TECHNICAL COMMUNICATION
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
The auditory evoked potential known as the middle la-
tency response (MLR), evoked with regular click stim-
ulation at around 5 Hz, has been suggested as an indi-
cator 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
T
he middle latency response (MLR) of the audi-
tory evoked potential (AEP) is a possible indica-
tor 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 av-
erage of 250 –1000 successive responses (1), where the
auditory stimulus triggers the synchronization pro-
cess. 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 back-
ground noise (3– 6), but these methods become in-
creasingly inaccurate as SNR deteriorates. An alterna-
tive 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
Accepted for publication September 7, 2005.
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@
svr.soton.ac.uk.
DOI: 10.1213/01.ane.0000189191.71449.48
©2006 by the International Anesthesia Research Society
0003-2999/06
new technique in a clinical environment. Significant
changes in MLR amplitude, but not latency, were mea-
sured for six of seven subjects in association with
changes in responsiveness to command using the iso-
lated forearm technique. The absence of any latency
shift differs from other studies of the MLR during anes-
thesia and highlights the limited understanding of the
relationship between anesthesia and the MLR.
(Anesth Analg 2006;102:495–8)
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).
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 co-
chlea, whereas low-frequency components cause max-
imum 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 pro-
duced using clicks, using the convention that latency
is measured from the stimulus onset.
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 approxi-
mately 14 times in young subjects with normal hear-
ing, compared with conventional click stimulation at 5
Hz (10). This technique may therefore improve the
Anesth Analg 2006;102:495–8 495
496 TECHNICAL COMMUNICATION BELL ET AL.
AUDITORY EVOKED POTENTIAL EVOKED WITH MIDDLE LATENCY RESPONSE CHIRP
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 deconvolu-
tion. The final response is identical to that obtained using conven-
tional stimulation, but more responses have been averaged in the
same time period.
Figure 2. A chirp sweeping from 0.1 Hz to 10 kHz in 10.4 ms.
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 hypoth-
esis that the morphology of the MLR evoked using
new stimulation methods would change with the re-
sponsiveness of the patient.
ANESTH ANALG
2006;102:495–8
Methods
After Ethics Committee approval and written patient
consent, we studied 10 male patients in the anesthetic
room before elective cardiac surgery. The patients re-
ceived 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 rub-
bing the skin with surical spirit, for acquisition of the
EEG. The ground electrode was on the low forehead,
the active on Fz 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
␮1401 and 1902; Cambridge Electronic Design, Cam-
bridge, UK). It was then bandpass filtered from 15–250
Hz with a rolloff of 48 dB/octave (VBF-8 Dual Vari-
able filter; Kemo Electronics, Langen, Germany), dig-
itized 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 Re-
search, 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 inter-
stimulus 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 com-
mand using the “isolated forearm technique” (15). The
AEP recording was restarted, the propofol infusion
was started at 2 mg 䡠 kg⫺1 䡠 h⫺1, then anesthesia was
induced using fentanyl 100 ␮g 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 re-
sponded to the command, the propofol infusion was
restarted at 6 mg 䡠 kg⫺1 䡠 h⫺1. At 10-min intervals the
infusion rate was reduced to 4 mg 䡠 kg⫺1 䡠 h⫺1 and
then to 2 mg 䡠 kg⫺1 䡠 h⫺1. Every 20 –25 min the tour-
niquet was deflated and the arm was allowed to reper-
fuse 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.
ANESTH ANALG TECHNICAL COMMUNICATION BELL ET AL. 497
2006;102:495–8 AUDITORY EVOKED POTENTIAL EVOKED WITH MIDDLE LATENCY RESPONSE CHIRP

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 gener-
ated from 1000 successive stimuli.

Results
Usable data were obtained from 7 patients. The aver-
age age of the patients was 61.4 years. More than one
nonresponse/response/nonresponse transition was
made in 4 patients, providing 11 instances of respon-
siveness with the isolated forearm. None of the pa-
tients 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 peri-
ods of responsiveness of the isolated forearm (Fig. 3),
but there was no systematic shift in Nb wave latency
as reported previously (1). When the patients were
anesthetized the Pa–Nb complex reduced in ampli-
tude, almost disappearing, and then increased again
when the patients responded with their isolated fore-
arm. 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).
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
Figure 3. Middle latency response (MLR) waves for patient 6. From
amplitude of the MLR was very small because of the top downwards, responses obtained before anesthetic induction,
profound high-frequency hearing loss and high levels after induction, responding with the isolated forearm and when
of electrocardiogram interference, respectively. For all reanesthetized. The vertical axes are MLR amplitude in microvolts,
the horizontal axes are time in ms. Responses were derived using a
patients, a threshold of 0.09 for MLR variance pro- moving average of 1000 epochs with an artifact rejection level of 30
duced a sensitivity for responsiveness of 36%; speci- microvolt.
ficity for nonresponsiveness was 97%. Excluding pa-
tients 3 and 4 increases the sensitivity to 64%.
For each patient, the variance data were averaged
shift (1,2,17). One explanation for the discrepancy is
into bins of 1-min duration. Mean values of MLR
that the rapid stimulation rates used with the MLS
variance were calculated for periods of responsiveness
technique may stress the auditory pathway more than
or nonresponse with the isolated forearm (Fig. 5).
conventional click stimulation, making our system
There is a significant increase in variance between
more sensitive to anesthetic-induced disruption of the
response and nonresponse conditions in six of the
auditory pathway.
seven patients. This confirms the hypothesis that the
Should we expect a graded or a categorical change
MLR evoked using MLS and chirps changes with the
in the MLR with increasing “depth” of anesthesia? A
responsiveness of the patient.
graded change is expected if increasing cerebral con-
centrations of the anesthetic progressively disrupt
neural activity. Alternatively, activity in the auditory
Discussion pathway may be affected by the state of arousal of the
In this preliminary study we found a change in MLR subject, with categorical changes in arousal producing
variance as a result of anesthesia, in contrast with corresponding categorical changes in the MLR. In this
other studies, one from our group, reporting a latency case, a prolonged averaging time for the MLR may
498 TECHNICAL COMMUNICATION BELL ET AL.
AUDITORY EVOKED POTENTIAL EVOKED WITH MIDDLE LATENCY RESPONSE CHIRP
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.
Figure 5. Mean values and standard errors by subject of the middle
latency response variance 20 to 70 ms poststimulation for respond-
ing (open bars) and nonresponding (shaded bars) states. Signifi-
cance of two-tailed Mann-Whitney U-tests: #P ⬍ 0.05; *P ⬍ 0.01.
artifactually smear a categorical change into what ap-
pears 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 ampli-
tude 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 pa-
tients 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 popu-
lation, increasing to 4% in the 61- to 70-year age group
ANESTH ANALG
2006;102:495–8
and 10% in the 71- to 80-year age group (14,18). This is
a preliminary study of the MLS-chirp technique; fur-
ther development is needed to improve the reliability
of the MLR measurement and to define a parameter of
the MLR to indicate adequate anesthesia.
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