Effect of a mother's recorded voice on emergence from general anesthesia in pediatric patients: Study protocol for a randomized controlled trial

Abstract

Background:
Emergence delirium is a behavioral disturbance after general anesthesia in children and may distress both the patients and the primary caregivers, such as parents and medical staff, looking after the patients. Various medical and emotional interventions have been investigated to reduce emergence delirium; however, none are completely effective. This trial intends to assess whether the mother's recorded voice can reduce this adverse post-anesthesia event and facilitate arousal from general anesthesia.

Methods/design:
This is a prospective, double-blind, single-center, parallel-arm, superiority, randomized controlled trial to be conducted in participants aged 2-8 years who are undergoing elective surgery requiring general anesthesia. Participants will be randomly assigned to one of two groups: those who are stimulated to wake up by listening to their mother's recorded voice (maternal group, n = 33) or a stranger's voice (stranger group, n = 33) during anesthetic emergence. The primary outcome is the initial emergence delirium score in the post-anesthesia care unit (PACU). The secondary outcomes are hemodynamic parameters, including heart rate and mean blood pressure, the duration of time between the cessation of anesthetics and a BIS level of 60, 70 and 80, eye-opening or purposeful movement time, extubation time, total consumption of analgesics, PACU stay time, emergence delirium and pain scores during the PACU stay.

Discussion:
This is the first randomized controlled trial to investigate the effect of a mother's recorded voice during emergence on the pediatric emergence profile after general anesthesia. It may provide prophylactic treatment options to decrease emergence delirium and enhance arousal from general anesthesia.

Trial registration:
ClicnicalTrials.gov, ID: NCT02955680 . Registered on 2 November 2016.

Full text

S T U D Y P R O T O C O L Open Access
Effect of a mother’s recorded voice on
emergence from general anesthesia in
pediatric patients: study protocol for a
randomized controlled trial
Seok Young Song
1
, Sang Gyu Kwak
2
and Eugene Kim
1*
Abstract
Background: Emergence delirium is a behavioral disturbance after general anesthesia in children and may distress both
the patients and the primary caregivers, such as parents and medical staff, looking after the patients. Various medical and
emotional interventions have been investigated to reduce emergence delirium; however, none are completely effective.
This trial intends to assess whether the mother’s recorded voice can reduce this adverse post-anesthesia event and
facilitate arousal from general anesthesia.
Methods/design: This is a prospective, double-blind, single-center, parallel-arm, superiority, randomized controlled trial to
be conducted in participants aged 2–8 years who are undergoing elective surgery requiring general anesthesia. Participants
will be randomly assigned to one of two groups: those who are stimulated to wake up by listening to their
mother’s recorded voice (maternal group, n=33) or a stranger’svoice(strangergroup,n= 33) during
anesthetic emergence. The primary outcome is the initial emergence delirium score in the post-anesthesia
care unit (PACU). The secondary outcomes are hemodynamic parameters, including heart rate and mean
blood pressure, the duration of time between the cessation of anesthetics and a BIS level of 60, 70 and 80,
eye-opening or purposeful movement time, extubation time, total consumption of analgesics, PACU stay time,
emergence delirium and pain scores during the PACU stay.
Discussion: This is the first randomized controlled trial to investigate the effect of a mother’s recorded voice during
emergence on the pediatric emergence profile after general anesthesia. It may provide prophylactic treatment options
to decrease emergence delirium and enhance arousal from general anesthesia.
Trial registration: ClicnicalTrials.gov, ID: NCT02955680. Registered on 2 November 2016.
Keywords: Emergence agitation, Emergence time, Bispectral index (BIS), General anesthesia, Mother’svoice
Background
Emergence delirium (ED) is described as a “mental disturb-
ance during recovery from general anesthesia consisting of
hallucinations, delusions and confusion manifested by
moaning, restlessness, involuntary physical activity, and
thrashing about in bed”[1]. It can cause self-injury, dressing
disruptions, surgical dehiscence, and dislodged indwelling
catheters and can lead to parents’and surgeons’dissatisfac-
tion with the anesthetic. The incidence of ED in pediatric
patients after general anesthesia is reported to be between
10 and 80% [2]. Several factors, such as sevoflurane or
desflurane anesthesia, younger age, pain, anxiety and the
temperament of the child have been suggested to contribute
to ED, but the precise etiology remains uncertain [2, 3]. Vari-
ous studies have tried to reduce emergence delirium after
anesthesia [4–6], but none have been completely effective.
Mothers usually spend a large amount of time with
their children. Therefore, mothers can be assumed to
contribute to their children’s emotional status and
* Correspondence: tomomie@cu.ac.kr
1
Department of Anesthesiology and Pain Medicine, Daegu Catholic
University Medical Center, School of Medicine, Daegu Catholic University,
Daegu, Republic of Korea
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Song et al. Trials (2017) 18:430
DOI 10.1186/s13063-017-2164-4
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

