Awareness During Emergence from Anesthesia: A Research Study

This report summarizes a study published in the British Journal of Anaesthesia, investigating awareness during emergence from anesthesia in patients with butyrylcholinesterase deficiency. The study included interviews with 70 patients, revealing that 50% experienced awareness while paralyzed during emergence. Notably, 80% of these patients were not monitored with a nerve stimulator, compared to 49% of the unaware patients (P=0.012). Furthermore, 86% of aware patients reported distress, and they scored higher in screening for post-traumatic stress disorder (P=0.006). The study emphasizes that butyrylcholinesterase deficiency is a significant risk factor for distressing awareness, and the lack of neuromuscular monitoring increases this risk. The findings support the application of neuromuscular monitoring, even when using short-acting neuromuscular blocking agents, to improve patient outcomes and reduce psychological sequelae. The research highlights the importance of monitoring and the potential for psychological distress associated with awareness during emergence, particularly in patients with specific enzyme deficiencies. The research underscores the significance of neuromuscular monitoring in preventing awareness and its associated psychological distress.

A R T I C L E
Awareness during emergence from anaesthesia:
significance of neuromuscular monitoring in patients
with butyrylcholinesterase deficiency†
J. L. Thomsen*, C. V. Nielsen, K. Z. Eskildsen, M. N. Demant, and M. R. Gätke
Danish Cholinesterase Research Unit, Department of Anaesthesiology, Herlev Hospital,
University of Copenhagen, Herlev, Denmark
*Corresponding author. E-mail: [e-mail]
Abstract
Background: Butyrylcholinesterase deficiency can result in prolonged paralysis after administration of succinylcholine or
mivacurium. We conducted an interview study to assess whether patients with butyrylcholinesterase deficiency were more
likely to have experienced awareness during emergence from anaesthesia if neuromuscular monitoring had not been applied.
Methods: Patients referred during 2004–2012 were included. Data on the use of neuromuscular monitoring were available from a
previous study. Interviews, conducted by telephone, included questions about awareness and screening for post-traumatic stress
disorder. Reports of panic, hopelessness, suffocation, or a feeling of being dead or dying resulted in the experience being classi fied
further as distressful. Patients were categorized as aware or unaware by investigators blinded to use of neuromuscular monitoring.
Results: Ninety-five patients were eligible to be interviewed. Of the 70 patients interviewed, 35 (50%) were aware while paralysed
during emergence. Of these, 28 (80%) were not monitored with a nerve stimulator when awakened, compared with 17 (49%) of the 35
unaware patients (P=0.012, Fisher’s exact test). Thirty (86%) aware patients reported distress compared with seven (20%) unaware
patients (P<0.001). The aware patients scored higher in screening for post-traumatic stress disorder (P=0.006, Mann–Whitney U-test).
Conclusions: Butyrylcholinesterase deficiency is a major risk factor for distressing awareness during emergence. Lack of
neuromuscular monitoring increases the risk significantly. Neuromuscular monitoring should be applied even when using
short-acting neuromuscular blocking agents.
Key words: anaesthesia awareness; butyrylcholinesterase deficiency; neuromuscular block; neuromuscular monitoring
Editor’s key points
• Prolonged paralysis after succinylcholine or mivacurium
occurs in patients with butyrylcholinesterase deficiency.
• Patients suspected of butyrylcholinesterase deficiency were
interviewed to determine their experience of awareness of
paralysis during emergence from anaesthesia.
• Of the patients interviewed, 50% reported paralysis,and
these patients were less likely to have had neuromuscular
function monitoring.
Patients with butyrylcholinesterase (BChE) deficiency could be at
risk of experiencing severe residual neuromuscular block
because the enzyme deficiency causes prolonged duration of
action of the short-acting neuromuscular blocking agents suc-
cinylcholine and mivacurium. 1 2 Butyrylcholinesterase defi-
ciency may be suspected if neuromuscular monitoring shows
no response to nerve stimulation when anaesthesia is about to
be terminated. If neuromuscular monitoring is not applied, par-
alysis and apnoea upon discontinuation of anaesthesia may lead
to suspicion of BChE deficiency.3 4
† This Article is accompanied by Editorial Aev143.
Accepted: February 11, 2015
© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: [e-mail]
British Journal of Anaesthesia 2015, i78–i88
doi: 10.1093/bja/aev096
ARTICLE
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The recently published 5th National Audit Project (NAP5) on
accidental awareness in general anaesthesia revealed that the
experience of emerging from anaesthesia with residual neuro-
muscular block was interpreted by many patients as anaesthesia
awareness.5 Failure to monitor the degree of neuromuscular
block with a nerve stimulator was judged causal or contributory
in the majority of these instances.
