EFTA02695993

Music and Medicine v, hit :epub.cor Effects of Music on Physiological and Behavioral Indices of Acute Pain and Stress in Premature Infant; Clinical Trial and Literature Review Mark Jude Tramo, Miriam Lense, Caitlin Van Ness, Jerome Kagan, Margaret Doyle Settle and Jonathan H. Cronin Music and Medicine 2011 3: 72 DOI: 10.1177/1943862111400613 The online version of this article can be found at: http://mmd.sagepub.com/content/3/2/72 Published by: OSAGE hun wwww sancin:• :)n5 corn On behalf of: I 1\I \ I International Association for Music and Medicine Additional services and information for Music and Medicine can be found at: Email Alerts: 1p://mmd.sagepub.cornrcgiralerts Subscriptions: .m://mmd.Sagepub.comrsubscriptionS Reprints: hIlpliwww.sagepub.comtpumalsReprints.nav Permissions: http://www.sagepub.comfjoumalsPermissions.nav EFTA_R1_02048096 EFTA02695993 Armies Effects of Music on Physiological and Behavioral Indices of Acute Pain and Stress in Premature Infants: Clinical Trial and Literature Review Mark Jude Tramo, MD, PhD", Miriam Lense, MSI '2'4, Caitlin Van Ness, MSTI '2, Jerome Kagan, PhD25, Margaret Doyle Settle, RNC, MSN", and Jonathan H. Cronin, MD6 Mean and Modem* 3(2) 72-83 {LL The Author(s) 2011 Rennet' and perm anon uplink tonepuonalsPermtssions nay OOt. 10.1177:1943862111400613 InenEmmidtagepub corn ®SAGE Abstract Infants in intensive care units often undergo medically necessary heel-stick procedures. Because the risks of administering analgesics and anesthetics are often thought to outweigh the benefits, there remain no proven means of ameliorating the pain and stress these infants suffer, particularly during procedures. This study examined the controlled use of recorded vocal music to attenuate physiological and behavioral responses to heel stick In 13 premature infants via an experimental design. In both instances, infants exposed to music and infants in the control group, heart rate, and respiration rate increased during the heel-stick procedure (P's — .02) and nearly all infants cried. During a 10-minute recovery following the heel stick, heart rate, and crying significantly decreased in infants exposed to music (P = .02) but not in unexposed infants. Controlled music stimulation appears to be a safe and effective way to ameliorate pain and stress in premature infants following heel sticks. Keywords NICU music, infant, heart rate, pain, heel suck, premature Introduction Ample empirical evidence indicates that music stimulates cognitive, emotional, and sensoritnotor processing across widely distributed brain regions.I.2 The strong physiological and emo- tional effects of music on many listeners" and the wealth of qua- litative and quantitative findings provided by music therapy"' motivate the development of standardized protocols for the use of music in a wide range of clinical settings. Prospective, randomized-controlled clinical trials are needed in order to eluci- date how music's effects can be harnessed to ameliorate suffering and, possibly, decrease morbidity and mortality independent of, and additive to, benefits related to therapist skills." Two recent Cochrane Database reviews have examined the use of music for pain relier and end-of-life care." Neonates, especially premature infants, constitute a needy population of patients who might benefit from the implementa- tion of standardized protocols incorporating music for analge- sia, stress reduction, and auditory enrichment." 1'13 The human cochlea is anatomically developed by 24 weeks gestational age.14 and auditory evoked responses have been recorded in premature infants as early as 26 weeks gestational age. I5.16 The results of many recent studies of the fetus and infant are consis- tent with the notion that perceptual competence develops prenatally.'" Fetuses from 27 to 35 weeks gestational age demonstrate behavioral habituation to auditory stimuli." Heart rate (HR) changes in response to music have been observed in fetuses of 28 to 38 weeks gestational age.20 Functional Magnetic Resonance Imaging (fMRI) studies indicate left tem- poral lobe activation to sound in fetuses at 33 weeks gestational age.2' Newborns demonstrate ERP sensitivity to 10% devia- tions in tonal frequency.22 Approximately, 12% of the US births are premature (ie, before 37 weeks)23; about half of these require immediate hospital admission and many need long- term care. Neurological complications of premature birth include learning disorders in as many as 2 in 5 school-age I The Institute for Musk & Brain Science, Health & Medicine Program, Boston, MA, USA Harvard University Mind/Brain/Behavior Initiative. Cambridge. MA, USA 'Departments of Neurology and of Ethnomusicology. David Geffen School of Medicine & Herb Alpert School of Music, UCLA, Westwood, CA. USA 4 Vanderbilt Kennedy Center. Vanderbilt University. Nashville. TN, USA 'Department of Psychology. Harvard University. Cambridge. MA. USA Newborn Intensive Care Unit, Massachusetts General Hospital, Boston. MA. USA Corresponding Author: Miriam Lense. Department of Psychology. Vanderbilt University. Peabody Box PO. 230 Appleton Place, Nashville, TN 37203 Email: mlense©postharvard.edu ecemrdre Prom • , ro uaa. try Mint pro 0, Lint N. 20 EFTA_R1_02048097 EFTA02695994 Tram° et al 73 children,24 a 2.6 relative risk for attention deficit hyperactivity disorder (ADHD),25 and a significant risk of hypothalamic- pituitary dysfunction.36 Developmentally, sensitive care that incorporates noise management as well as human contact and other "positive" stimuli appear to improve clinical outcome and decrease costs associated with inpatient care for prema- ture infants.22-32 The acoustic environment in which many premature infants