medical tourism & health policy

8/18/2019 Medical Tourism & Health Policy

1/11

TheEffectsofMusic

Listeningon

InconsolableCryingin

PrematureInfants

G.Nityanandan


2/11

Background

Premature infants in the Neonatal Intensive care units (NICU) across England and much of the

developed world receive high end, highly technical care to ensure survival and healthy transition from

the neonatal phase into infancy. The complexity of many of these procedures use to aid the neonates inthe NICU may cause harm by acting as a stressor to the immature physiology of the neonates. For

example, it is a well-documented phenomenon that frequent touch assessments and invasive

interventions are a potential source of stress for the neonates.1

These stress inducing factors can lead to the decline in the stability of the neonate, thereby causing a

notable depression in vital signs. This will then lead to more interventions being performed to stabilise

the infant and this continues the vicious cycle of interventions that are potential stressors and the

resultant stress that neonates are exposed to. If vital signs continue to drop, (e.g. if the baby has poorer

oxygen saturation), insults to the delicate neurological makeup of the infants may occur – this leading

to a variety of problems for the infant – both long term and short term2.

Measures to improve and perhaps eradicate the negative effects of stress factors on the stability of

neonates need to be explored.3 This would mean that interventions can be provided in a structured and

safe manner in a way that it doesn’t have any negative impacts on the neonate.

The idea of Music therapy as a means to help stabilize the negative physiologic changes upon exposure

to stressors is not something that’s new to medicine. In adult medicine, Music Therapy has long been

touted as an effective way to enhance the healing process (example analgesia in a cancer patient). The

purpose of my paper is to uncover and assess the evidence that exists to back up the use of music therapy

in the NICU when performing procedures that may be a potential stressor for the neonates. (E.g.

Endotracheal Suctioning)

A key point to note is that this paper is only looking at music therapy as an adjunct during stress inducing procedures and phenomena. It’s not an attempt to examine the validity of Music Therapy as a treatment

in itself.

A premature infant undergoes a stark change in environment when transitioning from the mother into

the hospital environment. These neonates are subject to

Premature infants transition too early from the safety of the womb into the unprotected world of the

NICU environment. These neonates, with an immature neurological and vascular systems, are exposed

to a myriad of stimuli that can be found in any normal ward environment. Touching a baby to assess its

physical state is known to be a major cause of unfamiliar stress to the neonate. The average neonate in

the Intensive Care Unit is touched, examined and repositioned around 10 times in a given 3 hour period4.

1 Zahr LK, Balian S. Responses of premature infants to routine nursing interventions and noise in the NICU. Nurs

Res. 1995;44:179 –185. [PubMed] 2 Rees S, Harding R, Walker D. The biological basis of injury and neuroprotection in the fetal and neonatal

brain. Int J Dev Neurosci. 2011;29:551 –563. [PMC free article] [PubMed]

3 Kuhn P, Zores C, Pebayle T, et al. Infants born very preterm react to variations of the acoustic

environment in their incubator from a minimum signal-to-noise ratio threshold of 5 to 10 dBA. Pediatr

Res.2012;71:386 –392. [PubMed]

4 Zahr LK, Balian S. Responses of premature infants to routine nursing interventions and noise in the NICU. Nurs

Res. 1995;44:179 –185. [PubMed]

http://www.ncbi.nlm.nih.gov/pubmed/7761295http://www.ncbi.nlm.nih.gov/pubmed/7761295http://www.ncbi.nlm.nih.gov/pubmed/7761295http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168707/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168707/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168707/http://www.ncbi.nlm.nih.gov/pubmed/21527338http://www.ncbi.nlm.nih.gov/pubmed/21527338http://www.ncbi.nlm.nih.gov/pubmed/21527338http://www.ncbi.nlm.nih.gov/pubmed/22391640http://www.ncbi.nlm.nih.gov/pubmed/22391640http://www.ncbi.nlm.nih.gov/pubmed/22391640http://www.ncbi.nlm.nih.gov/pubmed/7761295http://www.ncbi.nlm.nih.gov/pubmed/7761295http://www.ncbi.nlm.nih.gov/pubmed/7761295http://www.ncbi.nlm.nih.gov/pubmed/7761295http://www.ncbi.nlm.nih.gov/pubmed/22391640http://www.ncbi.nlm.nih.gov/pubmed/21527338http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168707/http://www.ncbi.nlm.nih.gov/pubmed/7761295