The Danish Cholinesterase Research Unit (DCRU) receives
referrals of patients suspected of BChE deficiency. 6 In a
DCRU registry study (Thomsen and colleagues), 7 we found
that application of neuromuscular monitoring was associated
with lower risk of premature awakening in patients suspected
of BChE deficiency. However, it has never been investigated
whether patients with BChE deficiency are genuinely at in-
creased risk of awareness. In the present interview study, we
investigated whether patients suspected of BChE deficiency
were more likely to have experienced awareness during emer-
gence from anaesthesia if they were not monitored with a
nerve stimulator.
Methods
The Committees on Health Research Ethics in Denmark confirmed
that the study could be initiated without approval (H-4-2013-164).
The Danish Data Protection Agency (HEH-2014-003/02597)
approved the study. The DCRU is a clinical database registered
with the Danish Data Protection Agency.
Eligibility
We included patients referred to the DCRU from January 2004 to
May 2012. Data on the use of neuromuscular monitoring were
available from an earlier study. In that study, two groups were
defined: patients monitored with a nerve stimulator from the be-
ginning of anaesthesia (monitored group), and patients not mon-
itored at all (unmonitored group). Patients for whom a nerve
stimulator was applied only when residual neuromuscular
block was suspected were also included in the unmonitored
group because this was considered inappropriate use of neuro-
muscular monitoring. Patients were excluded from the present
study if they were <18 yr old at the time of the interview, <15 yr
old at the time of the procedure leading to referral to the DCRU,
or were unable to complete the interview because of mental im-
pairment, non-Danish speaking, or death. Patients who declined
participation or who could not be contacted were also excluded.
Interviews
We designed an interview guide consisting of multiple choice
and open-ended questions related to the perioperative experi-
ence (Table 1).The interview guide was based on experiences
reported in studies of awareness in anaesthesia.8–10 A modified
Brice interview was included to differentiate between intraopera-
tive awareness and awareness during emergence from anaesthe-
sia.11As anaesthesia awareness can lead to post-traumatic stress
disorder (PTSD),13 we also included the PTSD checklist specific
version (PCL-S)12 to screen for long-term psychological sequelae.
The checklist consists of 17 items in four categories of PTSD
symptoms: re-experiencing, avoidance, numbing, and hyperar-
ousal. Each item is scored from 1 ‘not at all’ to 5 ‘extremely’,
resulting in a total score between 17 and 85. We chose a cut-off
value of 44 as indicative of possible PTSD as proposed by Blan-
chard and colleagues.14 The choice of cut-off value of the PCL-S
has an effect on the specificity and the sensitivity of the test as
a screening tool for PTSD. Also, the optimal cut-off value can be
found only when the true prevalence of PTSD in the population is
known. 15 Patients were asked to participate in the interview
study by letter. A reminder was sent to non-responders after
2 months. Three investigators (J.L.T., K.Z.E., and M.N.D.) con-
ducted the interviews by telephone. Before this, the investigators
discussed the interview guide extensively to ensure that inter-
views were conducted in the same manner. To reduce interview-
er bias, the investigators were blinded to all clinical information
except the following: the indication for the procedure, hospital,
date of surgery, and the patient’s age at the time of the procedure.
Patients were informed that the purpose of the study was to
describe their perioperative experience,but not about the in-
tended examination of the association between neuromuscular
monitoring and awareness during emergence from anaesthesia.
Replies were typed directly in an electronic form containing the
interview guide. Patients reporting psychological sequelae were
advised to contact their general practitioner.
Assessment and classification
Two investigators (J.L.T. and M.R.G.) reviewed the responses to
assess whether the patients had been aware while paralysed dur-
ing emergence from anaesthesia. Patients reporting actual par-
alysis, e.g. inability to open their eyes, move, breathe, or speak
while still in the operating room (OR), were classified as aware.
Patients with an uneventful emergence from anaesthesia and
no report of paralysis constituted the unaware group. Patients re-
porting ‘feeling heavy’, but not paralysed, or for whom it could
not be determined if the reported incident took place in the OR
or in the intensive care unit (ICU) were classified as ‘possible’,
and were included in the aware group. Patients who had experi-
enced paralysis after leaving the OR (i.e. in the ICU) were classi-
fied as paralysed in the ICU. Hence, a patient could be classified
as unaware (in the OR), but paralysed in the ICU. Finally, the as-
sessors judged whether the postoperative experience as a whole
was described as distressing, according to the Michigan aware-
ness scale.16 Among others, reports of panic, hopelessness, suf-
focation, or a feeling of being dead or dying (Table 1) resulted in
the experience being classified as distressful. Disagreements
were settled by discussion. The assessors were blinded to clinical
data (i.e. the use of neuromuscular monitoring).
Outcomes
The primary outcome was awareness during emergence from an-
aesthesia. Secondary outcomes were paralysis in the ICU, experi-
ence reported as distressing, and total PCL-S score. Patients with
pre-existing anxiety, depression, or PTSD were excluded from the
analysis of the PCL-S score.