spend their first days-to-months of life—hospital neonatal intensive care units (NICUs) and special care units (SCUs)— is at once impoverished and chaotic.33 Whether lying in a bas- sinet or enclosed in a temperature-controlled isolette on mechanical-assisted ventilation, hospitalized infants arc exposed to little in the way of speech, music, and other etholo- gically relevant sounds important for normal language and social development. Even worse, the sound environment is filled with unpredictable, sometimes loud acoustic stimuli (eg, alarms indicating a potentially dangerous change in a phy- siological measure)." The ambient sound level in an NICU can reach intensities as high as 90 dB SPL, several-fold louder than the ambient intrauterine intensities the infant had been accus- tomed to (50 dB SPL).35.36 Moreover, NICU sounds contain high as well as low frequencies, whereas the intrauterine envi- ronment only allows low-frequency sounds (less than 250 Hz) to reach the infant. Infants born before 36 weeks may be espe- cially sensitive, and thus vulnerable, to the effects of an impo- verished, chaotic auditory environment because their auditory discrimination capabilities are immamrc,37 and they remain unable to visually identify the sources of sound and have lim- ited exposure to faces and visual scenes in general. The infant's heightened auditory sensitivity requires that physicians and nurses determine the type, dose, and dose interval of acoustic stimuli empirically. What the optimal auditory conditions are, and how they could be provided in the NICU environment, remain unknown. The American Academy of Pediatrics" and the National Association of Neonatal Nurses" have proposed a number of procedural and technical strategies to reduce ambi- ent noise. One study of 30 premature infants showed that wear- ing earmuffs significantly increased quiet sleep timeo Another study of 24 very low birthweight neonates found that wearing silicone earplugs significantly increased weight gain:" However, there remains the possibility that quiet is sub- optimal because stimulation with music or other natural sounds would promote development while avoiding the potential dele- terious consequences of decreasing auditory and multimodal stimulation (for reviews see Philbin42 and Aucott et al43). Sev- eral researchers have explored the potential benefits of auditory stimulation with music in the NICU environment."'" In their recent review, Hartling et a15 found that the researchers have used a variety of musical types (eg, vocal vs instrumental, folk vs classical), presentation methods (recorded vs live), and acoustic environments (eg, music alone vs with intrauterine sounds) in the NICU.5 Methodological consideration, as the authors point out, preclude a straight forward interpretation of how the type of music and its presentation affect physiologi- cal and behavioral responses. Auditory stimulation, controlled with respect to music type, intensity, presentation, dose, and dose-interval, could counter the effects on unpredictable noise in the NICU environment and promote normal auditory and cognitive development via exposure to the language and music of the infant's culture. Acutely painful stimuli typically cause increases in HR, respiration rate, blood pressure, plasma cortisol levels, facial grimacing, crying and body movements, and decreases in oxy- gen saturation (O2-sap:I?" These responses, which could reflect an internal state of stress, can be difficult to appreciate in the most vulnerable premature infants because their imma- ture central nervous system precludes their ability to generate all the components of a stress response.67•4R Even routine pro- cedures administered to hospitalized infants have been shown to elicit a stress response:It" A recent study of 430 infants admitted to NICUs in Paris found that on average, each infant received 12 painful procedures daily during their first 2 weeks in the NICU 51 In another study, 54 infants admitted to a NICU over a 3-month period experienced 3283 invasive pro- cedures.52 The majority (56%) involved the "heel-stick" (aka "heel lance," "heel prick") procedure, a painful method of obtaining blood for serologic analyses in which the infant's heel is pierced with a sterile needle and squeezed repeatedly to express blood through the puncture site. The high meta- bolic demands of these repeated stressors could decrease energy stores available for growth. Moreover, adrenocortical responses to repeated stressful stimuli might weaken the infant's immune system and increase the risk of illness."'" Grunau53 has hypothesized that infants who receive frequent medical interventions without "positive" or soothing stimuli may develop a low pain threshold or become hypersensitive to touch. Recent evidence shows that 3- to 18-month preterm babies have abnormal basal cortisol levelsS6 and that 4- month-old infants have abnormal cortisol responses during pain associated with immunizations.S7 Abnormal cortisol lev- els may be one mechanism by which early pain exposure could compromise brain development.55 This, in turn, could contribute to learning, attentional, and behavioral problems later in childhood." Although infants undergo many painful procedures and may perceive pain more acutely than do adults, pain management for this population is less than optimal 51.594' There is wide variation in the use of pharmacological analgesics in N1CUs,62 which increase fluid retention and bilirubin levels and routinely raise concerns about CNS depressant effects, including respira- tory depression. Standardized protocols for nonpharmacologi- cal analgesia are lacking, and NICU personnel may not be adequately trained in pain assessment, management, and pre- vention.63 A better understanding of nonpharmacological treat- ments is needed to advance the development of protocols to alleviate pain and stress without the risks of potential medica- tion side efects.33 As a noninvasive, analgesic, and anxiolytic intervention, controlled auditory stimulation with music may provide a treatment with a high benefit:risk ratio. The present study tests the hypothesis that music attenuates physiological and behavioral responses to heel stick. inewooded 7.16-1,1t. by Mae. 