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Trajectories of Terminally Ill Patients' Cardiovascular Response to Receptive Music Therapy in Palliative Care

  • Author Footnotes
    ∗ Drs. Warth and Kessler contributed equally to this work.
    Marco Warth
    Correspondence
    Address correspondence to: Marco Warth, MA, Center of Pain Therapy and Palliative Care Medicine, Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 131, 69120 Heidelberg, Germany.
    Footnotes
    ∗ Drs. Warth and Kessler contributed equally to this work.
    Affiliations
    Center of Pain Therapy and Palliative Care Medicine, Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany

    School of Therapeutic Sciences, SRH University Heidelberg, Heidelberg, Germany
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  • Author Footnotes
    ∗ Drs. Warth and Kessler contributed equally to this work.
    Jens Kessler
    Footnotes
    ∗ Drs. Warth and Kessler contributed equally to this work.
    Affiliations
    Center of Pain Therapy and Palliative Care Medicine, Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
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  • Thomas K. Hillecke
    Affiliations
    School of Therapeutic Sciences, SRH University Heidelberg, Heidelberg, Germany
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  • Hubert J. Bardenheuer
    Affiliations
    Center of Pain Therapy and Palliative Care Medicine, Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
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  • Author Footnotes
    ∗ Drs. Warth and Kessler contributed equally to this work.
Open AccessPublished:April 15, 2016DOI:https://doi.org/10.1016/j.jpainsymman.2016.01.008

      Abstract

      Context

      Relaxation interventions are frequently used to promote symptom relief in palliative care settings, but little is known about the underlying mechanisms.

      Objectives

      The present analysis aimed at examining the psychophysiological pathways of terminally ill patients' cardiovascular response to a live music therapy vs. prerecorded mindfulness exercise.

      Methods

      Eighty-four patients of a palliative care unit were randomly assigned to either of the two interventions. Multilevel modeling was used to analyze trajectories of physiological change. Vagally mediated heart rate variability (VM-HRV) and blood volume pulse amplitude (BVP-A) served as indices of autonomic nervous system response. Participants' gender, age, baseline scores, self-rated pain, and assignment to treatment were entered to the models as predictors.

      Results

      Both VM-HRV and BVP-A showed significant linear and quadratic trends over time, as well as substantial heterogeneity among individuals' trajectories. Baseline scores, pain, and treatment significantly accounted for random variation in VM-HRV intercepts. BVP-A levels were significantly higher in women than in men. Moreover, assignment to treatment significantly accounted for differences in the linear slopes of peripheral blood flow.

      Conclusion

      Higher levels of VM-HRV in the music therapy group highlight the importance of a therapeutic relationship for the effectiveness of relaxation interventions in end-of-life care settings. Music therapy caused significantly stronger reductions of vascular sympathetic tone and, therefore, may be indicated in the treatment of pain and stress-related symptoms in palliative care. Initial self-ratings of pain moderated patients' physiological response and need to be taken into account in clinical practice and future theory building.

