title
stringlengths 1
1.19k
| keywords
stringlengths 0
668
| concept
stringlengths 0
909
| paragraph
stringlengths 0
61.8k
| PMID
stringlengths 10
11
|
|---|---|---|---|---|
Methods | OHCA, comatose | BLOOD, COMATOSE | In a double-blinded trial, we randomly assigned 60 comatose patients following OHCA to low (63 mmHg) or high (77 mmHg) mean arterial blood pressure (MAP). The trial was a sub-study in the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX). Global cerebral metabolism utilizing jugular bulb microdialysis (JBM) and cerebral oxygenation (rSO | PMC9951410 |
Results | SEPARATION | We found a clear separation in MAP between the groups (15 mmHg, | PMC9951410 |
|
Conclusions | ROSC, comatose | COMATOSE | Among comatose patients resuscitated from OHCA, targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism within 96 h of post-resuscitation care. Patients with a poor clinical outcome exhibited significantly worse biochemical patterns, probably illustrating that insufficient tissue oxygenation and recirculation during the initial hours after ROSC were essential factors determining neurological outcome. | PMC9951410 |
Supplementary Information | The online version contains supplementary material available at 10.1186/s13054-023-04376-y. | PMC9951410 |
||
Keywords | PMC9951410 |
|||
Introduction | OHCA, cardiac arrest, comatose | CARDIAC ARREST, COMATOSE | Survival rates remain around 50% for comatose patients treated in the Intensive Care Unit (ICU) after out-of-hospital cardiac arrest (OHCA) [Adequate mean arterial blood pressure (MAP) is vital to maintain cerebral blood flow (CBF) at a level sufficient for preserving oxidative energy metabolism. Cerebral autoregulation is impaired or right-shifted in approximately 30–50% of patients following cardiac arrest [This randomized trial was designed to compare the effect of two levels of MAP on global cerebral energy metabolism in comatose patients resuscitated from OHCA. Therefore, we tested the hypothesis that higher MAP improves CBF, cerebral oxygenation and oxidative metabolism by lowering the LP ratio, during post-resuscitation care compared with lower MAP. | PMC9951410 |
Methods | PMC9951410 |
|||
Trial design | S-20150173 HLP | BLOOD | The trial was a sub-study in the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX), see Supplementary Methods [According to national requirements and the principles of the Declaration of Helsinki, informed consent was obtained from next of kin and one independent medical doctor not involved with the trial. In addition, informed consent was obtained from patients who regained appropriate neurological function for independent decision-making. The Danish Regional Committee on Health and Research Ethics and Danish Data Protection Agency approved the protocol (S-20150173 HLP). The study was registered at ClinicalTrials.gov, identifier: NCT03095742 (30/03/2017). | PMC9951410 |
Patients | This sub-study included patients in a tertiary heart center, Odense University Hospital, Denmark. Inclusion and exclusion criteria have been published elsewhere [ | PMC9951410 |
||
Randomization and blinding | Patients were randomly assigned in a 1:1 ratio to low or high MAP using a web-based system involving dynamic permuted block sizes. The MAP intervention was double-blinded (see intervention). The physicians taking care of trial patients and assessing neurological prognosis were not blinded to bedside JBM and cerebral saturation. The neurophysiologist analyzing the EEGs and evaluating neurologic outcomes was unaware of the trial-group assignments and microdialysis data. | PMC9951410 |
||
Intervention | SEPARATION | The MAP intervention commenced at randomization and continued as long as the patients needed invasive blood pressure measurements. Patients were randomly monitored with a module (Phillips M1006B) offset to – 10% or a module offset to + 10%. Targeting a MAP of 70 mmHg during treatment in both groups caused a blinded comparison of approximately 63 and 77 mmHg, a 20% separation (Supplementary Methods). A randomized clinical study has validated the method for double-blinded comparison of MAP targets in the ICU setting [A protocol provided a recommendation for targeting a MAP of 70 mmHg in a three-stage approach: volume resuscitation to a central venous pressure of 10 mmHg, norepinephrine infusion, and the addition of a dopamine infusion for a maximal dose of 10 μg per kilogram of body weight per minute, if needed. | PMC9951410 |
|
Post-resuscitation procedure | normocapnia | Targeted temperature management (TTM) commenced at ICU admission targeting 36.0 °C for 24 h, followed by rewarming at a rate of 0.5 °C/h. Sedation was mandated in both groups during the TTM period. Mechanical ventilation was adjusted to ensure normocapnia (PaCO | PMC9951410 |
|
Neuromonitoring | neurological damage | JBM commenced after ICU admission and continued for 96 h or until arousal utilizing identical techniques as previously published (Additional file Bilateral, regional cerebral oxygen saturation (rSOThe biomarker of neurological damage, plasma neuron-specific enolase (NSE) level at 48 h, was measured by electrochemiluminescence and by a COBAS analyzer system (Roche Diagnostics) [ | PMC9951410 |
|
JBM reference values and classification of ischemia | mitochondrial dysfunction, jugular venous blood, cerebral ischemia | MITOCHONDRIAL DYSFUNCTION, CEREBRAL ISCHEMIA | The definition of normal microdialysate values (lactate, pyruvate, glucose, glycerol, glutamate, LP ratio) in human jugular venous blood was based on JBM reference values obtained in anesthetized patients undergoing elective cardiac bypass surgery [Definitions of the biochemical patterns for cerebral ischemia and mitochondrial dysfunction were based on principles obtained from intracerebral microdialysis [ | PMC9951410 |
