Volume 130, Number 2, February 2023

British Journal of Anaesthesia, 130 (2): e209ee212 (2023)

doi: 10.1016/j.bja.2022.09.010
Advance Access Publication Date: 4 November 2022
© 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

EDITORIALS

Presumption of insensibility during general anaesthesia

Andrew E. Hudson
Department of Anesthesiology, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA and
Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, USA

E-mail: ahudson@mednet.ucla.edu

This editorial accompanies: Connected consciousness after tracheal intubation in young adults: an international multicentre cohort study by
Lennertz et al., Br J Anaesth 2023:130:e217ee224, doi: 10.1016/j.bja.2022.04.010

Summary
Whilst the general presumption of the public is that general anaesthesia prevents awareness of any sensory stimuli,
Lennertz and colleagues have shown in this issue of the British Journal of Anaesthesia that 11% of young adults were able to
respond to auditory commands when neuromuscular blocking drugs were prevented from reaching one arm using the
isolated forearm technique. This occurred with anaesthetic regimens that followed usual clinical practice in each of the
10 countries that enrolled patients, and it was significantly more common in women than in men. This high incidence
demands attention. Further characterisation of the experience of these patients is essential to our understanding of the
state of general anaesthesia.

Keywords: accidental awareness during anaesthesia; cognitiveemotor dissociation; consciousness; general anaesthesia;
isolated forearm technique; qualia

‘The operation lasted 4 or 5 min, during which time the patient
betrayed occasional marks of uneasiness, but upon subse-
quently regaining her consciousness, she professed not only to
have felt no pain but to have been insensible to surrounding
objects, to have known nothing of the operation, being only
uneasy about a child left at home’.1
Since Bigelow’s initial breathless report of the demonstra-
tion of ether anaesthesia at the Massachusetts General Hospi-
tal by William Morton in 1846, the expectation amongst surgical
DOI of original article: 10.1016/j.bja.2022.04.010.
patients is that they will be unconscious (‘insensible to sur-
rounding objects’) during general anaesthesia. Anaesthetists
routinely affirm that patients during general anaesthesia will
not be aware during the procedure. Yet, that claim may be
overconfident and unjustified; after all, consciousness is a
subjective experience that is not directly ascertainable by an
outside observer, so why are we so sure our patients are un-
aware during their surgical procedures? Our only way to
determine that someone is conscious is to judge whether their
reactions to their environment accord with our understanding
of what a conscious being would do under those circumstances.
Given that balanced anaesthetic regimens prevent movement,

