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TECHNOLOGY, COMPUTING, AND SIMULATION

The Auditory Middle Latency Response, Evoked Using Maximum Length Sequences and Chirps, as an Indicator of Adequacy of Anesthesia

Steven L. Bell, BA, MSc, PhD, David C. Smith, BMedSci, BM, BS, DM, FRCA^*, Robert Allen, BSc, PhD, CEng, FIEE, FIMechE, FIPEM^*, and Mark E. Lutman, BSc, MSc, PhD^*

*Institute of Sound and Vibration Research, University of Southampton, Department of Anaesthetics, Southampton General Hospital, Southampton, United Kingdom

Address correspondence to S. L. Bell, BA, MSc, PhD, Institute of Sound and Vibration Research, University of Southampton, Southampton SO17 1BJ, United Kingdom. Address e-mail to slbi{at}svr.soton.ac.uk.

	Abstract

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The auditory evoked potential known as the middle latency response (MLR), evoked with regular click stimulation at around 5 Hz, has been suggested as an indicator of adequacy of anesthesia. The MLR is a very small signal embedded in high levels of background noise, so it can take a long time to acquire. However, using a stimulus paradigm of chirps presented in a maximum length sequence, the acquisition of the MLR can be improved compared to using conventional click stimulation. In this pilot study, we investigated this new technique in a clinical environment. Significant changes in MLR amplitude, but not latency, were measured for six of seven subjects in association with changes in responsiveness to command using the isolated forearm technique. The absence of any latency shift differs from other studies of the MLR during anesthesia and highlights the limited understanding of the relationship between anesthesia and the MLR.

	Introduction

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The middle latency response (MLR) of the auditory evoked potential (AEP) is a possible indicator of the adequacy of anesthesia (1,2), defined as lack of conscious awareness. The MLR is a very small signal buried in a lot of background noise, producing a signal-to-noise ratio (SNR) <1:10 (–20 dB). The MLR is usually derived from a synchronized ensemble average of 250–1000 successive responses (1), where the auditory stimulus triggers the synchronization process. At stimulation rates of 5–6 Hz the averaged wave can take 3 min to acquire. Advanced signal processing techniques may help to extract the MLR from background noise (3–6), but these methods become increasingly inaccurate as SNR deteriorates. An alternative approach is to optimize the evoking stimulus, reducing the need for signal processing.

One way to obtain an average more quickly is to increase the stimulation rate, but if the inter-stimulus interval is too short, the end of one response will be truncated by the next stimulus, triggering a second response; 12.5 Hz is the limit with the MLR. Maximum length sequences (MLS) are a form of pseudo-random binary sequence with mathematical properties that enable evoked potentials to be acquired at stimulation rates up to 333 Hz (7–10). Although the individual responses overlap in time, a process of deconvolution (7) is used to recover the individual responses (Fig. 1).

View larger version (18K): [in this window] [in a new window]   Figure 1. The Maximum Length Sequence (MLS) technique. The left side shows a stimulation sequence and corresponding response for conventional stimulation at 11 Hz (90 ms interstimulus interval). Each stimulus produces an identical response. The right side shows a MLS of 15 stimuli repeating every 90 ms at a maximum rate of 167 Hz, the corresponding response, and the response after deconvolution. The final response is identical to that obtained using conventional stimulation, but more responses have been averaged in the same time period.

Click stimuli with a sharp onset are traditionally used to evoke the MLR, on the assumption that the response occurs to the onset of the stimulus. However, high-frequency components of the stimulus cause maximum displacement at basal regions of the cochlea, whereas low-frequency components cause maximum displacement at the apex some 10 ms later, leading to loss of neural synchrony (10–13). A chirp stimulus that compensates for this delay (11) is shown in Figure 2. The response occurs to the offset of the chirp, rather than the onset, so the latency of the MLR waves is increased by 10 ms compared with that produced using clicks, using the convention that latency is measured from the stimulus onset.

View larger version (32K): [in this window] [in a new window]   Figure 2. A chirp sweeping from 0.1 Hz to 10 kHz in 10.4 ms.

