (BIS) monitoring. Cortinez and colleagues 18 nicely demonstrated, with the help of a pharmacodynamic model, the dynamic relationship between end-tidal sevoflurane concentrations and BIS values. As we did treat age as a continuous variable but did not monitor the group of adults, the presented age-dependent regression analyses have some limitations. For this reason, we also investigated single age groups. Taking into account that the age groups are quite small in sample size, the results have to be regarded carefully, as some comparisons could be underpowered, even though we did not adjust the significance level for multiple comparisons. Nevertheless, we found that in all groups, latencies significantly increased with higher minimal alveolar concentrations of sevoflurane. As the MAC is an age-dependent and corrected value, 19 volume percentages of sevoflurane were additionally recorded during AEP detection. 12 The reason why MAC levels of sevoflurane were chosen was to evaluate the MAC system in correspondence with changes in MLAEP latencies. As the data from Table 3 and Figure 2 nicely show, there is a clear correlation between MAC levels and MLAEP increase in each age group. However, the age-correction, when using the MAC system, overlaps the actual effect of sevoflurane concentrations in different age groups and is in this way a limiting factor. For this reason, specific comparable states including the premedicated awake phase and continuous levels of 1.3 vol% and 2.3 vol% end-tidal sevoflurane were used to compare age effects on MLAEP peaks. Elderly people need less sevoflurane to achieve similar MLAEP latencies when compared with infants. This is consistent with the findings when age was treated as a continuous parameter (Table 2). It is a well-known phenomenon that volatile anaesthetics have an agedependency in onset and maintenance of expiratory levels. These findings give a new perspective to MLAEP alteration under general anaesthesia in different age groups. As previously reported by the investigators and also by others, 1 22 a significant decrease in MLAEP latencies can be found in the awake child up to an age of 12 yr due to effects of maturation processes of the auditory pathway. 17 The results here show that age-related MLAEP changes primarily exist under general anaesthesia with sevoflurane. Furthermore, we investigated the influence of sufentanil on MLAEP latencies. Several authors investigated the effect of opioids on MLAEP, showing only slight changes in the specific MLAEP latencies. This is in good accordance with the presented results here for the patients at 1 MAC sevoflurane where the latencies remain stable after the application of sufentanil. As this study was performed in a clinical set-up, some limitations of this examination have to be addressed. Besides two patients, everyone received midazolam as premedication. In the group of the infants, the highest doses of midazolam per kilogram body weight were given. Accordingly, the group of elderly received the lowest amount. By reviewing the literature, it was shown that the single application of benzodiazepine did not markedly alter MLAEP 7

6 731 Table 3 Results of linear regression and for MLAEP peaks,,, and due to different sevoflurane concentrations and MAC in the age groups; P,.5 AEP latencies Infants Linear regression equation C sev C sev C sev C sev C sev C sev C sev C sev R 2 of linear regression coefficient.163.8,.1,.1,.1,.1,.1,.1 significance Schoolchildren Linear regression equation C sev C sev C sev C sev C sev C sev C sev C sev R 2 of linear regression coefficient.3.3,.1,.1,.1,.1,.1,.1 significance Elderly Linear regression equation C sev C sev C sev C sev C sev C sev C sev C sev R 2 of linear regression coefficient significance.4.2,.1,.1,.1,.1,.1,.1 Effects of increasing sevoflurane MAC levels on MLAEP