'WU, MM, n 20" EFTA_R 1_02048098 EFTA02695995 74 Music and Medicine 3(2) Table I. Age, Sex. Weight, and Apgar Scores of Participants Infant Sex Age (days) Birth weight (g) GA at birth (weeks: days) al Apgar 5 m Apgar IC Male 28 1200 30:6 2C Male 28 1260 30:6 7 8 3C Male 4 1790 340 8 9 5C Male 4 2305 34:3 8 9 6C Female 1780 34:0 8 9 7C Female 1 I 1900 31:5 7 7 IT Male 16 1960 32:4 5 9 2T Male 35 1260 30:6 7 8 3T Female 4 2195 34:0 8 9 41 Female 4 2160 34:0 7 8 5T Female 4 2175 34:3 4 9 61 Male 2600 34:0 9 9 7T Male I0 1800 32:4 8 8 Abbreviations: C. control: T. treatment Methods The study protocol was approved by the Institutional Review Boards of the hospital and university where the study was conducted. Participants All participants were premature infants in the hospital SCU. All admission logs and medical charts were reviewed soon after patients were admitted to the unit. We identified infants who met the following selection criteria for inclusion: (I) gesta- tional age less than 36 weeks and birth weight no more than 2600 g, (2) not on a ventilator or receiving oxygen inhalation therapy for respiratory illness, and (3) no neurological disease. Individual cases were reviewed with nurses caring for each infant. Parents/guardians received a recruitment letter detailing the study; they were given one week to decide about participa- tion and were offered a video of their infant on DVD as a reward for participation at the conclusion of the study. Par- ents/guardians and nurses were instructed not to play music to the infant from the time of enrollment to the experimental procedure. Written consent was obtained from the parents of 14 infants. Participants were pseudorandomized into the treatment group (N = 7 [4 males]) and control group (N =7 [5 males]) irrespec- tive of sex and ethnicity. In total, 6 participants were from 3 fraternal twin pairs and 2 participants were from fraternal triplets; in these cases, one sibling was assigned to the treat- ment group and the other to the control group. Data for one male infant in the Control Group were excluded from the anal- ysis because of a protocol violation: a parent played recorded music to him several hours a day. Each infant was tested indi- vidually in her/his isolette. The age, sex, birthweight, gestational age, and Apgar scores of each participant are listed in Table I. The median gestational age for the control group was 33 weeks, one day; for the Treatment Group, the median gestational age was 34 weeks. The median postdelivery age at the time of study was 7.5 days for the control group and 4 days for the treatment group. All infants had 5-minute Apgar scores of 7 or greater. There were no significant differences between groups for any of these background variables. The parents of all infants were English-speaking. Special Care Unit Environment and Routine Care All infants were admitted to the SCU under the care of an attending perinatologist, pediatrician, or nurse practitioner. Infants were housed in closed or open isolettes. The standard SCU protocol called for serologic testing every Sunday night or Monday morning. Heel sticks typically occurred between the hours of 9 and 11 PM or between 4 and 6 am, just before night time or morning feeding, respectively. Standard approaches to developmentally sensitive care were implemen- ted throughout the infants' SCU stays (eg, swaddling, covering incubators to limit bright light exposure, limiting loud conversation). We measured the ambient sound level in the SCU on multi- ple occasions. A Quest Technologies Impulse Sound Level Meter Model 2700 was held at the head of an empty, open isol- ette. During daytime hours, the ambient sound level was approximately 62 dBA; at night, 56 dBA. Auditory Stimulation We listened to several commercially available CDs of lullabies sung by females in English. We selected one (SRT Music Groups') in which the lullabies were performed with simple accompaniment at moderate tempo. For each patient, the total music stimulation time was 10 minutes. We avoided starting the music shortly before and during the heel stick because we did not want the patient to asso- ciate music with the painful stimulus. We used a 10-minute window of observation because this provided a sufficient time window for normalization or near-nonnalization of pain- induced changes in outcome variables. 