Statistical analysis
Categorical data were compared using Fisher’s exact test. The
correlation between use of neuromuscular monitoring and
awareness during emergence from anaesthesia was calculated
using logistic regression and reported as odds ratio with 95% con-
fidence interval (CI). Possible confounders were tested for statis-
tical significance and, if found significant, included in the
analysis, giving an adjusted odds ratio. The PCL-S scores were
compared using the Mann–Whitney U-test. Analyses were done
in SPSS (version 19.0; SPSS Inc., Chicago, IL, USA) and R (version
3.1.0; R Foundation for Statistical Computing, Vienna, Austria).
A value of P<0.05 was considered statistically significant.
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Table 1 Interview guide. Based on experiences reported in awareness studies,8–10 the modified Brice interview,11 and the post-traumatic
stress disorder (PTSD) checklist specific version (PCL-S)12
Introduction to the participants:
You were referred to the Danish Cholinesterase Research Unit because you are suspected to be genetically disposed to prolonged duration
of action of a neuromuscular relaxant administered during your anaesthetic. Most of the following questions are multiple choice, while
some are open ended. Unless stated otherwise, options for answering are ‘yes’, ‘no’, and ‘cannot remember’. Most questions are
followed by an option to comment.
Introduction
How was your overall experience of the procedure and anaesthetic?
(a) Very good
(b) Good
(c) Neutral
(d) Bad
(e) Very bad
Modified Brice interview
What is the last thing you remember from before going to sleep?
What is the first thing you remember from after waking up?
Do you remember anything from the period between going to sleep and waking up?
Did you dream during your procedure?
What was the worst part?
(a) Before arrival to the operating room
(b) In the operating room, before anaesthesia was induced
(c) During the procedure
(d) In the operating room at emergence from anaesthesia
(e) In the postanaesthesia care unit
( f )After discharge from the postanaesthesia care unit
(g) No unpleasant experience at all
Emergence from anaesthesia
How was your experience of waking up?
(a) Very pleasant
(b) Pleasant
(c) Neutral
(d) Unpleasant
(e) Very unpleasant
( f )Cannot remember
What caused you to experience the awakening in such a manner?
Did you try to move?
Were you able to move?
Did you understand right away what was happening?
Did you experience (yes or no to each item):
(a) Feeling safe
(b) Being comforted verbally
(c) Hearing sounds
(d) Hearing voices
(e) Visual impressions
( f )Touch, without pain
(g) Fear of pain
(h) Light pain
(i) Severe pain
( j) Feeling unsafe
(k) Feeling panic
(l) Wanting to ask for help, but not being able to
(m)A feeling of hopelessness
(n) Suffocation
(o) Muscle weakness
( p) Paralysis
(q) Feeling that you were dead or dying
(r) Feeling that you were being betrayed by your physician or nurse anaesthetist, or both
(s) None of the above
(t) Other, elaborate
PTSD Checklist Specific Version (PCL-S)
Continued
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A sample size calculation was not conducted before initiation of
the study.
Results
A total of 127 patients were eligible, including the 123 patients
analysed in the companion paper.7 An additional four patients
who were excluded from the other study because of missing
information of the primary outcome were also included. Of 95 -
patients eligible for interview, contact could not be obtained in
24 instances and one patient declined to participate, resulting
in 70 interviewed patients (Fig. 1).
Interviews were conducted from December 2012 to March
2013. Patient characteristics and perioperative data for the
aware and unaware groups are shown in Table 2. The duration
of interview was mean 29 min (range 13–68) and 22 min (range
10–46) in the aware and unaware group, respectively. Interviews
were conducted with the aware and unaware patients 4 yr (range
1–9) and 5 yr (range 1–9) after the anaesthesia event that led to
referral to the DCRU. The cause for BChE deficiency was homozy-
gous mutations in the butyrylcholinesterase (BCHE) gene in 51
(73%) patients and heterozygous mutations in 10 (14%) patients
(Table 2). Five (7%) patients had a normal genotype with medica-
tion or conditions that decrease BChE activity, while four (6%) had
a normal genotype with non-BChE-related explanations for the
events that led to referral.
Awareness during emergence from anaesthesia
and paralysis in the intensive care unit
A total of 31 (44%) of the 70 patients interviewed had experienced
awareness during emergence from anaesthesia. An additional
four patients (6%) were classified as ‘possible’ and were included
in the aware group. Of the 35 patients in the aware group, 28 (80%)
were not monitored with a nerve stimulator when anaesthesia
was terminated, compared with 17 (49%) of 35 in the unaware
group (P=0.012). Neuromuscular monitoring reduced the risk of
awareness during emergence from anaesthesia [odds ratio 0.24
(95% CI 0.08–0.68),P=0.008].Possible confounders tested for
significance included the following: sex, ASA physical status,
age, neuromuscular blocking agent administered (succinylcho-
line vs mivacurium or combinations), genotype (homozygous
mutations vs others), and time since the procedure. Only age
proved statistically significant [odds ratio 0.97 (95% CI 0.94–
0.998),P=0.036] and was included in the analysis,resulting in
an adjusted odds ratio of 0.23 (95% CI 0.08–0.68; P=0.008).