Using chirp stimuli presented at an MLS rate of 167 Hz in the audiology laboratory, the time required to obtain a MLR of given SNR is reduced by approximately 14 times in young subjects with normal hearing, compared with conventional click stimulation at 5 Hz (10). This technique may therefore improve the acquisition of AEPs during anesthesia, especially with the high-frequency hearing loss that is common in the elderly. This report is of our pilot study with this technique. The study was designed to test the hypothesis that the morphology of the MLR evoked using new stimulation methods would change with the responsiveness of the patient.

	Methods

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After Ethics Committee approval and written patient consent, we studied 10 male patients in the anesthetic room before elective cardiac surgery. The patients received premedication of 10-15 mg diazepam per os, 10 mg morphine IM and 12.5 mg prochlorperazine IM 1.5 h before the study started. Disposable silver/silver chloride electroencephalogram (EEG) electrodes (Nicolet Biomedical, Warwick, UK) were attached, after rubbing the skin with surical spirit, for acquisition of the EEG. The ground electrode was on the low forehead, the active on F_z and the reference on the sternum. Electrode impedances were below 6 kilohm. A pure tone audiogram was then performed (14), followed by a baseline AEP recording.

Purpose-designed software, running on a portable PC, generated the chirp stimuli and derived the AEP. The EEG was amplified using an AC-coupled system with a bandpass of 1 Hz–3 kHz and a gain of 10⁴ (CED µ1401 and 1902; Cambridge Electronic Design, Cambridge, UK). It was then bandpass filtered from 15–250 Hz with a rolloff of 48 dB/octave (VBF-8 Dual Variable filter; Kemo Electronics, Langen, Germany), digitized at 20 kHz, and streamed to disk. The chirp stimuli were amplified to 60 dB nHL by an audiometer (GSI-16; Grayson-Stadler, Boston, MA) and presented binaurally via insert earphones (ER2, Etymotic Research, Elk Grove Village, IL). We used an MLS order 4 with 8 stimuli in a sequence, repeated every 90 ms. The average interstimulus interval was 11 ms, with an average rate of 91 Hz. The shortest allowable interstimulus interval in the sequence is 6 ms, giving a maximum stimulation rate of 167 Hz.

A cannula was then inserted into a forearm vein and attached to an infusion of 0.9% saline and a propofol infusion. A pneumatic tourniquet cuff was placed on the contralateral upper arm to detect response to command using the "isolated forearm technique" (15). The AEP recording was restarted, the propofol infusion was started at 2 mg·kg^–1·h^–1, then anesthesia was induced using fentanyl 100 µg and propofol 1 mg/kg. The tourniquet was then inflated to 300 mm Hg, and 0.1 mg/kg of vecuronium was given. The trachea was intubated and ventilation was adjusted to an end-tidal CO₂ tension of 4.5–5.0 kPa.

After 5 min the propofol infusion was stopped. Every subsequent minute the patient was asked to squeeze the researcher's hand. When the patient responded to the command, the propofol infusion was restarted at 6 mg·kg^–1·h^–1. At 10-min intervals the infusion rate was reduced to 4 mg·kg^–1·h^–1 and then to 2 mg·kg^–1·h^–1. Every 20–25 min the tourniquet was deflated and the arm was allowed to reperfuse for 5 min. The cuff was then re-inflated and a further 0.025 mg/kg of vecuronium was given. If time allowed, the procedure was repeated.

Data were analyzed off-line after down-sampling to 1 kHz and zero-phase digital filtration to exclude mains frequency interference. A bank of Butterworth notch filters at 50, 100, 150, 200, and 250 Hz were applied using the "Buttord" function in MATLAB (MATLAB v6; MathWorks, Natick, MA) to give at least 30 dB of attenuation in the stop band with a 4 dB bandwidth. A moving average AEP was then generated from 1000 successive stimuli.

	Results

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Usable data were obtained from 7 patients. The average age of the patients was 61.4 years. More than one nonresponse/response/nonresponse transition was made in 4 patients, providing 11 instances of responsiveness with the isolated forearm. None of the patients had normal hearing; deficits in the better ears were mild at low frequencies, but in 5 patients the higher frequency deficit was severe or profound (16).