      Key Words

      Introduction

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      more research exists on verbal MB interventions. Mindfulness is defined as to pay attention “on purpose, in the present moment, and nonjudgmentally.”
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      Study outcomes that have been commonly used for the operationalization of autonomic nervous system activity were 1) high-frequent (HF) oscillations in the beat-to-beat-intervals of successive heartbeats (i.e., heart rate variability [HRV]) as an index of vagally mediated (VM) cardiac outflow, and 2) the amplitude of peripheral blood flow (blood volume pulse amplitude [BVP-A]) as a measure of sympathetic tone.
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      In accordance with Porges's polyvagal theory, which emphasizes the role of myelinated vagus fibers in engaging in adaptive, prosocial behavior and in suppressing automated fear and stress responses, high VM-HRV seems to be positively correlated with resilience, social engagement, well-being, and psychological flexibility.
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      and BVP-A.
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      An observational study found evidence for a positive association between HRV and the ability to mindfully regulate one's attention.
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      Fewer studies evaluated the cardiovascular effects of MB interventions for clinical populations. Significant decreases in heart rate and increases in the HF spectrum were reported for chronic pain patients
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      but were not found in myocardial infarction patients.
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      Evidence on the effects of music on HRV is inconsistent. Clinical trials revealed significant increases in HF variation among preoperative patients undergoing a music listening intervention
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      and in elderly patients with cerebral vascular disease and dementia exposed to live music therapy sessions.
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      • et al.
      Effects of music therapy on heart rate variability in elderly patients with cerebral vascular disease and dementia.
      A pilot study with female cancer survivors replicated the pattern of decreased heart rate and increased VM-HRV after 2 hours of participating in MT.
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      In female cancer patients undergoing chemotherapy, however, listening to prerecorded monochord sounds led to a significant increase in the LF, but not in the HF spectrum.
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      To our knowledge, no study has yet examined the physiological response of terminally ill cancer patients to music or MT.
      The present study was designed to evaluate the efficacy of an MT relaxation intervention in palliative care patients. A prerecorded verbal mindfulness exercise served as an active control group condition.
      • Warth M.
      • Kessler J.
      • Koenig J.
      • et al.
      Methodological challenges for music therapy controlled clinical trials in palliative care.
      Pre-to-post changes in self-report data and physiological outcomes have been addressed in a previously published article,
      • Warth M.
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      • Hillecke T.K.
      • Bardenheuer H.J.
      Music therapy in palliative care: a randomized controlled trial to evaluate effects on relaxation.
      identifying significant between-group effects on self-reported relaxation, well-being, and fatigue, as well as changes in subjects' physiological state before versus after the intervention. However, preliminary analyses on the individual trajectories revealed significant heterogeneity in both baseline values and slopes among patients' cardiovascular response, raising the question of how to explain this between-subject variation.
      Hence, the present analysis aimed at investigating both individual- and group-level effects of terminally ill patients' cardiovascular response to short-term MT and MB interventions and at examining mechanisms underlying these trajectories of physiological change. Because of the design of the interventions, we hypothesized U- or inverted U-shaped quadratic trends over time for both groups. Because of the personal presence of a therapist and the soothing live music sounds, we predicted a stronger relaxation response to occur in the MT group.

      Methods

      Study Design and Procedures

      The study received institutional review board approval, was entered into the German Clinical Trials Register, and was carried out at St. Vincentius Hospital, Heidelberg between May 2013 and March 2015. A two-arm parallel randomized controlled trial was designed to evaluate and compare the effects of two different relaxation exercises for hospitalized patients in a palliative care unit. Patients were eligible for study participation if they met the following criteria: 1) receiving palliative care, 2) not in the final phase, 3) no cognitive or hearing impairments, 4) no signs of restlessness and agitation, and 5) sufficient understanding of the German or English language.
      Patients who were eligible and willing to participate signed informed consent and were randomly assigned to either two sessions of live MT or two sessions of a prerecorded MB exercise, each lasting for a total of 20 minutes. Both a five-minute preintervention and postintervention recording in a resting state enveloped all sessions. During the entire duration (30 minutes), patients lay in a supine position while continuous physiological data were recorded. We used a computer-based, permutated block randomization sequence, which was concealed by use of sequentially numbered, opaque-sealed envelopes. A study assistant who was not involved in providing the interventions carried out randomization and outcome assessment.
      The receptive MT intervention was carried out by a professional music therapist and included a brief body scan exercise (3 minutes), a vocal improvization (12 minutes), and a feedback conversation on the patient's experiences (5 minutes). The first 15 minutes were accompanied by improvised musical play on the monochord. The control group (CG) intervention comprised a 20-minute recording of a mindfulness exercise consisting of a standardized body scan and meditation for supine positions,
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      • Kesper-Grossman U.
      Stressbewältigung durch die Praxis der Achtsamkeit.
      which was provided via headphones. In contrast to the MT session, a study assistant remained silently inside the room. Both interventions did not differ between Sessions 1 and 2. The interventions are fully described in the study protocol.
      • Warth M.
      • Kessler J.
      • Koenig J.
      • et al.
      Music therapy to promote psychological and physiological relaxation in palliative care patients: protocol of a randomized controlled trial.