neurological development. In a previous study, maternal
voice had special importance and enhanced involuntary
attention [7]. Moreover, a mother’s voice elicited
stronger activations in specific cerebral regions than an
unknown voice in another study [8]. A recorded
mother’s voice increased the activation of the prefrontal
cortex compared to a stranger’s voice [9]. As shown by
these studies, a mother’s voice has been shown to have a
strong impact on both behavioral and neuronal re-
sponses in children.
However, the influence of a familiar voice, especially a
mother’s voice, on a child during anesthetic emergence
has been scarcely explored previously. Therefore, we will
investigate whether maternal voice supports emotional
stability and facilitates emergence during the emergence
period. We hypothesized that children would show
reduced ED and faster emergence when they heard their
mothers’recorded voices compared to a stranger’s re-
corded voice.
Methods
Study design
This prospective, single-center, parallel-arm, double-
blind, randomized controlled trial was approved by the
Institutional Review Board (IRB) of Daegu Catholic Uni-
versity Medical Center (CR-16-139-L) and registered at
ClinicalTrials.gov (NCT02955680) before enrollment.
This trial is conducted in a tertiary university hospital
(Daegu Catholic University Medical Center) in South
Korea. We report the protocol of this trial according to
the SPIRIT guidelines and the SPIRIT flow chart (Fig. 1
and Additional file 1, respectively). This protocol also
follows the CONSORT Statement.
Participants
Pediatric patients aged 2–8 years with an American
Society of Anesthesiologists physical status (ASA PS) of
1 or 2 who are scheduled to undergo ophthalmology or
otorhinolaryngology surgery requiring general anesthesia
will be enrolled. Potential participants who meet the
inclusion criteria will be recruited at outpatient clinics
or during preoperative visits before surgery. The exclu-
sion criteria are described as follows:
ASA PS 3 or 4
Presence of developmental delays or neurological
diseases
Deafness or hearing impairments
Enrollment Allocation Post-allocation
TIMEPOINT Pre-allocation preoperative T1T2T3T4T5T6T7T8
ENROLLMENT:
Eligibility screen X
Informed consent X
Voice recording X
Allocation X
INTERVENTIONS:
[recorded mother’s voice]
[recorded stranger’s voice ]
ASSESSMENTS:
Baseline variables XX
mYPAS X
BIS
ETsevo %X
Hemodynamic parameters*
Extubation time, eye opening time
BIS >60, 70, and 80 time
PAED and Watcha score
FLACC score
Postoperative analgesics
Primary caregiver satisfaction X
Fig. 1 The SPIRIT flow diagram: the schedule of enrollment, interventions and assessments. *including mean blood pressure and heart rate, T
1
at
preoperative waiting area, T
2
cessation of anesthetics, T
3
extubation, T
4
PACU arrival, T
5
10 min after post-anesthesia care unit (PACU) arrival, T
6
20 min after PACU arrival, T
7
30 min after PACU arrival, T
8
PACU discharge, mYPAS modified Yale Preoperative Anxiety Scale, BIS Bispectral Index,
ET
sevo
end-tidal sevoflurane concentration, PAED Pediatric Assessment of Emergence Delirium, FLACC face, legs, activity, cry and consolability
Song et al. Trials (2017) 18:430 Page 2 of 6
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History of allergies or contraindications to the use of
ketamine (increased intracranial pressure, open-globe
injury,orapsychiatricorseizuredisorder)
Maternal mutism
Absence of the mother
Ethics, consent and permissions
We will obtain written informed consents from all of the
legal guardians of the participants via a single investiga-
tor (SYS) prior to any study-related procedures.
Randomization and blinding
After recruitment, the participants will be randomized
to the maternal group or the stranger group with a 1:1
ratio (Fig. 2) using a computerized online tool (www.
Randomization.com). A random sequence will be
managed and kept within sealed, opaque envelopes by