000M040•0 Own nnvi tatrp.b by IAA Tivamo as MO* 2S. EFTA_R 1 _02 04 8 099 EFTA02695996 Tramo et al 75 Recordings of 3 complete songs and part of a 4th were pre- sented in the 10-minute music stimulation window: (I) "Row Row Row Your Boat" (duration = 3 minutes, 9 seconds), (2) "Baa Baa Black Sheep" (3:00), (3) "Are You Sleeping" (2:23). and (4) the first 1:28 of "Rock a Bye Baby" (original song length of 3:06). Each song began with a short instrumental introduction (range = 6-26 seconds) followed by a sung mel- ody whose pitches ranged from E3 to C59 on the equal- tempered scale (fundamental frequencies = 164.8-554.4)Iz, A4 = 440 Hz) and a moderate tempo of 84 to 88 beats per min- ute in 4/4 or 3/4 meter. Each recording contained only 3 to 4 instrumental voices with timbres varying among electric piano, electric organ, glockenspiel, and synthetic sounds. We chose traditional Western lullabies sung in English by a female because we thought they would have the highest probability of achieving a beneficial effect for our Western, English-speaking population, and because a female voice (ie, mother's voice) is the one most frequently heard prenatally in the womb. More- over, lullabies include both music and speech sounds, have cross-cultural significance in parent-infant communication, and have been shown to improve longer-term endpoints, such as weight gain in hospitalized infants.65 Each CD track was converted to a monophonic mp3 file and uploaded onto an Apple iPod. Stimuli were presented at an intensity of approximately 70 dBA using one JBL Duet speaker placed in the sagittal midline at the foot of the infant's isolette, approximately 50 cm from her/his head, outside the field of the heel-stick procedure. The advantages of using a sin- gle speaker playing a monophonic recording (less space, fewer wires) outweighed the advantages of using 2 speakers playing a stereo recording, in our opinion, because we did not hypothe- size that this difference in the spatial mix of the music would influence the results. The iPod was placed on a small dock at the bedside. Physiological Responses For each infant, HR, respiratory rate (RR), and O2-sat were continuously monitored before, during, and after the heel- stick procedure using a GE Medical Clinical Information Center Pro system. During 1 to 2 minutes before the heel- stick procedure, throughout the procedure. and during the first 4 minutes postprocedure, a trained observer (ML or CV) recorded at least 4 measurements of each of the 3 dependent variables per minute. At the beginning of the study, data were recorded every IS seconds online in real time by reading the output of the HR, RR, and Orsat monitors. About halfway through the study, we were able to analyze the output of the monitors offline, which recorded data every 2 seconds, after data collection was finished. Finally, during the last half of the post heel stick epoch, data were sampled at 3 points: 5, 7, and 10 minutes postprocedure. For the purpose of population data analyses, data collected preprocedure, during the procedure, and ≤4 minutes postprocedure were calculated using a bin width of 15 seconds. We checked that there were no significant differences between the means calculated from 15 seconds sample points and 2 seconds sample points for each dependent variable. Behavioral Responses Behavioral responses were recorded before, during, and after the heel-stick procedure with a Samsung SCD-23 digital video camera. At the start of the procedure, the camera was mounted on a tripod at the foot of the isolette; after the nurse completed the heel-stick procedure, the camera was moved closer to the infant alongside of the isolette. Digital videos were converted to QuickTime movie files for offline analysis. We initially aimed to code whether or not each of the following behaviors occurred before, during, and after the heel-stick procedure: (I) eye-opening, (2) head movements, and (3) crying. How- ever, we were unable to reliably code eye-opening and head movements. Behavioral data could not be collected during blood collection for 3 babies because the nurse blocked the camera's view; in general, reswaddling of infants following heel stick compromised the observations of changes in beha- vior. Behavioral data from one infant was lost due to equipment malfunction. Experimental Procedure Figure I depicts the timeline of the heel-stick procedure, audi- tory stimulation (for the treatment group), and data collection. The heel-stick procedure was performed by Registered Nurses caring for the SCU patients. Stimuli were presented and data collected by I of the 2 investigators (ML or CV). who were trained in experimental psychology, acoustic calibration, and music. First, with the infant at rest, undisturbed in her/his isolette, we recorded baseline HR, RR, and O2-sat data and started the video. Second, during the prepuncturc handling period, a nurse prepared the infant's heel with a warm pad followed by an alco- hol swab. There were differences among nurses with respect to preparation routine and pre and post heel-stick swaddling. In all. 2 infants in the control group and 2 in the treatment group were swaddled at baseline and remained so throughout the heel-stick procedure and recovery period. One infant in the control group and 2 in the treatment group were not swaddled at baseline and remained unswaddled throughout the heel-stick procedure and recovery period. One infant in the Control Group was swaddled at baseline, unswaddled during handling and blood collection, and remained unswaddled during the recovery period. One infant in the control group was not swaddled at baseline, remained unswaddled during handling and blood collection, and then swaddled during postpuncture handling and the recovery period. A total of 3 infants in the treatment group were swaddled at baseline, unswaddled during handling and blood collection, and reswaddled during post- puncture handling and the recovery period. Four infants in the control group and 4 in the treatment group were given a pacifier during prepuncturc handling; 2 of the pacifiers given to the control group and all 4 given to the treatment were sweetened 000M00000 Mom vro :cut. •.• by M0t limo 4:a~ 05. 