Upon completion of the study, we grouped patients according
to reported experience, use of neuromuscular monitoring, and
cause of prolonged neuromuscular block. Patients representa-
tive of these groups are reported in Table 3. Six (17%) patients
in the aware group also reported being paralysed in the ICU
after leaving the OR (Table 3, section B). Of the unaware patients,
nine (26%) reported being paralysed in the ICU, but did not recall
anything from the OR (Table 3, section C). The unaware patients
Table 1 Continued
In the following, 17 problems and complaints that people sometimes have in response to stressful life experiences will be mentioned. In
this case, the stressful experience refers to the procedure and anaesthetic. Please listen to each one carefully, and then give your
answer to indicate how much you have been bothered by that problem in the past month. For each question, please choose the best-
suiting answer: not at all, a little bit, moderately, quite a bit, and extremely.
In the past month, to which degree have you been bothered by:
1. Repeated, disturbing memories, thoughts, or images of the stressful experience?
2. Repeated, disturbing dreams of the stressful experience?
3. Suddenly acting or feeling as if the stressful experience were happening again (as if you were reliving it)?
4. Feeling very upset when something reminded you of the stressful experience?
5. Having physical reactions (e.g. heart pounding, trouble breathing, sweating) when something reminded you of the stressful
experience?
6. Avoiding thinking about or talking about the stressful experience or avoiding having feelings related to it?
7. Avoiding activities or situations—including avoiding anaesthesia or going to the hospital—because they reminded you of the stressful
experience?
8. Trouble remembering important parts of the stressful experience?
9. Loss of interest in activities that you used to enjoy?
10. Feeling distant or cut off from other people?
11. Feeling emotionally numb or being unable to have loving feelings for those close to you?
12. Feeling as if your future somehow will be cut short?
13. Trouble falling or staying asleep?
14. Feeling irritable or having angry outbursts?
15. Having difficulty concentrating?
16. Being ‘super alert’ or watchful or on guard?
17. Feeling jumpy or easily startled?
Were any of the five lastly mentioned problems present before the stressful experience?
Remark: each item is scored as 1 (not at all), 2 (a little bit), 3 (moderately), 4 (quite a bit), or 5 (extremely). A total symptom severity score
(range=17–85) is obtained by summing the scores from each of the 17 items.
Concluding questions
Did you receive any kind of professional counselling because of your experience?
Did you suffer from any diagnosed psychiatric illness before the experienced event or have you been diagnosed after the experience?
Do you have any supplementary information that you find relevant for this study?
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typically remembered nothing at all from the OR (Table 3, sec-
tions D and G). Seven patients experienced awareness during
emergence from anaesthesia despite the use of neuromuscular
monitoring (Table 3, section F). In five of these patients, neuro-
muscular monitoring was applied but apparently malfunction-
ing, or results were disregarded. In the remaining two patients,
no problems with the nerve stimulator were reported in the
anaesthesia records. While patients homozygous for BCHE muta-
tions accounted for the most distressing instances of awareness
during emergence from anaesthesia, six patients with heterozy-
gous mutations or normal genotype with acquired BChE defi-
ciency also reported being paralysed in the OR (Table 2 and
Table 3, sections H and I).
Distress
The experience was assessed to be distressing in 30 (86%) of the
aware patients and seven (20%) of the unaware patients
(P<0.001). Of the five patients in the aware group reporting no dis-
tress, two had experienced the event as in a dream, one was half-
asleep when realizing he was paralysed, one was conscious for
only a very short time, and one described how the anaesthesia
personnel calmly explained that the paralysis was only tempor-
ary (Table 3, section E). Of the seven unaware patients reporting
distress, six had experienced paralysis in the ICU, explaining
their distress (Table 3, section C).
Screening for post-traumatic stress disorder
In screening for PTSD, three patients were excluded because of a
psychiatric condition diagnosed before the procedure: two with
PTSD (one in the aware group, PCL-S score 62, one in the unaware
group, PCL-S score 56) and one with anxiety and depression
(unaware group, PCL-S score 72). This information was revealed
at the end of the interview (Table 1). The median PCL-S scores
in the 34 aware and 33 unaware patients were 19 (range 17–51)
and 17 (range 17–35), respectively (P=0.023). One patient in the
aware group had a PCL-S score of 51, indicating possible PTSD
(Table 3, patient 2).