an assistant who is not involved in this study. When a
patient is enrolled in the study, an anesthesia nurse will
open a sealed envelope and prepare the mother’sora
stranger’s recorded voice file using a voice recorder
according to the group allocation. The voice recorder
will be delivered to the operating room after the patient
arrives and will be connected to noise-cancelling head-
phones before surgical draping.
Allocations will be concealed to all investigators and
participants except the anesthesia nurse who delivers the
voice recorder to the investigator. If serious adverse events
that threaten the safety of patients occur (such as death or
irreversible injury), we will stop the intervention immedi-
ately, break the blinding, and contact the IRB.
Withdrawal, dropout, and discontinuation
Participants are free to withdraw at any time during the
trial at their own or their legal representative’s request.
If the continuation of the trial may threaten the partici-
pant’s health, a participant can be withdrawn based on
the investigators’judgment. Reasons for withdrawal will
be recorded in case report form. All data will be
analyzed according to the intention-to-treat principle.
Confidentiality
Personal information including names, social security
numbers or chart numbers will not be collected. Only
the study code will be collected and managed separately.
The collected data will remain confidential until the in-
vestigators analyze the data. The final dataset will be
managed by the chief investigator (EK). After the com-
pletion of the study, the collected data will be encrypted
and stored for 3 years and then discarded.
Intervention
At the preoperative waiting room, patients are premedi-
cated with atropine (0.02 mg/kg) and ketamine (1 mg/kg)
administered intravenously in the parental presence. After
a patient enters the operating room, standard monitoring
Fig. 2 CONSORT flow chart
Song et al. Trials (2017) 18:430 Page 3 of 6
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(electrocardiography, noninvasive arterial blood pressure,
and pulse oximetry) and the Bispectral Index (BIS; VIS-
TATM monitoring system; Aspect Medical Systems Inc.,
Norwood, MA, USA) will be applied. Anesthesia will be
induced using fentanyl (1 mcg/kg) and 5–6% of
sevoflurane via a scented facial mask. Rocuronium 0.6–
0.8 mg/kg will be given to facilitate intubation. Anesthesia
will be maintained with 1.5–2.0 MAC of sevoflurane
and 50% oxygen, with a BIS target range of 40–60.
At the end of the operation, pyridostigmine and
glycopyrrolate will be administered to antagonize
neuromuscular blockade. All patients will be given
prophylactic antiemetics with dexamethasone 0.1 mg/kg
and ondansetron 0.1 mg/kg.
According to the pre-assigned allocation, the patients
will be stimulated to wake up by a repeated recording of
the mother’s voice (maternal group) or a stranger’s voice
(stranger group) at the end of the operation. The voice
recording will be performed before the operation. In a
calm environment, the mother or a woman who does
not know the child is asked to speak the following
sentences in her usual tone of voice:
“OO (first name of child), wake up. Let’s go home
with mommy. OO, wake up. Open your eyes. Take a
deep breath.”
Only light patting on the shoulder and the recorded
voice will be allowed to stimulate the patients. The re-
corded voice will be delivered to the patient repeatedly
via noise cancelling headphones until extubation. An
investigator who is blinded to the assigned intervention
(EK) will check the BIS value and the end-tidal sevoflur-
ane concentration (ET
sevo
%) at the end of surgery, the
extubation time, the eye opening or purposeful move-
ment time and the time to BIS values of > 60, 70, and 80
during the emergence period. The BIS value will be
included if the electromyography score is < 50% and the
Signal Quality Index is > 75%. After gentle suctioning of
oral secretions from the oropharynx, extubation will be