      Outcomes

      For purpose of the present analysis, physiological data obtained from photoplethysmography served as a dependent variable. For noninvasive, continuous recordings of participants' physiological response during the interventions, a NeXus blood volume pulse sensor (128sps) was placed on the index fingertip of the nondominant hand, detecting changes in relative peripheral blood flow.
      • Alian A.A.
      • Shelley K.H.
      Photoplethysmography.
      The time point of the R-wave was used to extract interbeat intervals between successive heartbeats in milliseconds. HRV parameters were derived for six consecutive time segments of five minutes each.
      Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use.
      Because of the relatively fast response times of parasympathetic fibers and their close linkage to respiratory rhythms, HF oscillations in interbeat intervals (0.15–0.4 Hz) are mainly attributed to vagal modulation of cardiac outflow.
      • Shaffer F.
      • McCraty R.
      • Zerr C.L.
      A healthy heart is not a metronome: an integrative review of the heart's anatomy and heart rate variability.
      The HF power density in ms2, therefore, was used as a biomarker of parasympathetic activity.
      The amount of peripheral blood flow in the fingertips' capillaries, on the other hand, is predominantly subject to adrenergic innervation by the sympathetic nervous system, leading to tonic vasoconstriction. An increase in BVP-A, therefore, is associated with a reduction in sympathetic arousal. Thus, the mean BVP-A of each five-minute segment was considered an inversely related index of vascular sympathetic tone.
      • Alian A.A.
      • Shelley K.H.
      Photoplethysmography.

      Statistical Analysis

      Sample size calculations were adapted for the analysis of covariance models used within the primary analysis
      • Warth M.
      • Kessler J.
      • Hillecke T.K.
      • Bardenheuer H.J.
      Music therapy in palliative care: a randomized controlled trial to evaluate effects on relaxation.
      and were presented in the study protocol.
      • Warth M.
      • Kessler J.
      • Koenig J.
      • et al.
      Music therapy to promote psychological and physiological relaxation in palliative care patients: protocol of a randomized controlled trial.
      Baseline characteristics were analyzed with means, standard deviations, frequencies, independent-samples t-tests, and χ2-tests.
      Multilevel modeling with the software package HLM 7
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      • Bryk A.S.
      • Congdon S.
      HLM 7 for windows.
      was used to analyze trajectories of patients' physiological response because different observations in the dependent variable were “nested” within participants, and preliminary analysis revealed substantial between-subject heterogeneity regarding the intercepts and slopes. Two models were calculated for each outcome independently: The first model (M1) included two repeated-measures factors only (TIME and TIME2) and examined, whether mean data of the entire sample showed the expected linear and quadratic trend over time. In addition, HLM detected the amount of random variation between individuals' intercepts, linear, and quadratic slopes.
      In case of significant heterogeneity, a second model (M2) was built, including the following set of predictors to account for random variance:

      Baseline

      Values from the 5-minute segment before the onset of the intervention were considered a covariate to account for between-subject variability in the subsequent trajectories of physiological change.
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      Considerations in the assessment of heart rate variability in biobehavioral research.
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      Multilevel models for repeated measures research designs in psychophysiology: an introduction to growth curve modeling.

      Age and Gender

      Previous findings identified a negative relationship between HRV and age. In addition, evidence suggests that HRV indexes are higher in men, whereas differences adapt with increasing age.
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      Influence of age, gender, body mass index, and functional capacity on heart rate variability in a cohort of subjects without heart disease.
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      The effect of gender on heart rate variability in asthmatic and normal healthy adults.
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      • Singer D.H.
      • McCraty R.
      • Atkinson M.
      Twenty-four hour time domain heart rate variability and heart rate: relations to age and gender over nine decades.
      Therefore, participants' age and gender were added as control variables.

      Pain

      Although the underlying mechanisms are still subject to discussion, several studies showed an association between pain and autonomic arousal.
      • Koenig J.
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      • Thayer J.F.
      Vagally mediated heart rate variability in headache patients-a systematic review and meta-analysis.
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      Heart rate variability and pain: associations of two interrelated homeostatic processes.
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      • Thayer J.F.
      Heart rate variability and experimentally induced pain in healthy adults: a systematic review.
      Hence, self-ratings of acute pain were assessed before each session via visual analogue scale, 0–10. Pain ratings were expected to moderate the effects.

