Decreasing Delirium through Music (DDM) in critically ill, mechanically ventilated patients in the intensive care unit: study protocol for a pilot randomized controlled trial
Khan et al. Trials
Decreasing Delirium through Music (DDM) in critically ill, mechanically ventilated patients in the intensive care unit: study protocol for a pilot randomized controlled trial
Sikandar H. Khan 0 1
Sophia Wang 2 3
Amanda Harrawood 1
Stephanie Martinez 1
Annie Heiderscheit 7
Linda Chlan 6
Anthony J. Perkins 2 5
Wanzhu Tu 9
Malaz Boustani 1 2 4 5 8
Babar Khan 0 1 8
0 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine , Indianapolis, IN , USA
1 IU Center of Aging Research, Regenstrief Institute , Indianapolis, IN , USA
2 Indiana University Center of Health Innovation and Implementation Science , Indianapolis, IN , USA
3 Department of Psychiatry, Indiana University School of Medicine , Indianapolis, IN , USA
4 Division of Geriatrics and General Internal Medicine, Department of Internal Medicine, Indiana University School of Medicine , Indianapolis, IN , USA
5 Indiana Clinical and Translational Research Institute, Indiana University School of Medicine , Indianapolis, IN , USA
6 Department of Nursing, Nursing Research Division, Mayo Clinic , Rochester, MN , USA
7 Music Therapy Department, Augsburg College , Minneapolis, MN , USA
8 Sandra Eskenazi Center for Brain Care Innovation, Eskenazi Hospital , Indianapolis, IN , USA
9 Department of Biostatistics, Indiana University School of Medicine , Indianapolis, IN , USA
Background: Delirium is a highly prevalent and morbid syndrome in intensive care units (ICUs). Changing the stressful environment within the ICU via music may be an effective and a scalable way to reduce the burden of delirium. Methods/design: The Decreasing Delirium through Music (DDM) study is a three-arm, single-blind, randomized controlled feasibility trial. Sixty patients admitted to the ICU with respiratory failure requiring mechanical ventilation will be randomized to one of three arms (20 participants per arm): (1) personalized music, (2) non-personalized relaxing music, or (3) attention-control. Music preferences will be obtained from all enrolled participants or their family caregivers. Participants will receive two 1-h audio sessions a day through noise-cancelling headphones and mp3 players. Our primary aim is to determine the feasibility of the trial design (recruitment, adherence, participant retention, design and delivery of the music intervention). Our secondary aim is to estimate the potential effect size of patient-preferred music listening in reducing delirium, as measured by the Confusion Assessment Method for the ICU (CAM-ICU). Participants will receive twice daily assessments for level of sedation and presence of delirium. Enrolled participants will be followed in the hospital until death, discharge, or up to 28 days, and seen in the Critical Care Recovery Clinic at 90 days. Discussion: DDM is a feasibility trial to provide personalized and non-personalized music interventions for critically ill, mechanically ventilated patients. Our trial will also estimate the preliminary efficacy of music interventions on reducing delirium incidence and severity. Trial registration: ClinicalTrials.gov, Identifier: NCT03095443. Registered on 23 March 2017.
Delirium; Music; Critical care
Delirium is characterized by a disturbance of
consciousness, the presence of inattention, disorganized thinking,
and a fluctuating course [
]. It has an incidence as high as
85% in mechanically ventilated patients, and is associated
with longer hospital stays, increased hospital and
post-discharge mortality as well as higher healthcare costs [
Furthermore, over 30% of patients with delirium experience
long-term cognitive impairment [
Despite the incidence and morbidity associated with
delirium, effective pharmacological and non-pharmacological
interventions to treat this condition are lacking. Music
listening is a unique, non-pharmacological intervention that
may reduce delirium incidence and severity through the
inhibition of inflammation. Prior music listening research
has demonstrated a calming effect with slow-tempo music.
This is hypothesized to be secondary to entrainment of the
autonomic nervous system, reduction in sympathetic
activation and dampening of the inflammatory state [
various pathophysiological models for delirium implicating
neuro-inflammation, neurotransmitter imbalances and an
aberrant stress reaction, [
] this makes music listening a
promising intervention to prevent or treat delirium.
Music intervention studies in the intensive care unit
(ICU) have focused on its effects on anxiety, pain,
tolerance of non-invasive ventilation, and physiological
indicators of the stress response (heart rate, blood pressure,
catecholamines, cortisol), but, to date, studies on the effect
of music listening on ICU-related delirium have not been
]. Our study aims to test the feasibility
of music listening, and estimate the potential effect size of
music listening on delirium, in critically ill patients on
We are conducting a feasibility trial to deliver
personalized music for critically ill patients based on preferences
supplied by their surrogates or family members.