Discussion
Our study revealed that 50% of patients referred to the DCRU be-
cause of suspected BChE deficiency had experienced awareness
during emergence from anaesthesia, thereby establishing BChE
deficiency as a major risk factor for awareness. Aware patients
were not monitored with a nerve stimulator in 80% of instances,
or neuromuscular monitoring was applied only when BChE
deficiency was suspected,which was after a failed attempt to
awaken the patient. Furthermore, patients who had experienced
awareness during emergence from anaesthesia scored higher in
screening for PTSD.
Table 2 Characteristics of the 70 interviewed patients with and without awareness during emergence from anaesthesia. Data are mean
(range) or number of patients (percentage). Aware, patients who experienced awareness during emergence from anaesthesia; BChE,
butyrylcholinesterase enzyme; BCHE, butyrylcholinesterase gene; Unaware, patients who did not experience awareness during emergence
from anaesthesia
Aware (n=35) Unaware (n=35)
Patient
Sex (male:female) 13:22 19:16
Age at the procedure 41 (16–69) 50 (18–86)
Weight (kg) 82 (48–150) 78 (44–130)
Height (cm) 174 (156–194) 173 (158–198)
ASA physical status (I/II/III) 19/13/3 16/13/6
Procedure priority
Urgent 16 (46%) 21 (60%)
Elective 17 (48%) 11 (31%)
Unknown 2 (6%) 3 (9%)
Neuromuscular blocking agent administered
Succinylcholine 23 (66%) 20 (57%)
Mivacurium 6 (17%) 10 (28%)
Succinylcholine and mivacurium 2 (6%) 3 (9%)
Succinylcholine and other non-depolarizing neuromuscular blocking agent 4 (11%) 2 (6%)
Cause of prolonged duration of action of neuromuscular blocking agent
Homozygous for BCHE mutations 27 (77%) 24 (69%)
Heterozygous for BCHE mutation with or without concurrent medication or conditions
that decrease BChE activity
3 (9%) 7 (20%)
Normal genotype with medication or conditions that decrease BChE activity 3 (9%) 2 (6%)
Normal genotype with non-BChE-related explanation for the events that led to referral,
such as overdosing of neuromuscular blocking agents
2 (5%) 2 (5%)
Referred to the DCRU and
eligible for inclusion
n=127
Eligible for interview
n=95
Interviewed
n=70
Excluded
Age <15 years n=8
Dead n=19
Dementia or severe
psychiatric disorder n=5
Eligible but not included
No contact obtained n=24
Declined to participate n=1
Fig 1 Study flow. DCRU, Danish Cholinesterase Research Unit.
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Table 3 Patients of special relevance. BChE, butyrylcholinesterase enzyme; BCHE, butyrylcholinesterase gene; DCRU, Danish Cholinesterase Research Unit; Het
mutation with or without medication or conditions decreasing BChE activity; Homozygote, homozygous for BCHE mutations; ICU, intensive care unit; OR, operat
stress disorder checklist; TOF, train of four
Patient
no.
Sex,
age (yr)
Procedure Cause of BChE
deficiency
Reported experience of awareness during
emergence from anaesthesia
PCL-S
score
Neuromuscular
monitoring
Clinical data f
and the DCRU
Section A: aware, unmonitored
1 F, 47 Arthroscopy Homozygote Woke up in the OR and felt fine, except breathing
took an effort. Received neostigmine (the patient
is a nurse), which eased her breathing initially,
but as they moved her to the hospital bed, her
tongue fell back, choking her. Panicked, but
could not advise the staff that she was awake.
Pulse oximetry was applied. Received
neostigmine again, this time resulting in
complete paralysis. Was awake while being bag
mask ventilated.
Follow-up: received counselling from a
psychologist.
23 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
succinylch
Trachea e
Received
130 min. B
Tracheally
with a sec
succinylch
monitoring
reintubati
2 F, 28 Diagnostic
laparoscopy
Homozygote Nurse telling her to breathe or try to move. Heard
and understood everything, but unable to follow
instructions. Nurse said ‘we have to put her back
to sleep’. Woke up abruptly, and the tracheal
tube was removed. Was told that she almost
died.
Follow-up: saw a psychologist 6 months later.
51 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
succinylch
Return of
with tidal
80 min. Re
3 F, 39 Nasal surgery Homozygote Was thinking that something was very wrong.
Could hear the staff talking, but could not see
anything or move. Tried to move her finger to
give a signal that she was awake. Heard someone
say ‘she is waking up’. The staff did not panic, but
she could tell that it was an unusual situation.
Took a long time before they reassured her that
everything was going to be fine. Felt loss of
control and wanted to scream.