2011 E FTA_Ri _02048100 EFTA02695997 76 Music and Medicine 3(2) BASELINE infant at rest in isolate: clan data collection HANDLING Iscel.mek prcparation: unswaddliag, IrJ warmer, alcohol swabbing BLOOD COLLECTION erase punctures skin of heel with blade, squeezes heel to express blood L HANDLING RECOVERY lied lance instruments removed infant undisturbed and from isolate. tem.:addling at nal in InOICHC min Intedian 655) I -I2 min (median62s) 2.15 Min (median 270s) 20s-2min (median 43s) In min Wormer Ike lied is AI sic begins Music ends in place puncture bandaged eatment (Ttratmein ;tour) (Troup) F sure I. Experimental procedure. with sucrose. Blood collection began with the nurse puncturing the skin of the prepped heel using a sterile, spring-loaded blade; squeezing of the heel to collect blood into a tube followed. Fol- lowing blood collection and subsequent handling, including bandaging of the puncture site, the infants in the treatment group were stimulated with music for 10 minutes. Statistical Analysis After collecting data from 13 infants over 8 months, we examined our data using nonparametric statistics (Wilcoxon Signed-Rank Test) to compare the physiological-dependent variables before, during, and following the heel-stick procedure. Persistence or cessation of crying from the heel-slick to the recovery period was compared between the treatment and control groups using Pearson x 2 test. Given that we had tested our working hypothesis at this juncture. we ceased enrollment of additional infants. Results Physiological Results Figure 2A-C illustrates HR, RR. and O2-sat population data, respectively, collected before and during heel stick and blood collection. There was a significant increase in HR from base- line to blood collection (Wilcoxon Signed-Rank Test [WSRT], Z = —2.36, P = .02); on average. HR increased 19%. All infants showed an HR increase of at least 5 beats per minute (bpm); in 8 (62%), HR went above normal limits (>160 bpm). There was no significant increase in HR coefficient of variation (CV) across the 2 epochs (WSRT. Z = —0.53, P = .60). There was a significant increase in RR from baseline to blood collection (WSRT, Z = —2.24, P = .02]; on average, RR increased 39%. All infants showed an increase of at least 5 inspirations per minute (ipm); in 10 (77%), RR went above 40 ipm. There was also a significant increase in RR CV (WSRT Z = —2.37, P =.02). There was no significant change in O2-sat from baseline to blood collection (WSRT, Z = -0.14, P = .89). The nadir 02-sat fell below 90% for only 3 infants. There was no significant change in 02-sat CV (WSRT, Z= —1.07. P = .29). Figure 3A-C illustrates HR, RR, and 02-sat population data, respectively, collected during blood collection and the 10-minute recovery period (Figure 3). In the treatment group, there was a significant decrease in HR across the 2 epochs (WSRT Z = —2.37, P = .02). On average, HR decreased 17%. In 6 of the 7 infants (86%) in the treatment group, HR decreased by 10 bpm or more. In the control group, there was no significant change in HR (WSRT Z = —1.15, P = .25), aver- age HR decreased only 6%, and only 3 of the 6 infants (50%) showed an HR decrease of 10 bpm or more. No significant change in HR variability during recovery versus blood collection was found for either the treatment group (WRST Z = -0.68, P = .50) or the control group (WSRT Z= —1.07, P =.29). There was no significant change in RR or RR CV from blood collection to recovery in either the treatment group (respectively, WSRT 2 = -0.34. P =.74; 2 = -0.08, P = .93) or the control group (Z = —1.36, P = .17; = —0.94. P = .35). There was no significant change in 02-sat or 02-sat CV from blood collection to recovery in either the treatment group (respectively, WSRT Z = -0.17, P =.86; Z = -0.81, P = .42) or the control group (Z = —0.21, P = .83; Z = —0.37, P = .71). To further depict the time course of HR, RR, and 02-sat data across the various epochs of data collection, we present the results from a single premature infant in the treatment group (Figure 4). These are representative of data collected: (I) before and during heel stick and blood collection for the entire study population of 13 infants and (2) after blood collection for the population of 7 infants in the treatment group, who received controlled auditory stimulation with vocal music during the 10-minute recovery period. This patient was a 2.6-kg male twin born at 34 weeks gestation with 1-min and 5-min Apgar scores of 9. He was admitted to the SCU after delivery with a OsonlosOnd Own rrnd 'tr by Inn Tio on Won a5.2011 EFTA_R1_02048101 EFTA02695998 Teraina et al 77 A. 180 170 160 150 140 130 120 Pre-handkng Handling Blood Collection Post.sock handling Epoch 8. 60 50 40 30. 20. 10 0 Pra.handling Handling Blood Collection Post-stick handling Epoch C. 100 98 96 94 Pre-handling Handling Blood Coleman Posl-slick handing Epoch Figure 2. Populadon data collected before and during heel-stick procedure. Error bars represent ± I standard error from the mean. diagnosis of prematurity. The heel-stick procedure was per- formed during postnatal day one to check bilirubin levels. Ten minutes before skin puncture, his foot was unswaddled and prepped with a warming pad. In the minutes before skin punc- ture, the patient was lying quietly with his eyes closed and no head movements; the HR ranged from 118 to 132 bpm (mean = 121 bpm; CV = 17%). During the 33 seconds of handling prior to skin puncture. HR rose to 141 bpm; he remained quiet and still with eyes closed. Immediately upon skin puncture, he began to cry: by 10 seconds postpuncture, Hit was 153 bpm, by 30 seconds it was above the normal limit of 160 bpm (161 bpm), and by one minute it was 178 bpm (47% above the baseline mean). During blood collection, mean HR was 175 bpm, and the CV rose to approximately 5 times what it was at baseline; the peak HR was 192 bpm (59% above baseline) at 150 seconds postpuncture. The infant cried for more than 3 minutes, until he was given a pacifier; his