Participants in the study are unlikely to be able to communicate
or choose their own music due to invasive mechanical
ventilation, the need for high ventilator support, and
hemodynamic instability. Our study design also includes
single blinding and three intervention arms (personalized
music, non-personalized, investigator-selected music, and
attention-control) which adds complexity to the unique
Our study aims to gather data to help inform a
definitive randomized controlled trial.
Our study aims to answer the following question: In
critically ill patients on mechanical ventilation, is the
design and implementation of music listening feasible?
The primary outcomes of our study are: (1) to assess
recruitment rates, described by the number of participants
approached and their rates of consent, (2) to assess
adherence to the intervention by number of listening sessions
completed per patient, and (3) to assess retention by the
number of participants completing the study.
The secondary outcome in the study is to estimate the
potential effect size of patient-preferred music in
reducing delirium incidence as measured by the Confusion
Assessment Method for the ICU (CAM-ICU).
DDM is a feasibility study with a three-arm, single-blind,
randomized controlled design.
Patients admitted to the ICU with respiratory failure
requiring mechanical ventilation are eligible. Sixty
participants will be randomized to one of three arms (20 patients
per arm): (1) personalized music, (2) non-personalized
relaxing music, or (3) attention-control (see Fig. 1).
Participants will receive two 1-h audio sessions a day through
noise-cancelling headphones (and mp3 players). We chose
an attention-control arm (rather than usual care) to test the
feasibility of a placebo, and to control for the non-specific
effects of headphone and non-audio sounds in the study.
The trial protocol was written according to the
Standard Protocol Items: Recommendations for Interventional
Trials Statement (SPIRIT). A SPIRIT Figure is provided
(see Fig. 2) and a SPIRIT Checklist is included as
Additional file 1.
Patients admitted to the medical or surgical ICU service
at Sidney and Lois Eskenazi Hospital (Indianapolis,
Indiana) are eligible. Eskenazi Hospital is a busy 618-bed,
urban, safety net hospital with 44 ICU beds (22 surgical,
22 medical), averaging 120 ICU admissions per month.
Demographics of this ICU are: mean age of patients
53.7 years, 45% African American, 47% female, 29% age
60 years or older, and 16% with Medicaid insurance.
The target population for our trial is adults aged 18 years
and older, admitted to the medical or surgical ICU on
invasive mechanical ventilation.
Individuals deemed eligible for the study will be approached
for consent. If on mechanical ventilation and unable to
consent, the patient’s surrogate or healthcare representative
will be approached for consent.
Inclusion criteria for our study are: (1) age 18 years or
older, (2) English speaking, (3) admitted to the ICU
n = 20
n = 20
n = 20
Blinded Initial Assessments
(Music preferences, IQCODE, Katz, Lawton, RASS, CAM-ICU, CPOT, clinical and laboratory data)
Two 60-min sessions up to 7 days
Blinded Assessments Until Hospital Discharge or 28 days
(RASS, CAM-ICU, CPOT, VASA, safety monitoring)
(Richard-Campbell Questionnaire, RASS, CAM-ICU)
Critical Care Recovery Center Follow Up
(medical or surgical), and (4) receiving mechanical
ventilation for an anticipated duration of 24 h or longer, provided
that the patient has not already been on the ventilator
longer than 48 h at the time of enrollment.
the medical team; (9) inability to obtain consent from
legally authorized representative within 72 h of meeting
eligibility; and (10) attending physician or healthcare
Patients are excluded from our study if any of the
following conditions are present: (1) severe dementia or chronic
neurological disease, with an IQCODE score of 4.5 or
] (2) acute or subacute severe neurological
deficit or injury; (3) severe psychiatric illness (not
including depression) or developmental problems; (4) suspected
or confirmed drug or alcohol intoxication/overdose or
withdrawal; (4) uncorrected or severe hearing or vision
impairment; (5) coma after cardiac arrest and/or
hypothermia protocol; (6) pregnant or nursing women; (7)
prisoners; (8) expected death within 24 h of enrollment or
lack of commitment to aggressive treatment by family or
Participants are provided with noise-cancelling
headphones (Maxell NC-IV Superior Noise Cancellation),
with mp3 player devices (Apple iPod Shuffle 2GB, 6th
generation or Goldenseller 16GB Mp3 Player) during
the trial. Music tracks and audiobooks were purchased
from Apple Music Store (iTunes).
