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BJA Advance Access originally published online on October 17, 2007
British Journal of Anaesthesia 2007 99(6):837-844; doi:10.1093/bja/aem267
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Midlatency auditory evoked potentials in children: effect of age and general anaesthesia

M. Daunderer1,*, M. S. Feuerecker1, B. Scheller2, N. B. Pape1, D. Schwender3 and G. E. Kuhnle1

1 Clinic for Anaesthesiology, Ludwig Maximilians University Munich, Nussbaumstr. 20, D-80336 Munich, Germany
2 Clinic for Anaesthesiology, Johann Wolfgang v. Goethe University, Frankfurt, Germany
3 Department for Anaesthesiology, Clinic Friedrichshafen, Lake of Constance, Germany

* Corresponding author. E-mail: dr.daunderer{at}web.de

Accepted for publication July 11, 2007.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
Background: Midlatency auditory evoked potentials (MLAEP) are a promising tool for monitoring suppression of sensory processing during anaesthesia and might help to avoid awareness. MLAEP in children are different to those in adults and the exact changes during general anaesthesia are unknown.

Methods: In 49 children of age between 2 and 12 yr, MLAEP were recorded before anaesthesia, during tracheal intubation, at steady-state balanced anaesthesia, and after extubation.

Results: MLAEP were recordable in all children in the awake (premedicated) state with latencies but not amplitudes dependent on children's age. MLAEP latencies significantly increased during tracheal intubation and steady-state anaesthesia. Changes in amplitudes were inconsistent. All MLAEP variables returned to near baseline values after extubation.

Conclusions: The results of this study imply that MLAEP can successfully be recorded during anaesthesia in children above the age of 2 yr. Further studies are necessary before MLAEP might be applicable for monitoring purposes in paediatric anaesthesia.

Keywords: anaesthesia, general; anaesthesia, paediatric; anaesthetics, volatile; monitoring, depth of anaesthesia; monitoring, evoked potentials


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
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Intraoperative awareness is a problem in anaesthesia, and monitoring devices based on spontaneous EEG (BIS, Narkotrend, Datex Entropy) and evoked potentials have been developed and investigated intensively in adults.1 Intraoperative awareness in children is as important as in adults,2 3 but the knowledge about neurophysiological monitoring in this group of patients is still poor. As the process of maturation is still ongoing during childhood, it is questionable if electrophysiological methods used in adults can be used in children at all.4

For the recording of midlatency auditory evoked potentials (MLAEP) in children, there are only a small number of studies with inconsistent results.5–9 Therefore, we recorded MLAEP in children aged from 2 to 12 yr before, during, and after general anaesthesia to investigate:

  1. if MLAEP variables show age dependency in the awake (premedicated) state;
  2. if MLAEP can be reliably recorded during general anaesthesia and surgery in children;
  3. if there is an increase in latency and decrease in amplitudes of MLAEP during general anaesthesia as described in adults;
  4. if there is a difference in MLAEP variables during anaesthesia between children of two different groups of age;
  5. if the changes of MLAEP during anaesthesia are reversed during emergence.


   Methods
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 Abstract
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 Methods
Results
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After ethics committee approval and obtaining informed written consent from the parents, 49 children, aged between 2 and 12 yr, ASA I or II, undergoing elective surgery were enrolled into the study. Children with a history of neurological disorders, hearing deficits, and children on centrally acting substances were excluded. The children were allocated to two different groups, that is, <4 and >4 yr of age. Children's age was defined as completed years with three decimals calculated by days after birthday divided by 365.