eyes remained closed, and no head movements were discernable. Heart rate began to decline after blood collection when the heel was bandaged. The heel remained unswaddled throughout the postpuncture-handling period and recovery period. During the 10 minutes of auditory stimulation with vocal music, HR continued to decline until approximately 100 seconds post- handling, when it reached a plateau of 125 bpm, near the base- line mean of 121 bpm. He remained quiet with his eyes closed. and he made a total of only 5 brief head movements. Changes in RR paralleled those of HR (Figure 413). At base- line, mean RR was 24.5 ipm with a CV of 4.5%. During pre- puncture handling, RR rose slightly, but immediately after skin puncture, when the infant began to cry, RR rose precipi- tously and became highly variable. During blood collection, RR peaked at 83 ipm approximately 100 seconds postpuncture, and mean RR rose to 46.3 ipm, 89% above baseline, with a 31% increase in CV. Within 100 seconds after initiation of auditory stimulation, RR decreased, though its mean and variance remained elevated relative to baseline. 00iniaidal Prom inn :cat, by WV% Vino <a IWO A. 2011 EFTA_R1_02048102 EFTA02695999 78 Music and Medicine 3(2) &180 170 ire iso 1140 130 120 B. 70 Blood Collection Recovery Blood Collection ■ Control ■ Treatment Recovery ■contra • Treatment Blood Coledlon OCOVe Figure 3. Population data collected during blood collection and recovery. Oxygen saturation data for this infant are shown in Figure 4C. Immediately after skin puncture and initiation of crying, O2-sat declined and its variance increased. With audi- tory stimulation, O2-sat immediately began to rise and its var- iance decreased. Oxygen saturation reached a plateau of approximately 98.5% within 100 seconds. Behavioral Results Behavioral data could be reliably recorded in 9 infants: 4 in the Treatment Group, 5 in the Control Group. During the heel-stick procedure, 8 out of the 9 cried. Crying ceased in all 4 infants who received auditory stimulation with vocal music during the recovery period, whereas 2 of the 4 infants in the Control Group continued to cry during the recovery period. There was a trend for a significant x2-test comparing cessation vs continuation of crying in the Treatment vs Control group (x2 = 2.667, P = .10) though the small sample size renders the significance test questionable. We were unable to reliably code eye opening and head movements owing to logistical problems (ie, view blocked by nurse, variability among nurses in swad- dling and pacifier use [as described previously)). Discussion The bed-stick procedure is routinely used to obtain blood for serologic analyses in small babies who lack peripheral venous access. The results from our study population of 13 premature infants demonstrate that the procedure precipitates sudden increases in HR, RR, and crying that peak within seconds and are sustained for several minutes after delivery of the acutely painful stimulus. We tested our working hypothesis that controlled audi- tory stimulation with vocal music attenuates physiological and behavioral signs of stress evoked by heel stick. We chose traditional Western lullabies as our auditory stimulus because we thought they might have the highest prob- ability of achieving a beneficial effect. Lullabies include both music and human vocal sounds, including words, and are ethologically and ethnologically relevant owing to their rich cross-cultural history in parent-infant communication. In the previous clinical studies, lullabies have been shown to acceler- ate weight gain in hospitalized infants." The results show a significant decrease in mean HR over the 10-minute postprocedure period in the treatment group (17% mean HR decrease) but not the control group (6% mean HR decrease). There were no effects of vocal music on RR or O2-sat. Qualitative differences between the treatment and con- trol groups were also observed for crying. We found no signif- icant difference between the treatment and the control groups with respect to procedure length, so it is unlikely that it contrib- uted to the observed effects on HR and behavior. Several limitations of our study may hamper its applicability to the general population of premature infants undergoing heel stick. Our population size was small. We studied the effects of music on a single heel stick; our study does not address the potential benefits of repeated music stimulation for the patients in NICU undergoing frequent heel sticks. There was variability across the clinicians with respect to swaddling, pacifier use, and sucrose use. Our results may have been influenced by the fact that a higher proportion of infants in the treatment group (57% vs 33% in the control group) received sucrose before and during the heel-stick procedure. However, the response to the heel stick was equally robust in both groups, and HR increased as much in the treatment group as in the control group during the heel-stick procedure. Our behavioral analyses were limited to crying due to logistical difficulties with video recording in the SCU. Future studies would benefit from using multiple cameras from different angles or a mobile camera to improve the behavioral data collection. With only one small SCU EFTA_R 1 _0204 81 03 EFTA02696000 Teraina et of 79 A. 200 190 • 180 170 160 150 140 130 120 110 100 B. Baseline Handling Blood collection Handling Recovery (music) • Baseline 100 A. 80 cc c 60 O 'Ts 40 E. 20 • 0 C. 100 - 98 - 92 Time (s) Handling Blood collection Handling —‘ 00C) F.) 0) 0 r ) CO 4. CO r.) 0 0 0 0 0 Time isi Recovery (music) Baseline Handling Blood Handling Music s 0 N.) O C0 A 0 a) ea 0 Co A 0 0 0 0 0 S 2t 0 0 S Time (s) S Figure 4. Single-neonate data collected before. during, and after heel-stick procedure. 