Patients admitted to the ICU are screened on a daily basis.
Music preference data will be collected from all enrolled
participants (through their surrogates) regardless of
Using a computer-generated list of random numbers
created by study statistician, participants are randomized by
permuted block with varying block sizes. Randomization
occurs within 48 h of enrollment in a 1:1:1 ratio, and only
the unblinded study coordinator, who also programs the
music devices, is aware of the randomization assignment.
The music intervention period is 7 days post
randomization. Participants will stop receiving music
sessions early if they choose to withdraw, are
transferred out of the ICU, die, or are discharged.
Inhospital follow-up continues to 28 days or until
discharge, whichever occurs earlier, by daily assessment,
unless they choose to withdraw. All participants will
be invited for follow-up in the Critical Care Recovery
Clinic at 90 days.
Upon enrollment, demographics, clinical data (vital signs,
pertinent laboratory and imaging data), severity of illness
(APACHE II and SOFA), comorbidity burden (Charlson
Comorbidity Index), pertinent home medications, reason
for admission, pre-hospital functional status (Katz and
Lawton), and cognitive function (Informant Questionnaire on
Cognitive Decline in the Elderly (IQCODE)) are obtained
]. Cumulative doses of antipsychotic, analgesic,
sedative, and anxiolytic medications are also recorded.
A previously described music-preference assessment
tool is utilized to obtain the participants’ music
preferences from family members/surrogates [
]. We collect
information about genre likes and dislikes, as well as
specific favorite artists, tracks, and instruments.
A pre-intervention level of consciousness and delirium
assessment is performed upon enrollment through the
Richmond Agitation Sedation Scale and the CAM-ICU,
Following enrollment consent, blinded research personnel
enter the participant’s music preferences into a Research
Electronic Data Capture (REDCap) database. The unblinded
study coordinator programs music devices based on an
individual study participant’s randomization status. For those
randomized to personalized music, Apple Music is utilized
to create a playlist based on their musical interests.
Participants randomized to non-personalized music
received an mp3 player programmed with slow-tempo,
relaxing music and instrumental sounds (piano, relaxing
rainfall sounds, and classical music). Finally, participants
randomized to attention-control receive a device with
audiobooks. The audiobooks include Treasure Island,
Harry Potter, and Dr. Seuss’ Oh the Places You’ll Go!, and
were chosen for their readability and for their broad appeal.
The playlist for each participant is carefully tracked,
which will permit subsequent analysis should particular
books or tracks be associated with increased delirium
incidence or severity.
To avoid unblinding study personnel to the
intervention arm, the coordinator waits a minimum of 4 h to
release the mp3 device for use in the study. Prior to
allocating devices to patient rooms, all devices are checked
to ensure that identifying data including name, artist,
collection, and genre have been removed, the device is
clean and in good functioning order, and volume is set
to a pre-specified level.
Music listening sessions are twice a day, for 1 h at a
time, from 10:00 to 11:00 and 14:00 to 15:00, for 7 days.
The times are based on feedback from ICU nurses
associated with least interference with clinical activities.
Music listening is provided for 7 days unless the
participant refuses, withdraws, is transferred out of the ICU, or
dies. Participants extubated within the 7-day period
continue to receive the intervention unless they are
transferred out of the ICU. Participants remaining in the ICU
after 7 days will not receive further intervention due to
the resource limitations of our feasibility study.
During listening sessions, a conducive listening
environment is created; medical teams are asked to avoid
non-urgent patient care activities, the in-room television
is turned off, family members are asked to limit their
interactions with the patient, and the door is closed to
limit outside noise. As all three arms of the trial will
receive a conducive listening environment, and due to
the use of noise-cancelling headphones in these
settings, we believe that the audio dose will remain as
the pure active intervention.
Participants receive their first dose of music listening, in
one of these windows, as soon after enrollment as possible.
The ICU clinical nurses receive on-site training in the
study protocol, and in the operation of the music devices
and headphones. Blinded research personnel and/or
hospital nurses start the music sessions by placing the
headphones on the participants and activating the audio.
Adherence is monitored by recording the start and stop
date and times for each session. The participant’s heart rate
and blood pressure pre and post session are also recorded.
All participants in the trial receive the ABCDEF
bundle that is standard of care in the ICU where the study
is being conducted. The ABCDEF bundled delirium care
protocol places a multidisciplinary focus on daily ventilator
liberation trials, sedation vacation, choice and optimization
of sedation, nursing-led delirium screenings, early mobility,
and family/social support [
]. Participants in the study
will continue to have physician-determined sedation
without input on choice of sedation from our trial.