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Each of these instances is a potential stressor for the neonate5. Each of these instances can adversely

affect oxygenation, blood flow, heart rate, and behavioural responses.6

In a quixotic world, it might be possible to eliminate all the sources of stress in an NICU. However, if

we were to temper that ideal with a bit of realism, we soon realise there are some non-essential stressors

that can be eradicated from our clinical environments. One of the chief stressors as far as neonates are

concerned is loud sounds or noise. This is indeed a modifiable factor that can not only be eradicated but

also modified to possibly deliver a therapeutic effect.

Enter Music Therapy. Music or sound therapy is the transmission of waveforms through the air,

subsequent reception and interpretation of these sounds or vibrations by our auditory system. The

structures in this system are formed in early foetal life.7 An extremely vital part of the auditory system,

the cochlea, is where the inner and outer hair cells develop. These then attach to spiral ganglion cells

that connect to the brainstem and the auditory cortex.8 An insult to the cochlea – be it ototoxic drugs or

loud noises is a concern in our NICUs.9 The American Association of Paediatrics recommends that

sound levels in NICUs should be kept under 45 dB10 the decibel level for common sound in the NICU

are listed in Table 1 below.

Table 111: Noise levels in the NICU

Quiet Room 47dB

Radio Switched On 53dB

Cardiorespiratory Alarm 78dB

Endotracheal Suctioning 63dB

Telephone Ringing 78dB

Cardiorespiratory Alarm (Inside Incubator) 52db

High Frequency Ventilation (Inside Incubator) 64db

At this point, it does seem rather counterintuitive to add additional sounds in the NICU Environment

given that we are already well above the recommended levels of 45 dB However, it’s still imperative

that we forge ahead and explore the viability and value of using such therapy by critically appraising

studies that have been conducted around this topic.

5 Aita M, Johnston C, Goulet C, Oberlander TF, Snider L. Intervention Minimizing Preterm Infants' Exposure to

NICU Light and Noise. Clin Nurs Res. 2012 [PubMed] 6 Wachman EM, Lahav A. The effects of noise on preterm infants in the NICU. Arch Dis Child Fetal Neonatal

Ed. 2011;96:F305 –F309. [PubMed] 7 Graven S, Browne JV. Auditory Development in the Fetus and Infant. Newborn Infant Nurs Rev.2008;8:187 –

193.8 McMahon E, Wintermark P, Lahav A. Auditory brain development in premature infants: the importance of early

experience. Ann N Y Acad Sci. 2012;1252:17 –24. [PubMed] 9 Hall JW., 3rd Development of the ear and hearing. J Perinatol. 2000;20:S12 –S20. [PubMed] 10 Noise: a hazard for the fetus and newborn. American Academy of Pediatrics. Committee on Environmental

Health. Pediatrics. 1997;100:724 –

727. [PubMed] 11 Thomas KA, Uran A. How the NICU environment sounds to a preterm infant: update. MCN Am J Matern Child

Nurs. 2007;32:250 –253. [PubMed]

http://www.ncbi.nlm.nih.gov/pubmed/23275433http://www.ncbi.nlm.nih.gov/pubmed/23275433http://www.ncbi.nlm.nih.gov/pubmed/23275433http://www.ncbi.nlm.nih.gov/pubmed/20547580http://www.ncbi.nlm.nih.gov/pubmed/20547580http://www.ncbi.nlm.nih.gov/pubmed/20547580http://www.ncbi.nlm.nih.gov/pubmed/22524335http://www.ncbi.nlm.nih.gov/pubmed/22524335http://www.ncbi.nlm.nih.gov/pubmed/22524335http://www.ncbi.nlm.nih.gov/pubmed/11190691http://www.ncbi.nlm.nih.gov/pubmed/11190691http://www.ncbi.nlm.nih.gov/pubmed/11190691http://www.ncbi.nlm.nih.gov/pubmed/9836852http://www.ncbi.nlm.nih.gov/pubmed/9836852http://www.ncbi.nlm.nih.gov/pubmed/9836852http://www.ncbi.nlm.nih.gov/pubmed/17667291http://www.ncbi.nlm.nih.gov/pubmed/17667291http://www.ncbi.nlm.nih.gov/pubmed/17667291http://www.ncbi.nlm.nih.gov/pubmed/17667291http://www.ncbi.nlm.nih.gov/pubmed/9836852http://www.ncbi.nlm.nih.gov/pubmed/11190691http://www.ncbi.nlm.nih.gov/pubmed/22524335http://www.ncbi.nlm.nih.gov/pubmed/20547580http://www.ncbi.nlm.nih.gov/pubmed/23275433