      Treatment

      While controlling for the influence of the aforementioned variables, assignment to one of the two treatment groups was added to the model as a predictor. We expected an interaction between individual trajectories and treatment to manifest in stronger increases in parasympathetic activity and stronger decreases in sympathetic arousal in the MT group.
      In accordance with procedures from similar studies, each predictor was tested for significant influences on the intercepts, linear, and quadratic trends and was deleted from the model in case of nonsignificant associations.
      • Kristjansson S.D.
      • Kircher J.C.
      • Webb A.K.
      Multilevel models for repeated measures research designs in psychophysiology: an introduction to growth curve modeling.
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      Randomized controlled trial of cognitive behavioral therapy and acceptance and commitment therapy for social phobia: outcomes and moderators.
      Categorical variables were dummy-coded (0/1) and continuous predictors were grand-mean centered.
      • Raudenbush S.W.
      • Bryk A.S.
      Hierarchical linear models—Applications and data analysis methods.
      The repeated-measures factors TIME and TIME2 were coded so that “0” concurred with the first interval after the onset of the intervention (labeled in subsequent figures as “0–5 min.”). Outcome variables were log-transformed because of skewed distributions in raw data. For each time segment and patient, data were averaged between Sessions 1 and 2. Restricted maximum likelihood was chosen to estimate the model parameters.
      • Raudenbush S.W.
      • Bryk A.S.
      Hierarchical linear models—Applications and data analysis methods.
      Type-I error probability was set on α = 0.05 for all statistical tests.

      Results

      Eighty-four patients (60 female, mean age = 63.0 ± 13.4 years) with progressive, life-threatening disease participated in this study; 82 were diagnosed with advanced cancer. No significant differences occurred between treatment arms regarding gender, age, and diagnosis (all P > 0.05, Table 1). After removal of erroneous recordings from movement artifacts and low peripheral blood flow, physiological data from 80 (log_BVP-A) and 73 (log_HF) patients were available for statistical analysis. A patient flowchart for physiological outcomes is presented in Figure 1.
      Table 1Baseline Characteristics
      VariableMT (N = 42)CG (N = 42)P
      Statistically significant if P < 0.05.
      Gender (female)
      Mean, SD, t-test.
      28 (66.7%)32 (76.2%)0.33
      Age
      Frequency, χ2 test.
      63.8 (14.1)62.2 (12.8)0.59
      Diagnosis (Cancer)
      Mean, SD, t-test.
      41 (97.6%)41 (97.6%)1.00
      MT = music therapy; CG = control group.
      a Statistically significant if P < 0.05.
      b Mean, SD, t-test.
      c Frequency, χ2 test.
      Figure thumbnail gr1
      Fig. 1Patient flowchart. BVP-A = blood volume pulse amplitude; HRV = heart rate variability.
      First, M1 was built for the trajectories of parasympathetic modulation of heart rate (log_HF). Both a significant negative linear (P = 0.02) and positive quadratic fixed effect (P < 0.001) were found for the group mean development over time, indicating a U-shaped trajectory on average. Furthermore, as summarized in Table 2, HLM identified significant between-subjects variation regarding the intercepts (P < 0.001), linear (P = 0.003), and quadratic slopes (P < 0.001).
      Table 2Final Estimation of Variance Components (Random Effects)
      Random EffectModel 1 (M1)Model 2 (M2)
      Varχ2dfP-valueVarχ2dfP-value
      log_HF
       INTRCPT, r02.8121235.4972<0.0010.808395.7869<0.001
       TIME, r10.127109.46720.0030.129109.61710.002
       TIME2, r20.016151.9772<0.0010.016152.2972<0.001
       Residual, e0.4430.196
      log_BVP-A
       INTRCPT, r00.5477380.8879<0.0010.051728.1775<0.001
       TIME, r10.043489.9879<0.0010.027333.8276<0.001
       TIME2, r20.002474.9079<0.0010.002408.8078<0.001