For Permissions, please email: permissions@elsevier.com

e209
 e210 - Editorials
they largely obliterate the ability of patients to respond to their
environment, so our patients certainly appear unconscious,
regardless of their subjective experience during the procedure.
Fine, but patients must certainly remember if they endure
something as jarring as awareness during anaesthesia, right?
Overwhelmingly, our determination of a patient’s unintended
awareness comes after the fact when patients recall experi-
ences from the period when they were anaesthetised. Yet, most
sedativeehypnotic agents are amnestic even at sub-hypnotic
doses,2 so the relative rarity of reports must necessarily form
a lower limit on the incidence of accidental awareness during
anaesthesia. The 5th National Audit Project in the UK and
Ireland found that one in 19 000 general anaesthetics yielded a
spontaneous report of accidental awareness by the patient,
with the incidence increasing to one in 8000 cases when
neuromuscular blocking drugs were used.3 When actively
soliciting memories of the intraoperative period using a
modified Brice structured interview format,4 the apparent
incidence increases in high-risk populations by more than an
order of magnitude to one in 500e600.5e7 Given that a struc-
tured interview can prompt such a huge increase in the inci-
dence of probable awareness during anaesthesia, a number of
anaesthetists have wondered about studying patients who
retain a communication channel during a balanced anaesthetic
to allow direct querying of the patient’s mental status in real
time during anaesthetic administration.
Tunstall8 proposed the isolated forearm technique (IFT) as
a way to query patients directly for conscious experience
during general anaesthesia in 1977. In brief, anaesthetic in-
duction takes place as normal, but before administration of a
neuromuscular blocking drug a BP cuff is inflated above arte-
rial pressure in one arm, sparing it from delivery of the
neuromuscular blocking drug. This hand is then able to
squeeze in response to queries from the investigators.
Through careful titration, as many as one in three patients
receiving a light general anaesthetic have IFT responsiveness
(i.e. they respond appropriately to questioning with a hand
squeeze).9 In an attempt to understand the real-world inci-
dence of IFT responsiveness during general anaesthesia,
Sanders and colleagues10 reported in 2017 that the incidence of
IFT responsiveness in a multicentre prospective cohort study
of 254 patients was 4.6%, and that responders were younger
than non-responders. Interestingly, none of the IFT re-
sponders had any memories of the experience.
In this issue of the British Journal of Anaesthesia, an expanded
research group has submitted a follow-up to their 2017 study:
an international multicentre prospective cohort study
designed to assess IFT responsiveness shortly after tracheal
intubation in patients 18e40 yr old.11 For technical and philo-
sophical reasons, the authors describe conscious awareness of
study stimuli generating motor responses during general
anaesthesia as ‘connected consciousness’ to emphasise that
the conscious experience is connected to the outside envi-
ronment, as distinct from the ‘disconnected consciousness’ of
dreaming. Thus, ‘connected consciousness’ indicates some
level of conscious awareness of the environment. This has
perhaps added to the terminological clutter in the field, where
definitions are overlapping and vary from author to author. In
general, awareness has a long history as a term to describe the
contents of, as opposed to level of, consciousness.12,13 Thus,
connected consciousness is another name for awareness of
the external environment. This does not mean that connected
consciousness implies a particular type of experience (e.g. pain
during the operation). Normal wakeful conscious experience is
one of connected consciousness, although as we will see later,
it is unclear how IFT responders experience the phenomenon.
Consciousness and awareness can occur without explicit
memory formation, as when not recalling your drive home
from work despite awareness of the environment sufficient to
avoid an accident, and false explicit memories can be formed
of events that did not occur. These represent a challenge for
reliable eye witness testimony14 and for those interested in
studying awareness during anaesthesia.15
Lennertz and colleagues11 proposed to prospectively
investigate specific risk factors for connected consciousness
during general anaesthesia, including female sex and whether
anaesthesia is continuously delivered during the time be-
tween induction of anaesthesia and tracheal intubation, and
to characterise the IFT response with a mix of multiple audi-
tory stimulus types and tests for implicit and explicit memory
formation. Administration of anaesthetic drugs was at the
discretion of the anaesthetist, and enrolling centres were
located in 10 different countries, suggesting a relatively high
external validity. Target enrolment was 500 patients, but
funding constraints forced the study to stop short at 344
enrollees. Even with the decreased power, the group was able
to show that young adults have an 11% response rate after
intubation, with an adjusted odds ratio of 2.7 for female vs
male sex (95% confidence interval [CI]: 1.1e7.6), despite almost
no differences in dosing of anaesthetics between the sexes.
Delivery of anaesthesia during the interval between induction
and intubation, whether by i.v. infusion, intermittent boluses,
or inhalation, decreased the risk of IFT responsiveness, with
an adjusted odds ratio of 0.43 (95% CI: 0.20e0.96). Responses
were more likely to occur with commands than with random
non-command verbal stimuli. Perhaps most concerning, 18 of
37 responders endorsed being in pain when given the com-
mand, ‘If you are in pain, squeeze my hand two times’. There
was no evidence for implicit memory formation in the word
retrieval assay used by the team. Finally, the Brice structured
interview yielded an incidence of definite explicit recall of 0.3%
(95% CI: 0.03e1.3%), consistent with that reported previously.
It should be noted that assessors of IFT responsiveness were
not blinded to anaesthetic dosing, and assessors of intra-
operative recall were not blinded to IFT responsiveness.
These results, corroborating the 2017 report, are quite
disconcerting. Note that comparing incidence directly be-
tween the two studies is not possible, as the definition of a
response differs between the reports. If accidental awareness
does occur in ~1 in 10 young adults receiving general anaes-
thesia, that is orders of magnitude greater than the incidence
that most anaesthetists expect and wildly discordant with
public expectations. Moreover, these results suggest ~1 in
20 such adults are experiencing pain during this period of
awareness.
An important element of this study is the serial sampling of
responsiveness over time. Such an approach is an important
step for several reasons. One, effect-site concentrations are
fluctuating during the period after induction, making a varying
level of consciousness quite understandable, so patients
might respond at some time points and not at others. A
steady-state drug concentration does not guarantee stable
brain electrical behaviour,16 but at least it is more predictable.
We therefore cannot infer that this ability to parse statements
was necessarily stable over time. Second, multiple repeated
probes of responsiveness allow some attempt to understand
the patient’s conscious experience. Are they responding to any
auditory stimulus because they were instructed in advance to