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Music Therapy

Music Therapy as the name suggest is the culmination of a method and objective. It refers to the

utilisation of Music – sounds that are placed into soothing/pleasing scales, rhythm, tempo and volume

to deliver treatment goals.12 This could range from combatting depression to stress reduction for the patient.

Before we begin our search into the specific evidence, I would like to mention a noteworthy article that

I found on the Neonatal Network Journal (Appendix 1). Standley13 found that music therapy increased

feeding which may have benefits on length of stay and growth of neonates. Also a survey of Finnish

Neonatal Nurses showed music could increase the feeling of security, improve sleep, decrease stress,

and reduce pain in premature infants.14 In another study, parents thought that music would decrease

stress, improve sleep, and decrease crying in their infant hospitalized in the NICU.15 Surveys of both

parents and nurses found that Music has a certain anti-stress factor that can be very useful when it comes

to treating neonates.

However, to better appreciate the validity of these studies, I had to do a literature review to find evidence

of improved clinical outcomes for neonates when they’re exposed to a stress inducing scenario (e.g.

Endotracheal Intubation/ Heel Lance) due to the inclusion of Music Therapy.

12 Stouffer JW, Shirk BJ, Polomano RC. Practice guidelines for music interventions with hospitalized pediatric

patients. J Pediatr Nurs. 2007;22:448 –456. [PubMed] 13 .Standley J. Music therapy research in the NICU: an updated meta-analysis. Neonatal Netw.2012;31:311 –

316. [PubMed] 14 Polkki T, Korhonen A, Laukkala H. Nurses' expectations of using music for premature infants in neonatal

intensive care unit. J Pediatr Nurs. 2012;27:e29 –

e37. [PubMed] 15 Polkki T, Korhonen A, Laukkala H. Expectations associated with the use of music in neonatal intensive care: a

survey from the viewpoint of parents. J Spec Pediatr Nurs. 2012;17:321 –328. [PubMed]

http://www.ncbi.nlm.nih.gov/pubmed/18036465http://www.ncbi.nlm.nih.gov/pubmed/18036465http://www.ncbi.nlm.nih.gov/pubmed/18036465http://www.ncbi.nlm.nih.gov/pubmed/22908052http://www.ncbi.nlm.nih.gov/pubmed/22908052http://www.ncbi.nlm.nih.gov/pubmed/22908052http://www.ncbi.nlm.nih.gov/pubmed/22703690http://www.ncbi.nlm.nih.gov/pubmed/22703690http://www.ncbi.nlm.nih.gov/pubmed/22703690http://www.ncbi.nlm.nih.gov/pubmed/23009044http://www.ncbi.nlm.nih.gov/pubmed/23009044http://www.ncbi.nlm.nih.gov/pubmed/23009044http://www.ncbi.nlm.nih.gov/pubmed/23009044http://www.ncbi.nlm.nih.gov/pubmed/22703690http://www.ncbi.nlm.nih.gov/pubmed/22908052http://www.ncbi.nlm.nih.gov/pubmed/18036465


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Method

In order to give my search a more focussed direction and hone in on the most relevant resources, I

utilised the PICO (Population, Intervention, Control/Comparison, and Outcome) structure to create

terms for my database search. The terms that I used can be found in Table 2 below.

Table 2: Search terms for PICO

Definition Search Terms Used

Population Preterm Babies (


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Chosen Study

The search returned 4 studies that matched my inclusion and exclusion criteria. Unfortunately, 4 of the

studies had to be excluded after further review because of multiple, unclear methods. The ambiguity

did not allow for adequate interruption of the reported results and thus was not included in the review.

I chose the study by Keith, Russel, and Weaver 16 (Appendix 2) to be the most credible and valuable for

the reasons I shall discuss below. This essay aims to critically appraise this paper for its validity and its

applicability in the clinical setting in the NHS.