1,••• Minn 25,1411 EFTA_R1_02048104 EFTA02696001 80 Music and Medicine 3(2) participating, there were limited numbers of patients available for enrolment. A multisite study would be beneficial to increase the population size and examine reproducibility of results across different centers. Future studies with larger samples of babies born to English- speaking parents—no less infants from other cultures66•67—are needed to corroborate our findings and to ascertain whether different types of music. other auditory stimuli, or other types of ecologically and ethnologically relevant stimuli have more or less of an effect on physiological and behavioral indices of pain and stress. It is possible that live music may have an even greater effect on physiological recovery from heel stick, as a previous study demonstrated a decrease in HR in infants at rest after stimulation with live music, but not with recorded music or no music." Neural mechanisms mediating the effects of controlled audi- tory stimulation with music on HR and other aspects of auto- nomic function have not been fully elucidated. The results of experiments with chicks and rats indicate they are not specific to humans. For example, Sutoo and Akiyama69 played the Ada- gio by Mozart (IC 205) repeatedly to spontaneously hypertensive rats for 2 hours on 3 consecutive nights at 65 to 75 dB SPL. The rats' blood pressure as well as their behavioral activity decreased during the music, and the effect persisted for about 30 minutes after the music stopped. Compared to a control group that did not receive music stimulation, treated rats exhibited increased dopa- mine levels in the neostriatum. Moreover, pretreatment with a D2 receptor antagonist, but not a DI receptor antagonist, blocked the blood pressure response. These results indicate that music induced the activation of D2 receptors in the neostriatum, which in turn, decreased sympathetic tone. We restricted the recruitment of participants to premature infants who were free of brain disease and serious illness in order to minimize any risks from auditory stimulation. No com- plications were observed. Extending the research to include infants who are more compromised is feasible. In general, the younger the neonate at birth, the greater the risk of illness, the greater the number of procedures she/he undergoes, and conse- quently, the greater the risk of recurrent pain and stress?"' Fur- ther study is needed to determine the age groups and medical conditions of infant populations that benefit from controlled auditory stimulation. Previous Studies In general, clinical research on the potential benefits of audi- tory stimulation with music in premature infants has looked at the endpoints indexing effects of pervasive stress (eg, cardi- opulmonary events and weight gain). Relatively little work has focused on specific physiological and behavioral responses to sudden, noxious stimuli, such as those delivered during medi- cal procedures.79 Recordings of the mother talking soothingly to her baby, digitally filtered to simulate what they would sound like in the womb, failed to attenuate physiological and behavioral responses to heel stick in one study.71 Whipple found decreased behavioral, but not physiological, indices of pain and stress following heel stick using a music-reinforced, nonnutritive sucking paradigm that employed sung lullabies."2 Butt and Kisilevskyss investigated the effects of music on physiological and behavioral responses to the heel-stick proce- dure using a randomized-controlled, single-crossover design with 14 premature infants in levels I. II, and III nurseries. Infants were exposed to both a control and a music condition in 2 separate heel sticks (time lapse between heel sticks unknown). The music stimuli was either an instrumental ver- sion of Brahms's Lullaby (Op. 49, No. 4) performed on piano or a vocal version of the same excerpt, performed a capella. The absolute sound intensity, 76 dBA on average, was similar to ours, but the relative stimulus intensity was only about 4 dB (potentially lower for infants receiving mechanical support). compared to about 10 dB in our study. Consequently, the soft- est portions of the music may have not been audible, thereby rendering music discontinuous. The duration range of heel- stick procedure in their study overlapped with ours, and similar to our study, various aspects of developmentally sensitive care were "neither consistent nor universal." Setting aside reserva- tions about the use of a parametric statistic and multiple post hoc analyses with multiple factors in a small, clinically diverse patient population. and acknowledging differences in statistical and other methods, we note results are paralleling those of this study. First, a 3-way ANOVA carried out on data collected dur- ing the heel-stick procedure found an increase in FIR, a decrease in O2-sat, an increase in behavioral arousal score, and an increase in the facial pain expression score over time for all babies. Second, a 3-way ANOVA comparing data collected during the last half of the 10-minute postprocedure recovery period found smaller changes in HR and facial expression scores when the infants were played music. No clearcut differ- ences in the efficacy of instrumental vs a capella music were discernable. Bo and Callaghan's investigated the effects of music, a paci- fier, or both on physiological and behavioral responses during and after the heel-stick procedure in 27 Chinese pre- and full- term neonates. Their crossover design required infants to have a minimum of 4 heel sticks and the order of the 3 treatment con- ditions and