Thirty minutes before general anaesthesia, all children received midazolam 0.6 mg kg–1 orally or rectally as premedication, atropine 0.06 mg kg–1 was added when hypersalivation was evident. After the transfer to the operating theatre, the patients were started on standard ECG monitoring, pulse oximetry, and oscillometric arterial pressure monitoring. Electrodes for auditory evoked potentials (AEP) monitoring and headphones were applied. AEP recording were started during the premedicated state, when children were awake and calm with the eyes open. In 42 patients, anaesthesia was induced using face mask with sevoflurane and a mixture of oxygen 50% in nitrous oxide. In children with an i.v. cannula already in place (n=7), anaesthesia was induced with thiopentone 6–8 mg kg–1 i.v. After induction of anaesthesia, a 22 G i.v. cannula was inserted into a forearm vein. Then patients received either alfentanil 20 µg kg–1 or fentanyl 1.5 µg kg–1 depending upon the duration of the operation. A single dose of atracurium 0.3 mg kg–1 i.v. was used to facilitate tracheal intubation. Anaesthesia was maintained with isoflurane or sevoflurane. The dosage of the hypnotic agent was based on clinical routine. In addition, concentration of volatile anaesthetic was increased if spontaneous movements, which were regarded as a sign of inadequate anaesthesia, occurred.

The opioids were given pre-emptively before any anticipated painful surgical stimulation, and the dose was adjusted to suppress autonomic signs of inadequate analgesia (increase in heart rate, arterial pressure, sweating, and tear production). The anaesthetist was blinded to the recorded AEP signal. No further neuromuscular blocking agents were given. At the end of the surgical procedure (at least 20 min after the neuromuscular blocking agent), all anaesthetic agents were discontinued and mechanical ventilation was stopped when sufficient spontaneous breathing returned. The patients were given repetitive verbal commands (addressing the children by their first name and asking them to open their eyes) every 2 min. When the children presented the first directed movement towards the tracheal tube, or responded correctly to the command, the tracheal tube was removed. Data collection continued until patients regained consciousness or refused the measurement.

For auditory stimulation, rarefaction clicks of 98 µs duration and an intensity of 80 dB (SPL) were presented bi-aurally with a continuous repetition rate of 9.3 Hz via headphones.

AEP were recorded by Ag/AgCl adhesive electrodes (Neuroline 7200 00-S, Ambu/Medicotest, Denmark) placed after skin preparation with acetone on A1, A2, Fp1, Fp2, Fpz, and Cz according to the international 10/20 system. Interelectrode impedances were kept below 5 kOhm. The electrodes were connected to a specially designed preamplifier (POD, Siemens Medical, Erlangen, Germany) with short connecting cables wired to feed four recording channels (A1/Fp1, A2/Fp2, A1/Cz, and A2/Cz with Fpz as common ground). The signals were amplified and digitized (sensitivity 0.017 µV, sampling rate 4 kHz) within the preamplifier and transmitted to the recording system via broadband glass fibre cables.

The data were stored on a hard disc and the raw EEG signal and averaged AEP epochs of 500 sweeps were displayed on a screen for quality control. All events were coded by keystrokes on the recording system.

In an offline analysis with a customized program (NaMo v. 8.0, Toennies/Viasys, Hoechberg, Germany), 1000 successive EEG epochs of 100 ms duration after each stimulus were extracted. Epochs with amplitudes above 250 µV were rejected as artifacts. The remaining epochs were averaged and the sum of all data points within one signal subtracted from each data point, resulting in one AEP signal for each channel representing approximately 108 s of anaesthesia.

All AEP signals were inspected visually, the channel with the best recordings selected for each patient. All visual analyses were revised by one investigator aware of the individual patient and order of recordings but blinded to the patient's age and further clinical data, including the later classification of the anaesthetic state.

The quality of every signal was rated as excellent, acceptable, distorted, or insufficient for interpretation. AEP signals regarded as distorted or insufficient for interpretation were excluded from further analysis.

According to the nomenclature of Picton and colleagues,10 the negative and positive peaks of the MLAEP were identified and marked as Na, Pa, Nb, and P1. Also peak V of the BAEP was identified and marked. The latencies of all peaks with respect to the occurrence after the onset of the stimulus and the positive values of the interpeak amplitudes of Na/Pa, Pa/Nb, and Nb/P1 were measured.

The AEP segments were classified into the following states, according to the remarks documented with the signals:

  • awake, after premedication, before induction of anaesthesia, calm, responsive;
  • after induction of anaesthesia, with the start of tracheal intubation;
  • steady-state anaesthesia (during operation, later than 20 min after giving neuromuscular blocking agents, stable haemodynamics, no movement);
  • during extubation (first directed movement towards the tracheal tube).
Statistical evaluation was performed with the SPSS program (SPSS V 14.0.1, SPSS Inc., Chicago, IL, USA). Median values and variances of all AEP variables within each state were calculated and displayed as box plots.