       Residual, e0.0070.007
      Var = variance; df = degrees of freedom; log_BVP-A = log-transformed blood volume pulse amplitude; log_HF = log-transformed high frequency power.
      Hence, a second model was built including predictors that accounted for the observed heterogeneity. Regression coefficients and P-values are summarized in Table 3. Despite participants' baseline scores (P < 0.001), self-ratings of pain showed a marginally significant negative effect on the intercept (P = 0.055), and a significant positive effect on the linear slope (P = 0.003). Thus, log_HF was initially lower in patients reporting high levels of pain, but the increase in parasympathetic outflow over time was also stronger in these patients. While controlling for baseline and pain, assignment to either of the treatment arms significantly predicted the intercepts of log_HF scores (P = 0.002), indicating that log_HF was generally higher in the MT group than in the CG. Modulation of the patients' parasympathetic response by the factors pain and treatment is shown in Figure 2.
      Table 3Final Estimation of Fixed Effects (M2)
      Fixed EffectCoefficientSEt-valuedfP-value
      log_HF
       For INTRCPT, β0:
      INTRCPT, γ004.8170.14732.73369<0.001
      Treatment, γ010.5350.1793.154690.002
      Baseline, γ020.8600.05715.14169<0.001
      Pain, γ03−0.0940.048−1.953690.055
       For time, β1:
      INTRCPT, γ10−0.1680.071−2.347710.022
      Pain, γ110.0300.0103.022710.003
       For time2, β2:
      INTRCPT, γ200.0720.0203.57572<0.001
      log_BVP-A
       For INTRCPT, β0:
      INTRCPT, γ003.5310.05070.31475<0.001
      Treatment, γ01−0.0050.048−0.100750.921
      Gender, γ020.1030.0472.197750.031
      Baseline, γ030.9320.03824.79375<0.001
      Pain, γ040.0120.0111.059750.293
       For time, β1:
      INTRCPT, γ100.0880.0223.96376<0.001
      Treatment, γ110.0300.0142.227760.029
      Baseline, γ12−0.1640.029−5.68576<0.001
      Pain, γ13−0.0080.003−2.556760.013
       For time2, β2:
      INTRCPT, γ20−0.0260.006−4.62878<0.001
      Baseline, γ210.0270.0083.55278<0.001
      M2 = model 2; SE = standard error; df = degrees of freedom; log_HF = log-transformed high frequency power.
      Bold text indicates significant effects of treatment allocation.
      Figure thumbnail gr2
      Fig. 2Predicted values of log_HF modulated by treatment and pain (controlling for baseline scores). Group = treatment; High Pain = 2 points above average; log_HF = log-transformed high frequency power; Low Pain = 2 points below average.
      Similar model building procedures were applied to the analysis of sympathetic arousal (log_BVP-A). M1 identified a significant positive linear (P < 0.001) and negative quadratic trend over time (P < 0.001), resulting in an inversely U-shaped mean curve. The mean curve, again, did not adequately represent individual-level trajectories regarding intercepts (P < 0.001), linear (P < 0.001), and quadratic slopes (P < 0.001, Table 2).
      Despite the baseline values (all P < 0.001), pain, gender, and treatment contributed to the explanation of between-subjects differences. Participants' subjective level of pain significantly affected the linear slopes of log_BVP-A (P = 0.01), implying that high ratings of pain led to a slower reduction of sympathetic arousal. Patients' gender explained substantial differences in the general intercept of sympathetic arousal (P = 0.03), with women showing generally more arousal than men. Allocation to MT vs. CG (treatment) significantly predicted the linear slopes of peripheral blood flow (P = 0.03) with stronger increases in the MT group. Figure 3 illustrates the influence of pain and treatment on participants' sympathetic response.
      Figure thumbnail gr3
      Fig. 3Predicted values of log_BVP-A modulated by treatment and pain (controlling for baseline scores and gender). Group = treatment; High Pain = 2 points above average; log_BVP-A = log-transformed blood volume pulse amplitude; Low Pain = 2 points below average.