Journal Impact Factor (JCR)

The study and the results obtained have been published in the Journal of Music Therapy. As biased as

the name sounds, I found that this journal has been awarded a Journal Impact Factor of 0.80. This may

seem paltry when compared with the New England Journal of Medicine which has the highest impact

factor of 54.42. However, it must be noted that this is a journal that has a specific niche. It’s also worth

noting that a high JCR does not imply that all articles in that Journal are valid vice versa.We shall delve deeper into the characteristics of the studies to obtain a better picture of its credibility.

Title

The Title “The Effects of Music Listening on Inconsolable Crying in Premature Infants” is concise and

informative. Terms such as Inconsolable, Crying and Music are attention grabbing and give the reader

a clear picture of the clinical question.

Authors

One of the authors, Dr.Douglas R. Keith has a PhD in Music Therapy and is a practising Music Therapist

certified by the CBMT (Certification Board of Music Therapists). Co-author, Dr Kendra Russell has a

PhD in Nursing from Georgia State University. Co-author, Ms Barbara S. Weaver is a registered nurse.

Introduction

The study starts off by giving a good summary of the existing research that has been done. In paragraph

2 of the introduction, the author mention other studies that were conducted earlier (E.g. Evans,

Vogelpohl, Bourguignon, & Morcott, 1997). The literature that they have referenced clearly outlines

the pain associated behaviours that an infant can produce when exposed to a stressor.

Within the introduction the authors give a good summary about what is already known about the topic

area. In addition to that, they also justify the need for soothing infants by citing 2 studies (Ohgi,

Akiyama, Arisawa, & Shigemori, 2004) & ((Papou~ek & yon Hofacker, 1998) which show that

increased stress levels in an infant not only cause the infant to cry more but also negatively affect the

parent-infant bond and can lead to parents feeling inadequate or unable to soothe their children – a

common causal factor for Postnatal Depression amongst mothers.

Aims & Objectives

Upon reading the well-researched introduction, one might be inclined to question the necessity of

another study since all the evidence seems to already exist. In the concluding paragraph of the

Introduction, the authors mention that all the existing research into music therapy has either been

prophylactic or proactive. That is, there is no readily available research on the effectiveness of

16 Keith DR, Russell K, Weaver BS. The effects of music listening on inconsolable crying in premature infants. J

Music Ther. 2009;46:191 –203. [PubMed]

http://www.ncbi.nlm.nih.gov/pubmed/19757875http://www.ncbi.nlm.nih.gov/pubmed/19757875http://www.ncbi.nlm.nih.gov/pubmed/19757875http://www.ncbi.nlm.nih.gov/pubmed/19757875


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exposing infants in an acute state of distress to Music Therapy. To put it simply, in all previous studies

music was played either before a stressful event or immediately after a perceived stressful event –

regardless of whether the infant cries or not. This study only exposes infants to music therapy during

such acute crying episodes.

The a priori hypothesis is also clearly stated at the end of the Introduction.

“We hypothesized that providing a music intervention would lead to shorter and less frequent episodes

of inconsolable crying among these patients, and improved heart rate, respiration rate, oxygen

saturation, and mean arterial pressure.”

The secondary research question in this study addressed the effects of the music intervention on

physiological measures. The analysis compared the physiological data (respiration rate, heart rate,

oxygen saturation level and mean arterial pressure) taken from the infants when they attained

"inconsolable" status and when they stopped crying.

Subgroup Analysis

The Study is designed and powered to answer many clinical outcomes. (Inconsolable Crying, ImprovedHeart Rate etc.) The danger that is imminent in doing many subgroup analyses in one study is that the

authors are open to be accused of Data Dredging. Data Dredging is when more than one subgroup of

outcomes is examined and only the positive results are reported. In the context of this study, it’s worth

noting that instead of focussing on one clinical outcome, the authors have 5 different outcomes that are

being examined. However, I think this factor can be overlooked at this point as the authors have already

established, with the help of previous research that all these factors are noticeable stress responses. As

such it can be said that they’re only looking for one clinical outcome – the reduction of stress. A bit

more clarity about this in the introduction would offer one solace that the credibility of the study is

untainted.