The morphology of the MLR changed during periods of responsiveness of the isolated forearm (Fig. 3), but there was no systematic shift in N_b wave latency as reported previously (1). When the patients were anesthetized the P_a–N_b complex reduced in amplitude, almost disappearing, and then increased again when the patients responded with their isolated forearm. We therefore plotted the MLR variance (which estimates signal power), calculated between 20 and 70 ms after the stimulus, for each data set as a function of time (Fig. 4).

View larger version (18K): [in this window] [in a new window]   Figure 3. Middle latency response (MLR) waves for patient 6. From the top downwards, responses obtained before anesthetic induction, after induction, responding with the isolated forearm and when reanesthetized. The vertical axes are MLR amplitude in microvolts, the horizontal axes are time in ms. Responses were derived using a moving average of 1000 epochs with an artifact rejection level of 30 microvolt.

View larger version (35K): [in this window] [in a new window]   Figure 4. Variance of the middle latency response as a function of time for all patients. Responsiveness with the isolated forearm is indicated by filled rectangles, nonresponse with open rectangles. Responses were derived using a moving average of 1000 epochs with an artifact rejection level of 30 microvolt.

In five patients there is a clear change in MLR variance with responsiveness of the isolated forearm. This is not seen for patients 3 and 4, in whom the amplitude of the MLR was very small because of profound high-frequency hearing loss and high levels of electrocardiogram interference, respectively. For all patients, a threshold of 0.09 for MLR variance produced a sensitivity for responsiveness of 36%; specificity for nonresponsiveness was 97%. Excluding patients 3 and 4 increases the sensitivity to 64%.

For each patient, the variance data were averaged into bins of 1-min duration. Mean values of MLR variance were calculated for periods of responsiveness or nonresponse with the isolated forearm (Fig. 5). There is a significant increase in variance between response and nonresponse conditions in six of the seven patients. This confirms the hypothesis that the MLR evoked using MLS and chirps changes with the responsiveness of the patient.

View larger version (20K): [in this window] [in a new window]   Figure 5. Mean values and standard errors by subject of the middle latency response variance 20 to 70 ms poststimulation for responding (open bars) and nonresponding (shaded bars) states. Significance of two-tailed Mann-Whitney U-tests: #P < 0.05; *P < 0.01.

	Discussion

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In this preliminary study we found a change in MLR variance as a result of anesthesia, in contrast with other studies, one from our group, reporting a latency shift (1,2,17). One explanation for the discrepancy is that the rapid stimulation rates used with the MLS technique may stress the auditory pathway more than conventional click stimulation, making our system more sensitive to anesthetic-induced disruption of the auditory pathway.

Should we expect a graded or a categorical change in the MLR with increasing "depth" of anesthesia? A graded change is expected if increasing cerebral concentrations of the anesthetic progressively disrupt neural activity. Alternatively, activity in the auditory pathway may be affected by the state of arousal of the subject, with categorical changes in arousal producing corresponding categorical changes in the MLR. In this case, a prolonged averaging time for the MLR may artifactually smear a categorical change into what appears to be a progressive one.

If the variance of the MLR is to be useful, we need a threshold level of variance that indicates conscious awareness. This may be subject-specific, as the amplitude of the MLR varies with age and hearing loss. Hearing loss will affect the quality of an auditory response such as the MLR, and it is critical that patients are screened for hearing loss if the MLR is to be used routinely for clinical monitoring. Use of the MLR in anesthesia monitoring is probably not appropriate for patients with severe or profound hearing loss, which affects around 2% of the younger adult population, increasing to 4% in the 61- to 70-year age group and 10% in the 71- to 80-year age group (14,18). This is a preliminary study of the MLS-chirp technique; further development is needed to improve the reliability of the MLR measurement and to define a parameter of the MLR to indicate adequate anesthesia.

	Footnotes

 
Accepted for publication September 7, 2005.

	References

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