35 Not applied Anaesthesia d
succinylch
The patien
anaesthet
lifting a fin
eyes. Rese
4 M, 62 Unknown
procedure
Homozygote Could not move his body or eyes. Was able to
breathe, but it took an effort. Someone said ‘he is
awake’. Awake for about 5 min. Fell asleep again.
Follow-up: was offered psychologist counselling,
but did not feel the need.
17 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
succinylch
Resedated
attempted
5 M, 29 Oesophagoscopy Homozygote Woke up paralysed. Heard voices. Felt he was
choking. Could not tell the staff that he was
awake. Did not understand what was happening.
Follow-up: received a phone number in case he
17 Not applied Anaesthesia d
succinylch
Received
opioid ove

Table 3 Continued
Patient
no.
Sex,
age (yr)
Procedure Cause of BChE
deficiency
Reported experience of awareness during
emergence from anaesthesia
PCL-S
score
Neuromuscular
monitoring
Clinical data f
and the DCRU
needed to talk about it afterwards, but did not
need to.
Section B: aware postoperatively and experienced paralysis in the ICU
6 F, 33 Laparoscopic
cholecystectomy
Homozygote Saw a doctor opening her eye and telling her to
wake up. One of the staff said something like ‘let
us give her another 30 min’. Later, she heard a
nurse complaining about having to stay late
because of her. When transferred to the ICU, still
tracheally intubated and unable to move, they
addressed her, saying that everything was fine.
In the following hours, every time they opened
her eyes to check on her, she could track the time
on a clock hanging on the opposite wall. Drifted
in and out of consciousness.
Follow-up: consulted a psychologist.
34 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
mivacuriu
rate incre
Resedated
spontaneo
sufficient
7 F, 29 Appendectomy Homozygote Heard someone saying ‘you can wake up now’, but
could not open her eyes. Was thinking ‘I am
dying’. More staff entered the OR; they suspected
prolonged action of the medicine. Later, when
she woke up and opened her eyes, the tracheal
tube was quickly removed. Fully conscious while
someone lifted her jaw to help her breathe for ∼2
h. Tried hard to move just a hand or a finger.
Follow-up: was offered to see a psychologist, but
refrained. Had nightmares about the incident for
2–3 months.
17 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
succinylch
Received
20 min. Re
measured
extubated
jaw thrust
and suctio
Section C: unaware in the OR, but experienced paralysis in the ICU
8 F, 58 Gastroscopy Homozygote Nurse in the ICU asked how she felt. Could not
breathe, was only able to nod her head. Tracheal
tube in her mouth and a stinging sensation in
one hand.
Follow-up: reported a very active gag reflex after
the incident.
30 Not applied Anaesthesia d
succinylch
Shallow sp
end-tidal s
pressure o
Resedated
scan.
9 M, 68 Herniotomy Homozygote Felt as if everything but his brain was
anaesthetized. Experienced going towards a
bright light after someone said ‘he is not
breathing’. Was patted hard on the cheek and
told to wake up. Could only see when they
opened his eyes.
17 Not applied Anaesthesia d
succinylch
Resedated
ventilated
spontaneo
than 150
Section D: unaware, monitored
10 F, 35 Homozygote 17 Applied

Gynaecological
surgery
A caring nurse telling her that she was in the ICU.
Relieved. Did not realize that she had slept about
3 h longer than planned.
TOF count 0 m
mivacuriu
Change to
stimulator
increased
suspected
11 M, 21 Appendectomy Homozygote Woke up thirsty and hungry in the ICU.
Follow-up: the staff told him that he took a long
time to emerge from anaesthesia.
17 Applied Anaesthesia d
succinylch
TOF ratio
12 M, 24 Appendectomy Homozygote Woke up nauseated and with a headache in the
ICU. Very tired, felt like a hangover.
17 Applied Anaesthesia d
succinylch
TOF count
at 180 min
Section E: aware without distress
13 F, 53 Phlebectomy Homozygote Saw lot of people standing over her and shouting
her name, then fell back to sleep. Woke up in a
different hospital than where she had surgery
done. Strange experience, but felt no distress.
17 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
succinylch
Awakened
14 M, 64 Cholangiopancreato-
graphy
Homozygote Someone talking to him, unable to reply. Was half-
asleep, but understood that the anaesthetic did
not work as supposed.
23 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
succinylch
Neuromus
at 80 min,
1. Reseda
Section F: aware, monitored
15 M, 29 Endoscopy of jejunal
pouch
Homozygote Could not open his eyes or breathe. Realized he
was in the OR and that something was totally
wrong. Heard a slight panic around him.
Follow-up: was told that he had been awakened
though the nerve stimulator had shown no
response. Felt betrayed.
39 Applied Electrodes on
replaced.
15 min aft
administra
neostigmi
16 F, 21 Appendectomy Homozygote Heard people yelling at her to lift her head. Tried
to, but could not. Realized she had a tube in her
mouth; found it odd. Quickly fell asleep again.