no-treatment condition was pseudurandomized. The duration of the heel sticks, time lag between heel sticks, and characteristics of the developmentally sensitive care were not provided. The authors characterized the music stimuli as "soothing," but the specific music used, its intensity, the inten- sity of ambient room noise, and the amount of daily exposure to music were not specified. One-way and multivariate ANOVAs, the designs of which were not detailed, were reported to show the significant effects of treatment on HR. blood oxygenation. and Neonatal Infant Pain Scale (NIPS) scores. A Scheffe test analyzing all possible comparisons of the different treatment conditions at each data collection time showed that treatment with music was associated with the lowest HR, highest oxyge- nation, and lowest NIPS scores at multiple time points during and after treatment. At other times, treatment with music plus a pacifier was associated with these minima and maxima, but at no time did treatment with a pacifier alone produce this oxinads ta.n. by Mirk Two o0Alich 75. PM EFTA_R1_02048105 EFTA02696002 Tram et al 81 result. Acknowledging methodological differences with our study, most notably the timing of auditory stimulation, we interpret the findings of Bo and Callaghan as broadly consistent with ours. Beneficial effects of controlled auditory stimulation on acute pain and stress have been observed in the setting of other medical procedures. In a randomized trial of 58 healthy male neonates undergoing circumcision, Marchette et al74 reported that they were less likely to have tachycardia toward the end of the procedure (tightening the clamp, waiting for hemostasis, and cutting foreskin) if recorded "classical music for neonates"t1'2O was played. Burke ct a175 found that synthesized female vocals and womb sounds stabilized HR and behavioral agitation in 4 neonates following endotracheal suctioning, which is frequently performed in critically ill, intubated infants on mechanical ventilation. Chou et al,76 using the same auditory stimuli of Burke et al, reported that the musical stimuli improved O2-sat during endotracheal suc- tioning and may have hastened its return to baseline levels after suctioning in 30 infants. We explored the use of music to reduce stress caused by cra- nial ultrasound in a set of fraternal twins. One twin was played lullabies following the procedure and was found to have a lower mean HR, and unlike the unstimulated twin, did not cry. These anecdotal observations raise the possibility that music might decrease stress caused by cranial ultrasound, a procedure that is commonly performed on premature infants. Concluding Remarks There is growing awareness of the need for better manage- ment of pain and stress in hospitalized infants who undergo many medical procedures, standardized approaches to man- aging procedure-induced pain remain lacking.5941•63'77 Whereas the risk: benefit ratio of treatment with opioids and sedatives is high, owing to steep dose-response curves and the potentially devastating consequences of respiratory depression, nonpharmacological interventions such as controlled auditory stimulation with music carry little or no risk to the infant. The amount, timing, and type of controlled auditory stimulation that maximize its amelioration of procedure-induced distress remain unclear, and they may not be easy to predict. Future investigations aimed at optimizing and standardizing the use of music, other auditory stimuli, and multimodal treatment incorporating auditory stimuli are needed to advance the efforts to alleviate pain and stress in this needy patient population. Acknowledgments The authors thank Dr Verne Caviness. Dr Anne Young. Dr Kalpathy Krishnamoorthy, Dr Christine Koh, Natalie Cameron. Nom Huntley, Melanie Canales, Pamela Almeida, Chelsea Burleson, Sue Carver, Robert Escarto, Priscilla Frappicr, Mary Margaret Finley. Eileen Jones, Jean McAuliffe, Donna Meant, Cheryl Olsen, Linda Roth, and Deb Maddox for their contributions. Declaration of Conflicting Interests Thc author(s) declared no potential conflicts of interest with respect to the authorship and/or publication of this article. 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Music therapy following suctioning: four case studies. Neonatal Netw. 1995;14(7):41.49. 76. Chou L. Wang R. Chen S, Pai L. Effects of music therapy on oxy- gen saturation in premature infants receiving endotracheal suc- tioning. J Nun Res. 2003;11(3):209-216. 77. Larsson BA. Pain management in neonates. Acta Paediatr. 1999;88(12):1301.1310. Bios Mark Jude Tramo, MD, PhD, is Associate Professor in Neurology & Lecturer in Ethnomusicology at the David Geffen School of Medicine & Herb Alpert School of Music. UCLA; Medical Director of Neuro- logical & Rehabilitation Services at the Good Samaritan Hospital Los Angeles; and Director of the Institute for Music & Rmin Science. Miriam Leese, MS, is a PhD candidate in Clinical Psychology in the Department of Psychology and Human Development at Vanderbilt University, and a Research Associate at the Institute for Music and Brain Science. Caitlin Van Ness, MST. is a Research Associate at the Institute of Music and Brain Science. Jerome Kagan. PhD, is Professor Emeritus in Psychology and the director of the Mind/Brain/Behavior Initiative at Harvard University. Margaret Doyle Settle, RNC. MSN. is Nurse Director of the New- born Intensive Care Unit at Massachusetts General Hospital and a Research Associate at the Institute for Music and Brain Science. Jonathan H. Cronin, MD, is Chief of the Neonatology Unit at Mas- sachusetts General Hospital. Oontoodal Prom • ..-ro m.ao, by Wet limo an Mod 25, All EFTA_R1_02048108 EFTA02696005