A linear regression analysis and Pearson's correlation analysis were preformed for all MLAEP variables with respect to children's age. Regression curves, 95% confidence intervals and R2 values, correlation coefficients, and significance levels are presented for every test.

To search for significant differences in MLAEP values between the anaesthetic states and age groups, one-way ANOVA was calculated (with Tamhane T2, Dunnet T3, and Games Howell post hoc analysis) as all values were distributed almost symmetrically but not normally (verified by a Kolomogorov–Smirnov test) with different variances (verified by a Levane test). Any significant differences in the ANOVA were verified with a non-parametric Mann–Whitney U-test (two-tailed, exact significance, Bonferroni's correction for multiple comparisons). For all statistical tests, P<0.05 was taken as level of significance.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 References
 
Data from all 49 children were included for analysis. Relevant patient characteristics and details of the anaesthetic procedure are presented in Table 1.


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  		Table 1 Patient characteristics and overall anaesthetic details: data are number of cases, mean (range) or mean (SD). et, end tidal concentration

 
A total of 8544 AEP segments were recorded resulting in 2136 AEP segments from the channel of best quality. Within the channel of best quality, 935 AEP segments were classified as of excellent and 710 of acceptable quality and included into further analysis. Two hundred and seventy-one AEP segments were classified as distorted, 220 AEP segments could not be classified, and all these were excluded from further analysis.

All MLAEP amplitudes had a high inter-individual variability and there was no significant correlation with age. There was a clear negative correlation of all MLAEP latencies with age (Fig. 1, Table 2).


Figure 1
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  		Fig 1 AEP awake. Influence of age on latency peaks (A) V, (B) Na, (C) Pa, (D) Nb, and (E) P1. Linear regressions with 95% confidence interval. Parameters of regression are presented in Table 3.

 


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  		Table 2 Results of linear regression and Pearson's correlation for latencies V, Na, Pa, Nb, and P1 (awake, premedicated) with respect to children's age

 
Induction and maintenance of general anaesthesia delayed all MLAEP peaks with little influence on their amplitudes in the visual inspection of the signals. These changes were reversible after stopping anaesthesia. Exemplary AEP recordings of one younger and one older child are demonstrated (Fig. 2).


Figure 2
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  		Fig 2 Original recordings of AEP: (A) 4-yr-old boy and (B) 7-yr-old boy.

 
In the group analysis, all MLAEP amplitudes increased in median value and variance during intubation, steady state and extubation compared with the awake state, but only the comparison of Na/Pa and Pa/Nb during steady-state anaesthesia against the awake state reached the level of statistical significance.

Systematically, all AEP latencies were higher in the children under 4 yr of age but this difference was not statistically significant (Table 3).


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  		Table 3 Statistical analysis for AEP latencies during anaesthesia: values are mean differences. {dagger}P<0.05 ANOVA, {ddagger}P<0.05 Mann–Whitney U-test (after Bonferroni's correction). NS, not significant in any test

 
The magnitude of increase in latency during anaesthesia compared with the awake state was dependent on the temporal occurrence of the peaks; it was lowest for peak V and highest for peak Nb. For the peaks V and Na, all latencies were identified below the study's technical limit of 100 ms. For peak Pa, only outliners reached the limit of 100 ms during steady-state anaesthesia. For peaks Nb and P1, a relevant number of peaks fell outside the identification interval, instead they are displayed with the highest possible value of 100 ms (Fig. 3).


Figure 3
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  		Fig 3 AEP during anaesthesia: (A) latency Na, (B) latency Pa, (C) latency Nb, (D) latency P1. Horizontal line: median; box: inter-quartile range (IQR); whiskers: 1.5 IQR; O: outliners (1.5–3 IQR). *Extremities (>3 IQR).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
In this investigation, MLAEP could be recorded and interpreted in all children. This contrasts with the findings of earlier studies where the different MLAEP peaks were only recordable in a variable percentage up to the age of about 10 yr. Reasons for this might be that the children in these investigations were younger,7 or because children who were asleep were included,6 whereas in our study all children were premedicated and calm but awake.