Woke up under a heating blanket in the ICU. It
was not unpleasant waking up the second time.
21 Applied Changed to a
and electr
anaesthet
anaesthes
deficiency
anaesthes
it to be ca
malfunctio
discontinu
succinylch
Resedated
Section G: unaware, unmonitored
17 F, 30 Exploratory
laparotomy
Homozygote Does not remember anything from the OR. Woke
up in the ICU, still tracheally intubated. The tube
was removed promptly. Did not understand why
she was in the ICU. Saw the clock and realized
17 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
succinylch

Table 3 Continued
Patient
no.
Sex,
age (yr)
Procedure Cause of BChE
deficiency
Reported experience of awareness during
emergence from anaesthesia
PCL-S
score
Neuromuscular
monitoring
Clinical data f
and the DCRU
that quite a while had passed. A doctor explained
what had happened, taking it very seriously.
18 M, 86 Revision of crural
ulcer
Homozygote Woke up in the ICU, still tracheally intubated.
Recalled nothing from the OR.
19 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
succinylch
Trachea e
Ventilated
airway for
reintubate
Section H: patients heterozygous for BCHE mutation
19 F, 29 Surgery for
postpartum
haemorrhage
Heterozygote and low
BChE activity
attributable to
recent pregnancy
ICU nurse asked her to lift her arms or legs, but she
could not. Unable to speak, could only make
guttural noises.
17 Not applied Anaesthesia d
succinylch
resedated
extremitie
patient wa
respond a
20 F, 19 Uterine evacuation Heterozygote and oral
contraceptive
Could not move or breathe. Sensed people close to
her, like shadows, but could not open her eyes. A
frantic activity in the room. Realized she could
not breathe, panicked, and then fell asleep.
17 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
succinylch
resedated
respiration
activity.
21 F, 22 Nasal surgery Heterozygote and oral
contraceptive
Her body was not awake. Could not open eyes or
move, but heard everything that was being said.
They repeated the same sentence over and over,
until they realized that something was wrong.
Fell back to sleep.
17 Applied after
suspicion of
BChE
deficiency
Anaesthesia d
mivacuriu
Tracheal e
Laboured
Neuromus
applied, s
mask ven
22 F, 33 Arthroscopy of jaw Heterozygote and
sevoflurane
anaesthesia
Woke up in the OR. Could not speak or move, but
heard people around her. Realized that
something had gone wrong. Awake for only a
short time.
17 Not applied Anaesthesia d
mivacuriu
Resedated
Section I: aware, wild-type BCHE with low BChE
activity
23 M, 41 Electrical
cardioversion
Wild-type with
systemic disease
and medication
affecting BChE
activity
Could move only his eyes; otherwise, completely
paralysed. Tried to scream, but nothing
happened. Could not breathe; thought he was
permanently paralysed. He was in panic for 15–
20 min. Still with a tube in his mouth, he slowly
regained muscle strength and could move his
fingers.
Follow-up: saw a psychologist, but primarily
because of his illness.
25 Not applied Very low BCh
transplant
unknown.
return of s
25 min to

To our knowledge, no study has examined the subjective
experience of patients with BChE deficiency systematically.
Numerous case reports describe patients with prolonged neuro-
muscular block from succinylcholine or mivacurium. In some of
these, patients may have been conscious while paralysed,3 17 18
but the patient’s own experience is rarely described. Combining
data from the DCRU with structured interviews provided a unique
opportunity to describe the point of view of patients with BChE
deficiency. Our study showed that patients either homozygous
or heterozygous for BCHE mutations can experience postoperative
paralysis, resulting in awareness. Homozygosity of the clinically
most important BCHE mutation (the atypical variant A) occurs
with a frequency of one in 3000 in Caucasians and results in pro-
longed duration of action of 2–3 h after succinylcholine 1 mg kg−1
i.v. However, one in five people carry the most common low-
activity variant, the K-variant.19 Patients heterozygous or homo-
zygous for the K-variant have 30% prolonged neuromuscular
block,20which can also be clinically relevant for short procedures,
such as electroconvulsive therapy or reduction of hip disloca-
tion. 21 This indicates that awareness during emergence from
anaesthesia could be a common but underreported problem.
As in NAP5,22many patients in the present study found it very
distressing suddenly to be awake while paralysed; some even
believed that they were dead or dying. Others felt no distress be-
cause they were confident that the paralysis was only temporary.
Likewise, Pilgram and colleagues4 reported on a patient who ex-
perienced no fear or helplessness because she had faith in the
anaesthesiologist, who kept her calm through the 30 min that
passed before neuromuscular monitoring was applied and the
condition was recognized. Also, completely paralysed well-in-
formed volunteers reported no distress as long as they were not
hypercapnic.23 Unlike the patients in our study, the volunteers
had practised the procedure beforehand and were even able to
communicate through hand gestures, probably making it much
less traumatic. Our findings support that informing and calming
a patient who is unexpectedly conscious while paralysed is
important to prevent distress.