ConfoundersThe study at hand does not seem to address the issue of confounding. It might have been better if the

authors accepted that confounding may be an issue – in that the exposure to musical therapy may not

actually cause the improved clinical outcome. I see this perhaps as an issue that exists due to the main

author’s background as a music therapist. There is an assumption that the reader shares a similar belief

in the efficacy of music therapy.

Selection Bias

A paper is said to have selection bias when the choice of the population distorts the exposure outcome

relationship from that present in the target population. In the paper concerned, our ultimate target

population is infants in the NICU. However, the stringent exclusion criteria that have been put in place

by the researchers, means only babies in close to perfect health would be allowed to participate in the

study. This is not representative of the general patient populace that one would finds in the NICU.

Under the heading “Sample”, in the 2nd paragraph, the researchers clearly say that

“Several exclusion criteria were in place, babies known to be in pain, or receiving pain medication or

anxiolytic drugs were excluded. Related to this, babies known to be in withdrawal or having a history

of withdrawal from drugs, and those known to have a chromosomal abnormality, were excluded. No

infants in this study were mechanically ventilated, and none were being fed by mouth (NPO status).”

The exclusion criteria that have been put into place severely restricts the sample size for the study. As

such, the applicability of the findings may be affected. Given that the study focusses on babies in the

NICU, it’s rather short-sighted for the study to exclude “babies receiving pain medication, babies with

a chromosomal abnormality etc.”


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Study Design

The researchers used a repeated measures design to test the a priori hypothesis. The studies were

conducted in a longitudinal fashion, in that they dealt with a group of subjects, regularly over days and

took snapshots of the groups in different times. Since the babies were randomly assigned into music

and non-music therapy groups, there is a possibility that we can overlook selection bias within the study

itself – despite the exclusion criteria which severely cause a bias in recruitment to this study.

Sample Selection

The sample selection process is clearly outlined by the researchers. Despite having a small sample size

which could greatly affect the applicability of the results, the researchers have endeavoured to reason

this small sample size by referencing previous studies done by Standley et al.

The sampling method used by the researchers is known as convenience sampling. They simply selected

infants as they appeared and allowing the parents of said infants to choose if they would like to be

included in the sample or not.

While convenience sampling is relatively easy in terms of the actual process, it can be potentiallydangerous as good results can be obtained but just as often, the data set can be seriously biased.

Randomisation

The researchers have adopted an Adaptive randomisation approach in the study. This means that they

set out with a certain number of infants (n=24) however, as time wore on 2 of the infants dropped out

of the study and they chose to neglect the data that was randomly obtained from this two infants.

Results

The study used a repeated measures design. The study included 24 infants who were between 32 and

40 weeks gestational age. These infants did not respond to nursing interventions to alleviate crying

episodes. A crying episode was only considered to if it was at least 5 minutes long. Each infant was

exposed to the music condition after 5 minutes of crying when other nursing interventions (e.g.,

swaddling) were unsuccessful in arresting the crying episode.

Lullabies were played at below 70 dB for the infants. Heart rate, respiratory rate, oxygen saturation,

length of crying episodes throughout the day, and number of crying episodes throughout the day were

recorded.

The results indicated that the number of crying episodes was significantly less on days when the music

condition was provided. The duration of the crying episodes on the days with the music condition was

also significantly less than the no music days. On music condition days, heart rate and respiratory rate

decreased following the music intervention and oxygen saturation also increased. The days with nomusic showed no statistically significant differences in physiologic stability.

These results suggest that a music intervention may be useful when infants are inconsolable and other

nursing interventions have failed to pacify the distress infant.


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Analysis of Results

The results from the study has indeed identified promising results. However, the results must be

interpreted with caution.

Sample Size

The study was conducted on a small scale and only included 24 heterogeneous infants in a particular

hospital in the United States. The small sample size does raise the question of applicability of the results

of this study. While the small scale study does offer promise in terms of the viability of music therapy

more research needs to be done before we can implement a change in practice on wards.

Sound Levels

The American Association of paediatrics recommends that infants should not be exposed to sound levels

in excess of 45 decibels. However, in this study, infants were exposed to lullabies as loud as 70 decibels.

The impact of crossing the safe sound levels established by the AAP was not mentioned in the study.

Perhaps, it would have been useful if the researchers had followed up with some of the infants after the

study to assess if there are any adverse effects of exposing infants to such high levels of sound.