Blinding during intervention
We are using various measures to ensure concealment
of a participant’s allocation. Only the unblinded study
coordinator programs the audio devices, and ensures
that the tracks are anonymized (renamed to a series of
digits or letters), to prevent unblinding when bedside
staff view the audio device’s screen. Our protocol also
benefits from the fact that the majority of audio devices
lack screens entirely (Apple iPod Shuffle). Participants,
their family members/surrogates, and hospital nurses are
asked not to share a patient’s randomization with anyone
in the study, should they become aware of it. Audio is
not turned on until the headphones are securely placed
on the participant to prevent study personnel from
inadvertently hearing the output. Participants are permitted
to change tracks or adjust the volume if needed. Should
one of the study personnel become unblinded, they are
reassigned to other study participants. To assess the
fidelity of these efforts, we will survey research personnel
to predict patient randomization in a subset of
Assessments during intervention
All assessments are performed by blinded research
assistants. Assessments occur twice a day, approximately at
11:00 and 15:00 (after audio interventions). Study personnel
perform the following: (1) Richmond Agitation-Sedation
Scale (RASS) to document level of consciousness; (2)
Confusion Assessment Method for the ICU (CAM-ICU)
to screen for delirium [
3, 25, 27
], and CAM-ICU-7 to
determine delirium severity [
]; (3) Critical Care Pain
Observation Tool (CPOT) to determine level of analgesia
and symptom control [
]; (4) Faces Anxiety Scale
(performed after the morning listening session) [
physical therapy and occupational therapy notes are
evaluated and each participant’s mobility milestones are
recorded using Hodgson Mobility Scale ; and (6)
adverse events are assessed (including seizures while
listening, localized skin breakdown or cellulitis around the ears)
and are reported to the Institutional Review Board (IRB)
per usual protocol.
Participants receive in-hospital assessments by blinded
research personnel until hospital discharge, day 28, or they
withdraw or die. Twice a day, at approximately 11:00 and
15:00, study personnel perform the RASS, CAM-ICU,
CAM-ICU-7, CPOT, and the Faces Anxiety Scale, evaluate
mobility with the Hogdson Mobility Scale, and record
Beginning within 72 h of extubation or removal of
the endotracheal tube, and if the patient is CAM-ICU
negative, the participant is reconsented for the study.
The participant is also screened for obstructive sleep
apnea with STOP-BANG and the Richards-Campbell
Sleep Questionnaires, given the higher incidence of
delirium in patients with sleep apnea and disturbed
sleep quality [
Participants are invited to follow-up in the Critical Care
Recovery Center (CCRC) at 90 days from hospital
discharge. The CCRC is an outpatient interdisciplinary
clinic comprising care coordinators (social worker,
nurse), a critical care physician, psychometrician, and
psychologist. Its goal is to maximize the cognitive,
physical, and psychological recovery of ICU survivors
through comprehensive assessments and personalized
recovery plans incorporating self-management protocols.
Prior to the trial initiation, study personnel underwent
training sessions on data collection and were individually
tested on data entry as well as outcome assessments.
Study data have been collected and managed using
REDCap electronic data capture tools hosted at
Indiana University. REDCap is a secure, web-based
application designed to support data capture for research
studies, providing: (1) an intuitive interface for
validated data entry; (2) audit trails for tracking data
manipulation and export procedures; (3) automated
export procedures for seamless data downloads to
common statistical packages; and (4) procedures for
importing data from external sources.
On a daily basis during all phases of the study and for
up to 28 days, blinded personnel collect vital signs,
pertinent laboratory and imaging data, data to calculate
severity of illness, clinical events including surgery and
tracheostomy, duration and modes of mechanical
ventilation, cumulative daily doses of sedatives, analgesics,
antipsychotics, presence of shock requiring vasopressors,
and the administration of systemic steroids or paralytic
agents. We also collect disposition at discharge.
Sample size and feasibility
We determined criteria for feasible recruitment rates
based on prior research. A large trial of music in the
ICU had a recruitment rate of 33%, while delirium
studies have had recruitment rates close to 30% [
own recruitment experience at the institution where this
trial is being conducted suggests recruitment rates near
60%. Given a sample size of 60 participants, we will be
able estimate a recruitment rate of 60% to within a 95%
confidence interval of ± 12.40%. A recruitment rate of
48% would be lower than our institutional norm, but
remains higher than other similar trials.