carefully performed when the participants are able to
achieve spontaneous breathing and obey verbal
commands. Voice stimulation via headphones will be
maintained until the patients arrive at the post-
anesthesia care unit (PACU).
Measurements
The primary outcome measurement is the initial PAED
score in the PACU. The secondary outcomes are
hemodynamic parameters (heart rate, mean blood
pressure), the duration of time from the cessation of an-
esthetics to a BIS score of 60/70 and 80 (BIS > –60/70/
80 time), the eye-opening or purposeful movement time,
the extubation time, the total consumption of analgesics,
PACU stay time, and PAED, Watcha, and FLACC scores
in the PACU.
The Modified Yale Preoperative Anxiety Scale (m-
YPAS) will be used when the patients arrive at the
preoperative waiting room with their parents before pre-
medication [10, 11]. At the end of surgery, all anesthetics
will be stopped immediately and the BIS value and the
end-tidal sevoflurane concentration (ET
sevo
%) are
recorded. Hemodynamic parameters, including heart
rate (HR) and mean blood pressure (MBP), will be
checked at five time points; at the time of the cessation
of anesthetics (baseline, t
0
), time to reach a BIS value of
60 (t
1
), time of extubation (t
2
), time of PACU arrival (t
3
),
and time of PACU discharge (t
4
). BIS > 60, 70, and 80
times, defined as the time intervals from the cessation of
anesthetics until the BIS reached values of 60, 70, and
80, respectively, will be measured. Eye-opening or
purposeful movement time is defined as the interval
from the cessation of anesthetics to-eye opening or
purposeful movement of the patient. Extubation time,
defined as the interval from the cessation of anesthetics
until extubation, will also be measured.
Upon arrival to the PACU, a blinded investigator will
measure emergence delirium and pain scores at every
10 min for the first 30 min. Emergence delirium will be
measured by two methods, the Pediatric Assessment of
Emergence Delirium (PAED) and the Watcha scales.
The PAED scale has five categories (eye contact, actions,
awareness, restlessness, and consolability) scored from 0
to 4 and summed to obtain a total score with a range of
0–20 [12]. The degree of emergence delirium increased
directly with the total scores. The Watcha scale is a
four-point scale as follows [13]: 1, calm; 2, crying but
can be consoled; 3, crying and cannot be consoled; 4, ag-
itated and thrashing around. A total PAED score > 12 or
a Watcha score > 2 at any time is considered post-
anesthetic ED. Pain will be measured by Face, Legs, Ac-
tivity, Cry and Consolability (FLACC) scores ranging
from 0 to 15 [14]. In patients with a total PAED score >
12, a Watcha score > 2 or a FLACC score > 4 in the
PACU, fentanyl 0.5 mcg/kg will be administered as a res-
cue medication and repeated if the agitation does not
subside. Adverse events, such as postoperative nausea
and vomiting, excessive secretions, laryngospasm, or
desaturation and the total consumption of analgesics,
will also be measured. The patients will be discharged
when they are calm and meet a modified Aldrete
score ≥9 [15], and the duration of the PACU stay will
be recorded as the PACU stay time. The subjective
satisfaction of the primary care giver such as a parent
or the PACU nurse will be measured just before
PACU discharge on a five-point scale as follows: 1,
very disappointed; 2, disappointed; 3, so-so; 4, satis-
factory; 5, very pleased.
Song et al. Trials (2017) 18:430 Page 4 of 6
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Sample size
The primary outcome is the initial PAED score. In our
pilot study, the mean difference of the PAED score
between the stranger group and the maternal group was
1.6 with a standard deviation (SD) of 2.19. To attain an
alpha value of 0.05 and a test power of 0.8, 30 patients
are needed in each group using the following formula
[16]. We plan to enroll a total of 66 patients to allow for
a 10% dropout rate:
n¼2za=2þzβ