Paralysis in the intensive care unit
Some patients were conscious while paralysed, not only at the pri-
mary awakening attempt in the OR, but also when transferred to
the ICU, after BChE deficiency was suspected.They may have
been insufficiently sedated after BChE deficiency was recognized,
or they may have been awakened a second time after arrival to the
ICU before regaining full neuromuscular function. Most patients
receiving intensive care are only sedated lightly. In contrast, pa-
tients with newly recognized BChE deficiency may be completely
paralysed for hours without being able to communicate or under-
stand the situation. This emphasizes the importance of sufficient
sedation until neuromuscular function has fully recovered.
Long-term psychological consequences
Awareness has not been described systematically in patients
with BChE deficiency before, nor have its long-term psychological
consequences. Intraoperative awareness is reported to result in
PTSD in 0–71% of cases.12 We screened one patient positive for
PTSD in the aware group and none in the unaware group. How-
ever, our study is too small to draw any conclusions about the
true incidence of PTSD in this population. Our finding of a
small but statistically significant difference of two points in
PCL-S total score between patients with and without neuromus-
cular monitoring may be of questionable clinical significance in
itself. Even so, awareness during emergence from anaesthesia
must be considered a serious complication to anaesthesia
based on the primary outcome alone. Future studies may reveal
whether patients with BChE deficiency are indeed at risk of devel-
oping PTSD if aware while paralysed.
Significance of neuromuscular monitoring
Many of the distressing experiences reported could have been
avoided by careful application of quantitative neuromuscular
monitoring before awakening, reassuring the patient if awakened
prematurely, and by sufficient sedation until full recovery of
neuromuscular function. Experts in the field have recommended
the use of quantitative neuromuscular monitoring whenever a
non-depolarizing neuromuscular blocking agent is adminis-
tered.24 25 This recommendation should be applied to all neuro-
muscular blocking agents, including succinylcholine, because
the BChE activity of an individual patient is rarely known before
the procedure. In order to enable anaesthetists to comply with
such recommendations, there is a need for education in neuro-
muscular monitoring and rational management of the neuro-
muscular block.
Limitations
The study has some limitations. The questionnaire developed
was not validated, although the PCL-S screening instrument has
been validated in Norwegian, a language very similar to Danish.26
Furthermore, the PCL-S should be used cautiously when screen-
ing is not followed by a more thorough and time-consuming stan-
dardized diagnostic interview.15 The questionnaire could have
been tested on a group of surgical patients without BChE defi-
ciency, in order to determine the contribution of BChE deficiency
to the postoperative experience.The delay between procedure
and interview may have caused underreporting of awareness dur-
ing emergence from anaesthesia, perhaps especially in patients
without distress. The assessors of the experiences are not experts
in awareness. However, in contrast to intraoperative awareness,
the assessor did not judge the authenticity of the reported experi-
ences as is done when assessing intraoperative awareness, but
merely if paralysis was reported. The 25 patients who were eligible
but could not be interviewed may have affected our results.
Acknowledging these limitations, we believe that our findings
are relevant, not only to patients with BChE deficiency, but also
to any patient receiving a neuromuscular blocking agent.
Conclusion
In conclusion, we found that 50% of patients suspected of BChE
deficiency had experienced awareness during emergence from
anaesthesia. Neuromuscular monitoring was not applied before
awakening in the majority of aware patients, and it seems to be
the tool for preventing awareness during emergence from anaes-
thesia. Hence, neuromuscular monitoring should be applied
even when using short-acting BCHE-metabolized neuromuscular
blocking agents.
Authors’ contributions
J.L.T.: study conception and design, conduct of interviews,
analysis and interpretation of results, writing of first draft of
the paper. C.V.N.: study conception and design. K.Z.E. and M.N.
D.: conduct of interviews. M.R.G.: study conception and design,
analysis and interpretation of results. All authors have approved
Awareness during emergence from anaesthesia | i87
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the final manuscript for publication and agreed to be accountable
for all aspects of the work.
Acknowledgements
The authors thank Tobias Wirenfeldt Klausen for statistical
advice.
Declaration of interest
J.L.T.; C.V.N.; K.Z.E.; M.N.D.; M.R.G.; no interest declared. M.R.G. has
received payment and travel funding for lectures from MSD, and
has received funding to perform clinical studies from MSD.
Funding
Grants from The Lippmann Foundation, Professor, dr.med.
Bjoern Ibsens Fond, Toemmerhandler Johannes Fogs Fond, the
Research Council at Herlev Hospital, University of Copenhagen,
Denmark (to J.L.T.), and departmental funding.
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