Adherence to the intervention will be defined as the
percentage of audio sessions completed per patient (a
maximum of 14 sessions per patient at a rate of two
sessions per day for 7 days), adjusted for number of eligible
sessions based on length of stay in the ICU. Our sample
size of 60 participants will permit an estimate of the
adherence rate of 80% to within a 95% confidence interval
of ± 10.12%. We determined a retention rate of 80% for
feasibility, defined by the percentage of participants
completing all in-hospital components of the study,
which can be estimated with a similar confidence
interval. As a pilot study, we anticipate that a sample size of
60 participants will be sufficient to determine feasibility.
Our pilot study will help calculate sample size needed
for a definitive randomized controlled trial. A decrease
of 15% in delirium incidence between groups would
make a larger trial feasible, with a three-arm trial
requiring 548 participants (allowing 20% for attrition, α = 0.05,
power = 80%).
We will use chi-square tests to determine if study
retention rates differ across the three groups.
Adherence will be defined as the percentage of audio
sessions completed per patient, adjusted for number
of eligible sessions based on length of stay in the
ICU. Depending on the distribution of this outcome,
we will use either analysis of variance (ANOVA) (for
normally distributed data) or the Kruskal-Wallis test
(non-normal data) to determine if adherence differs
between the three study arms.
DDM is a feasibility trial for providing personalized and
non-personalized music interventions for critically ill,
mechanically ventilated patients. In our trial we also
estimate the preliminary efficacy of music interventions
on reducing delirium incidence and severity.
Our protocol builds on prior research as the anxiolytic
properties of music have been well documented [
Music interventions for hospitalized and non-hospitalized
patients have shown decreases in heart rate and blood
pressure, and were hypothesized to be a consequence of a
lower sympathetic drive [
]. Earlier studies have also
shown lower sedative doses for patients undergoing
procedures and utilizing preferred music listening . Prior
studies have been limited by methodological challenges,
including small sample size, lack of blinding, and
exclusion of the critically ill. The strengths of our protocol
include blinding of outcome assessors, twice daily
delirium assessments, as well as assessments of pain, anxiety,
and mobility milestones. Furthermore, our study benefits
from high external validity through inclusion of the ICU’s
Music listening has been shown to activate areas of
the brain involved with memory, cognitive function, and
]. By reducing brain dysfunction and
increasing activity in the areas related to memory, music
could help retain cognitive function, particularly in older
people who experience critical illness or injury. Extended
applications of our study could permit comparison of
neurocognitive outcomes between music and
attentioncontrol arms in future studies.
As a feasibility study, our protocol will enable us to
perform hypothesis testing, develop music algorithms,
and implement a music intervention protocol in a busy
ICU. The results of this study will inform the protocol
design of a larger study.
Enrollment is ongoing. Recruitment began in December
2016 and is expected to conclude in January 2018.
Target enrollment for the study is 60 participants. The
trial was retroactively registered at ClinicalTrials.gov.
Additional file 1: SPIRIT 2013 Checklist: recommended items to address
in a clinical trial protocol and related documents. (DOC 122 kb)
CAM-ICU: Confusion Assessment Method for the Intensive Care Unit;
DDM: Decreasing Delirium through Music; IQCODE: Information
Questionnaire on Cognitive Decline in the Elderly
We would like to thank Emily Behrens, the Regenstrief research team and
Eskenazi Hospital for their efforts in development of this protocol.
The DDM Trial is supported by Regenstrief Institute’s Innovations Grant.
Regenstrief Institute did not participate in the design of this study. SK is
supported by NHLBI 5T32HL091816-07.
Availability of data and materials
Data results from this feasibility study are unavailable at the time of publication.
Access to the final dataset will be retained with the study investigators.
Compensation for the trial, including harm, is not intended. Results of the trial are
intended for publication in a peer-reviewed journal, by the authors, and assistance
of professional writers is not expected. Results will be shared with participants of
the study by e-mail, and within our hospital system. Full access to the protocol or
participant-level dataset is available upon request.
Study concept and design: BK. Data acquisition: SK, SM, and AH. Data
analysis: AP. Drafting of manuscript: SK. Critical revision of the manuscript:
SW, MB, AH, LC, WT, and BK. Statistical analysis: AP. Obtained funding: BK.
Administrative support: AH. Study supervision: BK. All authors read and
approved the final manuscript.
Ethics approval and consent to participate
The DDM Trial received Indiana University’s Institutional Review Board
approval (IRB 1608887741A003).
For participants deemed eligible for enrollment, the patient and/or their
legal representative are approached for consent.
Consent for publication
Consent forms for the trial include consent for publication of results in
The authors declare that they have no competing interests.
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