2σ2
μc−μt
ðÞ
2
To compensate for the possibility of an over-estimated
effect size of the pilot study, we will perform an interim
analysis at 50% enrollment. If the sample size has signifi-
cantly lower power than our expectation, we will recruit
more patients. Otherwise, we will continue the study
according to our initial sample size calculation.
Statistical analysis
An intention-to-treat analysis will be performed and
missing data will be input with the last-observation-
carried-forward method. Continuous variables will be
presented as the mean and the SD or the median and
the interquartile range (IQR) according to the normality
assumption using the Kolmogorov-Smirnov test.
Categorical variables will be presented as numbers of
patients and proportions.
The primary outcome (the initial PAED score) will be
compared with an independent ttest or a Mann-
Whitney Utest. For secondary outcomes, continuous
variables will be compared with an independent ttest or
the Mann-Whitney Utest and categorical variables will
be compared with Pearson’s chi-squared test or Fisher’s
exact test. All tests are two-sided and P<0.05 is considered
statistically significant. A statistician (SGK) who is not
involved in the data collection will conduct all statistical
analyses with SPSS software (version 21.0; SPSS Inc., IBM,
Chicago, IL, USA).
Discussion
The effect of a mother’s voice elicited positive physio-
logic and behavioral responses in other clinical territor-
ies [17–19], but this has been scarcely reported in
perioperative settings. In a study by Kim and colleagues
[20], a mother’s recorded voice reduced preoperative
anxiety and emergence agitation during cardiac
catheterization using ketamine sedation. However, the
quality of mothers’voices was not standardized and the
control group did not receive any voice stimuli. In
contrast, we had the mothers read the same dialogue in
a calm environment in all study populations and
compared the mothers’voices with the stranger’s voice.
Additionally, we measured the BIS to quantify the
sedation level and the effects of a mother’s voice on the
emergence of her child compared with a stranger’s voice.
Other major differences are the level of anesthesia and
the surgical stimuli. Our study involves investigation
under general anesthesia using both ketamine and
sevoflurane inhalation, but Kim’s study was conducted
under modest sedation using ketamine only [20]. Sevo-
flurane or desflurane anesthesia is believed to contribute
to a higher frequency of emergence delirium [21].
In this study, patients are premedicated with ketamine
before entry to the operating room. Various agents have
been shown to be beneficial effect on prevention of ED
[3–6, 22–24]. Among the numerous drugs, a new
selective α
2
-agonist, dexmedetomidine has recently been
spotlighted as an effective prophylactic and treatment
agent for ED [2, 6, 22]. Despite the ongoing encourage-
ment from the previous findings, however, there have
been no officially approved indications for its use in the
pediatric population. Meanwhile, ketamine has been
safely used in pediatric anesthesia for over five decades.
It effectively decreased the incidence of emergence
delirium in previous studies [23, 24]. Moreover, it was
equally effective as dexmedetomidine in a study after
strabismus surgery with sevoflurane [25]. Taken all
together, we thought that ketamine would be suitable for
our settings.
To our knowledge, this is the first randomized
controlled trial to investigate the advantage of a mother’s
recorded voice during the emergence period on the
pediatric emergence profile after general anesthesia. If
the study is successful, this research will establish a new
prophylactic option to decrease emergence delirium and
enhance the wake up after general anesthesia.
Trial status
Patient recruitment is still ongoing since November 2016.
Additional file
Additional file 1: SPIRIT Checklist. (DOC 123 kb)
Abbreviations
BIS: Bispectral Index; FLACC: Face, Legs, Activity, Cry and Consolability; m-
YPAS: Modified Yale Preoperative Anxiety Scale; PACU: Post-anesthesia care
unit; PAED: Pediatric Assessment of Emergence Delirium
Acknowledgements
The authors are grateful to Sun-Kyung Park and Eon-Suk Um (head nurse and
charge nurse of PACU, respectively) for acquisition of data and managing the
participants for this trial.
Funding
None.
Availability of data and materials
Not applicable.
Song et al. Trials (2017) 18:430 Page 5 of 6
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Authors’contributions
SYS is responsible for the acquisition and interpretation of data and for drafting the
manuscript. SKG is responsible for the design of the study, interpretation of data,
data analysis and revising the manuscript. EK is responsible for the conception and
design of the study, interpretation and analysis of data, and drafting and revising
the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
As indicated in the section “Study design,”Institutional Review Board of Daegu
Catholic University Medical Center approved this research protocol (version 1.0,
reference number: CR-16-139-L, validated in October, 2016). This trial is conducted
according to the World Medical Association Declaration of Helsinki. As indicated
in the “Methods”section, we will obtain written informed consents from all the
legal guardians or parents of the participants via a single investigator (SYS) prior to
any study-related procedures.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Anesthesiology and Pain Medicine, Daegu Catholic
University Medical Center, School of Medicine, Daegu Catholic University,
Daegu, Republic of Korea.
2
Department of Medical Statistics, Daegu Catholic
University Medical Center, School of Medicine, Daegu Catholic University,
Daegu, Republic of Korea.
Received: 7 February 2017 Accepted: 29 August 2017
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