do so, even if they are not parsing the experience? A few pa-
tients (4/338) responded to the nonsense statement but not the
command to squeeze the investigator’s hand, suggesting that
this could plausibly be true, but more patients (13/338)
responded only to the command and not to the nonsense
statement. Use of more complicated probes (i.e. ‘If stones float
on water, squeeze my hand’) could be even more revealing,
but it would require more statistical power to interpret.
The incongruity of patients who respond to direct queries,
including queries about pain, in the affirmative but do not
necessarily move spontaneously in response to surgery has
prompted some to question whether the IFT response is suf-
ficient as an indication of consciousness, and whether the
degree of consciousness that it indicates is necessarily unac-
ceptable.17 Whilst consciousness is not necessarily all or none,
with gradations in level of arousal and content potentially
mediated by anaesthetic drug effects, it would seem that
decoding semantic content from an auditory stimulus and
then selecting an appropriate motor response (‘If you are in
pain, squeeze my hand twice’) clearly indicate some degree of
consciousness. Perhaps whatever that consciousness feels like
(in philosophical terms, its qualia) is not the same as normal
wakeful consciousness, but if it is experienced by one in 10
young adults it seems prudent to prepare patients for that
possibility.
This disconcerting revelation of how much we do not un-
derstand about the conscious experience in anaesthetised
patients has a clear parallel in the discovery of covert aware-
ness in patients with disorders of consciousness after a brain
injury, also known as cognitiveemotor dissociation. This is an
active area of research in disorders of consciousness.18 In-
vestigators have identified that a subset of brain-injured pa-
tients have electroencephalographic or functional imaging
evidence of brain activity congruent with following a com-
mand in response to verbal directions as opposed to closely
matched but scrambled auditory stimuli.19,20 The ongoing
work in cognitiveemotor dissociation may offer some insights
and methodologic inspiration for anaesthetists interested in
characterising the conscious experience of patients undergo-
ing general anaesthesia, and any resulting studies could
certainly inform investigations into mechanisms of other
disorders of consciousness.21 A number of open questions
with immediate clinical relevance clearly remain. Why are
women twice as likely to be IFT responders? Why does
neuromuscular block increase the incidence of awareness? Is
it simply that less hypnotic is administered, or is there
something intrinsically ‘arousing’ about paralysis?
Anaesthetists, we are now in an uncomfortable place
where it is clear that some fraction of young patients may
experience connected consciousness during general anaes-
thesia, but we are not yet able to determine the qualia of those
connected consciousness episodes, so we cannot counsel pa-
tients about what to expect from a first-person perspective in
the event of recall. At a minimum, further study into the na-
ture of whatever conscious experience of IFT responders is
necessary. This line of work may ultimately need to include
setting different expectations for patients undergoing general
anaesthesia, such that there is some non-zero chance that
they experience ‘connected consciousness’ during anaes-
thesia, but what shall we say they might be aware of? As of
now, all we know are the raw rates reported by Lennertz and
colleagues11: 11% (37/338) responded to auditory stimuli at
some point, almost half of whom (18/338) responded when
asked to squeeze the investigator’s hand if they were in pain,
Editorials - e211
but very few (1/338) remembered the experience. The low
incidence of complaints of accidental awareness with recall
certainly suggests that, for the majority of these patients, the
benefits of undergoing surgery with general anaesthesia
outweigh the risk of the potential experience of connected
consciousness during anaesthesia, and a disclosure of this
poorly defined potential experience might dissuade patients
from undergoing necessary procedures. Yet, a 5% incidence of
connected consciousness associated with pain is high enough
in this cohort that it could be argued that a reasonable person
might choose to decline general anaesthesia to avoid a
potentially uncomfortable experience. As a result, disclosure
around the risks of awareness during general anaesthesia has
been controversial.22 I foresee heated discussions ahead as we
wrestle with the implications of this new information. Within
a shared decision-making model, I would argue that, for the
patient that expresses concern about being aware during
anaesthesia, it is reasonable to consider beginning a
riskebenefit discussion with the low incidence of accidental
awareness with recall, to discuss the data of Lennertz and
colleagues11 as we know it, to assure the patient that we will
act if their vital signs suggest discomfort and to assure them
we will take steps to minimise the chance of an episode of
connected consciousness. For example, the results reported by
Lennertz and colleagues11 do offer one immediate suggestion
for clinical practice: providing anaesthesia continuously after
induction decreases the risk of IFT response by roughly a
factor of 2. It is reasonable to recommend that an induction
bolus dose of hypnotic should be followed by additional
anaesthetic administration, i.v. or inhaled, until the airway is
secured and maintenance anaesthetic delivery begins.
Declaration of interest
The author declares that they have no conflict of interest.
Funding
US National Institute for General Medical Science (1R01
GM135420).
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British Journal of Anaesthesia, 130 (2): e212ee214 (2023)

doi: 10.1016/j.bja.2022.08.024
Advance Access Publication Date: 29 September 2022
© 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Microf luidics-assisted bloodebrain barrier device: a powerful tool to

study perioperative neurocognitive disorder
Zhongcong Xie
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School,
Charlestown, MA, USA

E-mail: zxie@mgh.harvard.edu

This editorial accompanies: Protective effects of omega-3 fatty acids in a bloodebrain barrier-on-chip model and on postoperative delirium-
like behaviour in mice by Yang et al., Br J Anaesth 2023:130:e370ee380, doi: 10.1016/j.bja.2022.05.025

Summary
The dysfunction of the blood-brain barrier could contribute to the pathogenesis of the perioperative neurocognitive
disorder. In a recent study published in the British Journal of Anaesthesia, Yang and colleagues developed an innovative
microfluidics-assisted blood-brain barrier device to investigate the effects of neuroimmune interactions on blood-brain
barrier opening. The findings are important and timely to understanding the mechanistic insights of perioperative
neurocognitive disorder.

Keywords: anaesthesia; blood-brain barrier; interleukin-1b; neurocognition; omega-3 fatty acids; surgery

Perioperative neurocognitive disorder (PND),1 one of the most
common postoperative complications in older adults,2,3 is
DOI of original article: 10.1016/j.bja.2022.05.025.
potentially associated with Alzheimer’s disease, impairments
in daily functioning, government assistance dependency, and
increased morbidity and mortality.4 PND includes post-
operative delirium, delayed neurocognitive recovery (dNCR),
mild neurocognitive disorder (NCD), and major NCD.1