7 Feuerecker et al. 1 8 Infants MAC.5 MAC 1 MAC 1.5 MAC 1 8 Schoolchildren Elderly 1 # 8 MAC.5 MAC 1 MAC 1.5 MAC MAC.5 MAC 1 MAC 1.5 MAC # # # MAC.5 MAC 1 MAC 1.5 MAC MAC.5 MAC 1 MAC 1.5 MAC MAC.5 MAC 1 MAC 1.5 MAC Fig 2 Influence of sevoflurane (MAC level) on the best detectable latency peaks and in all different age groups (graphs for and not shown), one-way RM ANOA n¼1, P,.5 vs MAC; # P,.5 vs.5 MAC; P,.5 vs 1.5 MAC; linear regression, detailed parameters of regression are presented in Table 3. 5 months 8 y 81 y Awake, Awake, premedicated premedicated 1.3 vol% sevoflurane 1.3 vol% sevoflurane 2.3 vol% sevoflurane 2.3 vol% sevoflurane 1 m 1 m 1 m 8 1 ms 8 1ms 8 1ms Fig 3 Original recordings of a 5-month-old boy, an 8-yr-old girl, and an 81-yr-old lady at different states. latencies, 26 whereas the continuous application slightly affects the MLAEP latencies. 2 This result was also seen by Hotz and colleagues 27 where little changes occurred in MLAEP latency for midazolam when the patients remained awake. This could be in our study one confounder, although all patients were awake and contactable. Another limitation is that anaesthesia was induced in the elderly using a single shot of low-dose etomidate. Taking into account that the elderly often react with a delayed response to centrally acting substances, 28 this could have influenced our results, as this is a different anaesthetic induction technique. Etomidate is known to increase MLAEP latencies when applied as a continuous infusion. 29 To minimize this possibility, an additional 1 min were waited before the dose-related AEP measurements were performed. For this reason, we assume that at the time of 732

8 Effects of increasing sevoflurane MAC levels on MLAEP Table 4 Results for MLAEP peak latencies (ms) at comparable states in different age groups. One-way RM ANOA, infants n¼1, schoolchildren n¼12, elderly n¼1,p,.5 vs infants (bold), # P,.5 vs schoolchildren (bold) State Peak latencies (ms) Infants Schoolchildren Elderly Mean SD Mean SD Mean SD Awake vol% vol% # Table 5 MLAEP peak latencies (ms) previous and post-opioid application in all different groups at a constant sevoflurane level of 1. MAC; infants n¼6; schoolchildren n¼6; elderly n¼4 AEP detection, circumstances were comparable at every age group. Our results show a dose- and age-dependency of MLAEPs with increasing doses of sevoflurane and increasing age resulting in an increase in MLAEP peak latencies. This finding can be used for further studies evaluating MLAEP detection as a tool to monitor depth of anaesthesia. Acknowledgement The authors are grateful for the assistance of Dr Alex Salam, MBChB, in editing this paper and Dr Alexander Choukèr, MD, PhD, for his support during the review process and the advice on statistical questions. Conflict of interest None declared. Peak latencies (ms) Pre-opioid application Post-opioid application Mean SD Mean SD Infants Schoolchildren Elderly Funding For this investigation, in-house funding was received by the investigating institution (Department of Anaesthesiology, University of Munich, Munich, Germany). None of the authors received financial support associated with the topic of this article. References 1 Picton TW, Hillyard SA, Krausz HI, Galambos R. Human auditory evoked potentials. I. Evaluation of components. Electroencephalogr Clin Neurophysiol 1974; 36: Morlet D, Bertrand O, Salord F, et al. Dynamics of MLAEP changes in midazolam-induced sedation. Electroencephalogr Clin Neurophysiol 1997; 14: Schwender D, Daunderer M, Mulzer S, et al. Midlatency auditory evoked potentials predict movements during anesthesia with isoflurane or propofol. Anesth Analg 1997; 85: Schwender D, Faber-Zullig E, Fett W, et al. Mid-latency auditory evoked potentials in humans during anesthesia with S (+) ketamine a double-blind, randomized comparison with racemic ketamine. Anesth Analg 1994; 78: Hernandez-lazon J, Falcon-Arana LF, Domenech-Asensi P, et al. Effects of sevoflurane on mid-latency auditory evoked potentials and the 95% spectral frequency limit. Rev Esp Anestesiol Reanim 4; 51: Schwender D, Conzen P, Klasing S, et al. The effects of anesthesia with increasing end-expiratory concentrations of sevoflurane on midlatency auditory evoked potentials. Anesth Analg 1995; 81: Kameyama Y. Effect of isoflurane and sevoflurane on evoked potentials and EEG. Masui 1994; 43: Tatsumi K, Hirai K, Furuya H, Okuda T. Effects of sevoflurane on the middle latency auditory evoked response and the electroencephalographic power spectrum. Anesth Analg 1995; 8: Lamas FA, Lopez-Herce J, Sanchez PL, et al. Middle latency auditory evoked potentials in critical care children: preliminary study. An Pediatr (Barc.) 6; 64: Daunderer M,Feuerecker MS,Scheller B,et al. Midlatency auditory evoked potentials in children: effect of age and general anaesthesia. Br J Anaesth 7; 99:

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