This study confirms earlier findings that AEP amplitudes are not dependent on children's age.11 However, this statement cannot be generalized as there was a high inter-individual variability and other factors may have influenced interpeak amplitudes (e.g. electrode impedance, interelectrode distance, myogenic noise, and premedication). Although little is known about the effects of premedication on MLAEP in children, studies in adults consistently show a marked and sustained suppression of MLAEP amplitudes with little change in latency for midazolam as long as subjects remain responsive.12

For the MLAEP latencies, this study supports earlier reports of an age dependency,4 which can be seen as an electrophysiological correlate to the ongoing process of maturation of the auditory pathway documented up to the age of around 12 yr.13 However, it can be speculated that this linear correlation is not true for an age substantially below 2 yr where MLAEP can often not be recorded7 and for older children once adult values have been reached. For peak P1, this has been shown to occur at around 15 yr.14

To the best of our knowledge, this is the first description of MLAEP changes before and during different stages of general anaesthesia in children.

Prosser and Arslan8 reported gross abnormalities of the MLAEP in nine children during general anaesthesia with fluothane with normal BAEPs and a variable increase in MLAEP latencies with higher amplitudes. Unfortunately, the anaesthetic regimen was not further specified.

O'Kelly and colleagues tried to record MLAEP in children during general anaesthesia with 1% of isoflurane. They reported severe technical problems in children under the age of 2 yr mainly because of ECG artifacts.15 We identified no ECG artifacts in the averaged signal. The high common mode rejection of the amplifier, short recording electrodes, short interelectrode distances, stable interelectrode impedances, and a strict separation of EEG and ECG leads might have been beneficial in this sense. Also, the high gain of the EEG background signal (around 7% of the epochs above 250 µV) could have masked the ECG noise.

Kileny and colleagues16 were able to record stable MLAEP in infants after high-dose fentanyl and pancuronium. Furthermore, some investigations have already been performed in children using the AEP index, a parameter derived from AEP recording, but effects on MLAEP signals are not given.17

The results of this study concerning MLAEP amplitudes are confusing. Besides the high inter- and intraindividual variability, there was an increase in amplitudes Na/Pa and Pa/Nb during anaesthesia similar to the original MLAEP recordings of Prosser and Arslan.8 This contrasts with most studies in adults which show a decrease in MLAEP amplitudes during general anaesthesia.18 The reason for the increase in children remains unclear but has to be taken into account once automatic algorithms for MLAEP analysis in adults are used in younger children. It seems wise not to focus on changes in MLAEP amplitudes but on latencies.

In this study, MLAEP latencies significantly increased during induction and maintenance of general anaesthesia in all children which was almost completely reversed after extubation. This corresponds well to the results published for adults.18 The increase in latencies V, Na, and Pa was greater in the children under 4 yr, but the difference was not statistically significant. The power of this comparison may have been reduced as the different states were treated as independent observations (avoiding excessive dropouts in a pairwise comparison) and the clinical definition of the states (and not equivalent anaesthetic concentrations).

This study demonstrates that recording MLAEP may offer a suitable approach to monitor the effects of general anaesthesia in children. But further studies may be useful to investigate if monitoring MLAEP during general anaesthesia in children may improve the quality of anaesthetic control and help to overcome some of the specific problems in estimating the degree of sensory block in paediatric anaesthesia.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
The study received no funding. All expenses were covered by the investigating institution (Clinic for Anaesthesiology, Ludwig Maximilians University, Munich, Germany). The authors are not supported by, nor maintain any financial interest in any commercial activity that may be associated with the topic of this article.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
1 Drummond JC. Monitoring depth of anesthesia: with emphasis on the application of the bispectral index and the middle latency auditory evoked response to the prevention of recall. Anesthesiology (2000) 93:876–82.[CrossRef][Web of Science][Medline]