      Discussion

      Exceeding the scope of previous effectiveness research,
      • Hilliard R.E.
      The effects of music therapy on the quality and length of life of people diagnosed with terminal cancer.
      • Gutgsell K.J.
      • Schluchter M.
      • Margevicius S.
      • et al.
      Music therapy reduces pain in palliative care patients: a randomized controlled trial.
      • Warth M.
      • Kessler J.
      • Hillecke T.K.
      • Bardenheuer H.J.
      Music therapy in palliative care: a randomized controlled trial to evaluate effects on relaxation.
      the present findings add important insights to the study of the underlying mechanisms of relaxation and mindfulness techniques for terminally ill patients.
      VM-HRV was examined as a biomarker of parasympathetic cardiac outflow. Regarding the entire sample (M1), trajectories of change were not in the predicted direction, as with the beginning of the interventions, VM-HRV was initially reduced. With the progression of the treatment, the slopes became more positive, exceeding the initial values at the end of the session (Fig. 2). This finding contradicts the assumption of a simple, linear relation between the relaxation response and parasympathetic activity. Some authors argued that a state of subjective relaxation may rather be related to a general decrease in cardiac outflow with a relative shift toward parasympathetic dominance.
      • Krygier J.R.
      • Heathers J.A.J.
      • Shahrestani S.
      • et al.
      Mindfulness meditation, well-being, and heart rate variability: a preliminary investigation into the impact of intensive Vipassana meditation.
      • McCraty R.
      • Atkinson M.
      • Tomasino D.
      • Bradley R.T.
      The coherent heart—Heart-brain interactions, psychophysiological coherence, and the emergence of system-wide order.
      The psychophysiological interpretability of alternative HRV indices such as the frequency ratios, however, has been subject to controversial discourse.
      • Krygier J.R.
      • Heathers J.A.J.
      • Shahrestani S.
      • et al.
      Mindfulness meditation, well-being, and heart rate variability: a preliminary investigation into the impact of intensive Vipassana meditation.
      • Quintana D.S.
      • Heathers J.A.J.
      Considerations in the assessment of heart rate variability in biobehavioral research.
      • Heathers J.A.
      Everything hertz: methodological issues in short-term frequency-domain HRV.
      Clinically relevant inferences can be drawn from predictor analysis. Subjective ratings of acute pain significantly interacted with the linear slopes of VM-HRV. Interestingly, the positive linear slope over the entire duration of a session was more positive, if patients initially reported higher levels of pain (Fig. 2). This means that baseline differences in VM-HRV caused by pain can be compensated by use of MT and MB interventions.
      The type of treatment did not affect the slopes of the parasympathetic response. However, the level of VM-HRV was generally higher during the MT than during MB sessions. This finding is consistent with Porges's polyvagal theory, as one major difference between the two interventions was the presence of a therapeutic interaction in the MT group. Although the number of persons inside the patient's room was held constant across conditions, the therapeutic skills and both verbal and nonverbal communication initiated by the music therapist may have driven the patients to engage in prosocial behavior, resulting in increased vagal modulation of cardiac activity.
      • Porges S.W.
      The polyvagal theory: new insights into adaptive reactions of the autonomic nervous system.
      • Shaffer F.
      • McCraty R.
      • Zerr C.L.
      A healthy heart is not a metronome: an integrative review of the heart's anatomy and heart rate variability.
      Regarding sympathetic vascular tone, baseline values had a strong influence on the entire shape of each individual's response curve. Furthermore, BVP-A intercepts differed by gender, with women's levels of sympathetic arousal being significantly higher throughout the entire session. This corresponds to previous metaanalytic findings of women reporting a higher level of distress in the course of a cancer progression.
      • Hagedoorn M.
      • Sanderman R.
      • Bolks H.N.
      • Tuinstra J.
      • Coyne J.C.
      Distress in couples coping with cancer: a meta-analysis and critical review of role and gender effects.
      Self-ratings of acute pain moderated the trajectories of sympathetic tone. With higher scores on the visual analogue scale, the reduction of sympathetic tone was less pronounced. Hence, although even patients with high levels of pain showed the expected inversely U-shaped time course (Fig. 3), patients with lower levels benefited more from the interventions regarding the reduction of sympathetic arousal.
      While controlling for baseline differences, gender, and pain, the linear slopes differed significantly between treatment arms. Confirming the hypothesis, the average increase in peripheral blood flow was significantly higher in the MT group compared to the CG. This difference in the patients' growth rate can be interpreted as direct evidence for the stress-reducing effect of the MT relaxation intervention, which differed from the MB intervention in the live played soothing sounds of the monochord, vocal improvization synchronized with the patients breathing, and the building of a therapeutic relationship.
      Methodological limitations of the present study encompass the lack of outcome assessor blinding and the missing of a no-treatment condition. Furthermore, although the use of a photoplethysmography sensor causes significantly lower patient burden, it also carries the disadvantage of lower sampling rate compared to common electrocardiogram recordings. Hence, future studies may address these issues in subsequent designs making further use of the rapidly developing methods for minimally invasive, physiological measurements.
      The present study presents results of hierarchical linear modeling of objective, physiological data from a randomized controlled trial on the effects of MT intervention in palliative care. First, results highlight the importance of a therapeutic relationship for both an increase in VM-HRV and a reduction of sympathetic arousal, and thus, speak in favor of the application of live MT over, for example, music listening or music medicine interventions in end-of-life-care settings. Second, specific characteristics of the receptive MT intervention used in this study caused significant reductions of vascular sympathetic tone. Hence, the study presents evidence for an indication of MT in the treatment of pain and stress-related symptoms in palliative care. Finally, self-rated levels of acute pain proved to be an important moderator in explaining individual differences in the physiological response to relaxation interventions.

      Disclosures and Acknowledgments

      No funding was received for this study and the authors declare no conflicts of interest.

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