Tolerance to Intervention

The authors also fail to mention if all the infants tolerated the musical intervention. While the objective

of this study was to assess the effectiveness of music therapy in soothing inconsolable infants, it is also

important to look at the other end of the spectrum.

The study should have mentioned if all the infants exposed to the music intervention tolerated it or if

there were some infants who exhibited signs of stress (intolerance to intervention) when the music was

played.

This information will also aid in judging the universal applicability of this study. “Is music intervention

applicable for all infants or does it have a negative impact on some?”


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Statistical Analysis

Table 3 – Results of the study.

Without musicintervention

With musicintervention

Percentage decrease/%

No. of crying episodes

per day

7.21 4.29 40.5

Average duration of

crying episodes/min

23.14 5.53 76.1

The statistical analysis for the study involved comparing the effect of the intervention by taking the

average crying time for all infants over a specified period of time. As we can see in table 3, it is clear

that music intervention is a suitable intervention in soothing inconsolable infants. Music intervention

reduced the number of crying episodes by 40.5% and reduced the average duration of those episodes

by 76.1%.

The P value for this study is


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References

1. Zahr LK, Balian S. Responses of premature infants to routine nursing interventions and noise

in the NICU. Nurs Res. 1995;44:179 – 185. [PubMed]

2.

Rees S, Harding R, Walker D. The biological basis of injury and neuroprotection in the fetaland neonatal brain. Int J Dev Neurosci. 2011;29:551 – 563. [PMC free article] [PubMed]

3. Kuhn P, Zores C, Pebayle T, et al. Infants born very preterm react to variations of the acoustic

environment in their incubator from a minimum signal-to-noise ratio threshold of 5 to 10 dBA.

Pediatr Res.2012;71:386 – 392. [PubMed]

4. Zahr LK, Balian S. Responses of premature infants to routine nursing interventions and noise

in the NICU. Nurs Res. 1995;44:179 – 185. [PubMed]

5. Aita M, Johnston C, Goulet C, Oberlander TF, Snider L. Intervention Minimizing Preterm

Infants' Exposure to NICU Light and Noise. Clin Nurs Res. 2012 [PubMed]

6. Wachman EM, Lahav A. The effects of noise on preterm infants in the NICU. Arch Dis Child

Fetal Neonatal Ed. 2011;96:F305 – F309. [PubMed]

7.

Graven S, Browne JV. Auditory Development in the Fetus and Infant. Newborn Infant NursRev.2008;8:187 – 193.

8. McMahon E, Wintermark P, Lahav A. Auditory brain development in premature infants: the

importance of early experience. Ann N Y Acad Sci. 2012;1252:17 – 24. [PubMed]

9. Hall JW., 3rd Development of the ear and hearing. J Perinatol. 2000;20:S12 – S20. [PubMed]

10. Noise: a hazard for the fetus and newborn. American Academy of Pediatrics. Committee on

Environmental Health. Pediatrics. 1997;100:724 – 727. [PubMed]

11. Thomas KA, Uran A. How the NICU environment sounds to a preterm infant: update. MCN

Am J Matern Child Nurs. 2007;32:250 – 253. [PubMed]

12. Stouffer JW, Shirk BJ, Polomano RC. Practice guidelines for music interventions with

hospitalized pediatric patients. J Pediatr Nurs. 2007;22:448 – 456. [PubMed]

13.

Standley J. Music therapy research in the NICU: an updated meta-analysis. Neonatal

Netw.2012;31:311 – 316. [PubMed]

14. Polkki T, Korhonen A, Laukkala H. Nurses' expectations of using music for premature infants

in neonatal intensive care unit. J Pediatr Nurs. 2012;27:e29 – e37. [PubMed]

15. Polkki T, Korhonen A, Laukkala H. Expectations associated with the use of music in neonatal

intensive care: a survey from the viewpoint of parents. J Spec Pediatr Nurs. 2012;17:321 – 328.

[PubMed]

16. Keith DR, Russell K, Weaver BS. The effects of music listening on inconsolable crying in

premature infants. J Music Ther. 2009;46:191 – 203. [PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/19757875http://www.ncbi.nlm.nih.gov/pubmed/19757875http://www.ncbi.nlm.nih.gov/pubmed/19757875http://www.ncbi.nlm.nih.gov/pubmed/19757875

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