2 Davidson AJ, Huang GH, Czarnecki C, et al. Awareness during anesthesia in children: a prospective cohort study. Anesth Analg (2005) 100:653–61.[Abstract/Free Full Text]

3 Sebel PS, Bowdle TA, Ghoneim MM, et al. The incidence of awareness during anesthesia: a multicenter United States study. Anesth Analg (2004) 99:833–9. table.[Abstract/Free Full Text]

4 Ponton CW, Eggermont JJ, Kwong B, Don M. Maturation of human central auditory system activity: evidence from multi-channel evoked potentials. Clin Neurophysiol (2000) 111:220–36.[CrossRef][Web of Science][Medline]

5 Duncan PG, Sanders RA, McCulloch DW. Preservation of auditory-evoked brainstem responses in anaesthetized children. Can Anaesth Soc J (1979) 26:492–5.[Web of Science][Medline]

6 Kraus N, Smith DI, Reed NL, Stein LK, Cartee C. Auditory middle latency responses in children: effects of age and diagnostic category. Electroencephalogr Clin Neurophysiol (1985) 62:343–51.[CrossRef][Web of Science][Medline]

7 Rotteveel JJ, Colon EJ, de Graaf R, Notermans SL, Stoelinga GB, Visco Y. The central auditory conduction at term date and three months after birth. III. Middle latency responses (MLRs). Scand Audiol (1986) 15:75–84.[Web of Science][Medline]

8 Prosser S, Arslan E. Does general anaesthesia affect the child's auditory middle latency response (MLR)? Scand Audiol (1985) 14:105–7.[Web of Science][Medline]

9 Feuerecker MS, Daunderer M, Pape NB, Kuhnle GE. Detection of intraoperative awareness via auditory evoked potentials in an infant. Anaesthesist (2006) 55:1058–63.[CrossRef][Web of Science][Medline]

10 Picton TW, Hillyard SA, Krausz HI, Galambos R. Human auditory evoked potentials. I: evaluation of components. Electroencephalogr Clin Neurophysiol (1974) 36:179–90.[CrossRef][Web of Science][Medline]

11 Shafer VL, Morr ML, Kreuzer JA, Kurtzberg D. Maturation of mismatch negativity in school-age children. Ear Hear (2000) 21:242–51.[CrossRef][Web of Science][Medline]

12 Hotz MA, Ritz R, Linder L, Scollo-Lavizzari G, Haefeli WE. Auditory and electroencephalographic effects of midazolam and alpha-hydroxy-midazolam in healthy subjects. Br J Clin Pharmacol (2000) 49:72–9.[CrossRef][Web of Science][Medline]

13 Moore JK, Guan YL. Cytoarchitectural and axonal maturation in human auditory cortex. J Assoc Res Otolaryngol (2001) 2:297–311.[CrossRef][Medline]

14 Ponton CW, Don M, Eggermont JJ, Waring MD, Masuda A. Maturation of human cortical auditory function: differences between normal-hearing children and children with cochlear implants. Ear Hear (1996) 17:430–7.[Web of Science][Medline]

15 O'Kelly SW, Smith DC, Pilkington SN. The auditory evoked potential and paediatric anaesthesia. Br J Anaesth (1995) 75:428–30.[Abstract/Free Full Text]

16 Kileny P, Dobson D, Gelfand ET. Middle-latency auditory evoked responses during open-heart surgery with hypothermia. Electroencephalogr Clin Neurophysiol (1983) 55:268–76.[CrossRef][Web of Science][Medline]

17 Weber F, Bein T, Hobbhahn J, Taeger K. Evaluation of the alaris auditory evoked potential index as an indicator of anesthetic depth in preschool children during induction of anesthesia with sevoflurane and remifentanil. Anesthesiology (2004) 101:294–8.[CrossRef][Web of Science][Medline]

18 Schwender D, Klasing S, Conzen P, Finsterer U, Pöppel E, Peter K. Effects of anaesthesia with increasing endexpiratory concentrations of sevoflurane on mid-latency auditory evoked potentials. Anesth Analg (1995) 81:817–22.[Abstract]


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