Neurologic prognostication | status myoclonus, comatose | MULTIPLE ORGAN FAILURE, BRAIN DEATH, COMATOSE, REFRACTORY SHOCK | Active treatment continued until 72 h after TTM, except for patients with status myoclonus, brain death, or refractory shock with multiple organ failure. Patients who remained comatose despite cessation of sedation were evaluated by combining neurologic examination, EEG, somatosensory-evoked potential (SSEP), biomarkers (NSE) and brain CT. As previously described, EEGs were classified as highly malignant, malignant, or benign [ | PMC9951410 |
Outcome | bleeding, arrhythmia, seizures, ischemia, OHCA, infection, mitochondrial dysfunction | BLEEDING, ARRHYTHMIA, ADVERSE EVENTS, ISCHEMIA, INFECTION, MITOCHONDRIAL DYSFUNCTION, COMPLICATIONS | The primary outcome was the difference between time-averaged means of microdialysis parameters and LP ratio (intervals of 12 h) between low vs high MAP group within 96 h of post-resuscitation care. Secondary outcomes of clinical interest were to compare (i) variables reflecting cerebral energy metabolism and patterns of ischemia and mitochondrial dysfunction in patients with unfavorable and favorable neurological outcome [Neurological outcome was assessed at hospital discharge and 90 days after OHCA according to the Cerebral Performance Category (CPC) scale [The adverse events included in this report are bleeding, infection, arrhythmia, and seizures as well as complications related to the MD technique. | PMC9951410 |
Statistical methods | cerebral desaturation, ischemia, hypotension, seizures | REGRESSION, ISCHEMIA | We estimated that a sample of 46 patients would provide 90% power to detect a relative LP ratio reduction of 35% in the high MAP group, compared with the low MAP group, using a patient-to-patient variation with standard deviation (SD) of 15 [The mean between-group difference in blood pressure during the intervention period was calculated by mixed effects linear regression. Dynamic changes of MD variables were compared between treatment groups by linear mixed effects linear regression (Supplementary Methods).Time-averaged means of MD parameters in intervals of 12 h ensured statistical robustness in contrast to point values. Note that all hourly measurements were included in the mixed models, and only aggregated in the parametrization of the model, not in the measurements themselves.The mixed model fitting procedure handled missing values, assumed to be missing completely at random. Missing MD data rates were less than 5% and imputation where not used. Missing measurements were taken into account by the maximum likelihood estimation of the mixed models. Associations between MD variables, episodes of hypotension, EEG-verified seizures, cerebral desaturation, and neurological outcome were assessed with chi-square-test and logistic regression. Statistical comparison of episodes with ischemia and cerebral desaturation between outcome groups was performed using Mann–Whitney | PMC9951410 |
Results | PMC9951410 |
|||
Intervention | ROSC | SEPARATION | The median time from ROSC to randomization in the trial was 180 [120–210] min. There was a clear separation in MAP between the groups (mean difference: 15 mmHg ([CI], 13.1 to 17.3), p < 0.0001) (Fig. Mean arterial pressure during the intervention period. The MAP curves show the means, and the bars indicate ± 2 SD (95% of the observations are within the error bars). A clear separation in MAP between the groups (mean difference: 15 mmHg, Additional regulators of cerebral blood flow remained within therapeutic range with no difference in cardiac index, PaO | PMC9951410 |
Outcome | PMC9951410 |
|||
Jugular bulb microdialysis | ROSC | The median time from ROSC to microdialysis monitoring was 260 min in the low and high MAP groups with monitoring durations of 65 [47–91] and 63 [45–89] hours, respectively (Additional file | PMC9951410 |
|
Association between cerebral energy metabolism and MAP | No significant difference in microdialysis values between the two MAP groups was observed except for glycerol in the early post-resuscitation phase (12–36 h, Data are expressed as median (interquartile range). LP ratio: lactate/pyruvate ratio. Jugular bulb microdialysis variables in the study groups ( | PMC9951410 |
||
Association between cerebral energy metabolism and neurological outcome | Figure Median (IQR). Jugular bulb microdialysis parameters during the intervention period in patients discharged with unfavorable outcome (black line) (CPC 3–5, Non-survivors exhibited significantly increased levels of lactate, pyruvate, and glycerol (At 48 h, the median NSE ( | PMC9951410 |
||
Regional cerebral desaturation | During MAP intervention, no significant differences in rSOMedian (IQR). Regional cerebral oxygen saturation (rSO | PMC9951410 |
||
JBM variables in relation to critical episodes | EEG-verified | JBM levels in patients with EEG-verified epileptiform activity were not significantly different from other patients, except for significantly higher pyruvate levels during the first 48 h ( | PMC9951410 |
|
Neurological outcome | ANOXIC BRAIN INJURY | At hospital discharge 22 of 30 patients (73%) in the low MAP group and 15/30 (50%) in the high MAP group had a poor functional outcome CPC 3–5. Within 90 days, 12 of 30 patients (40%) in the low MAP group and 8 of 30 patients (27%) in the high MAP group had died. Overall mortality during hospital stay was 33% due primarily to severe anoxic brain injury and withdrawal of life-sustaining therapy. At 48 h, the median NSE level was 15 μg per liter in the low MAP group and 12 μg per liter in the high MAP group, | PMC9951410 |
|
Adverse events | sepsis, arrhythmia, seizures, bleeding | ADVERSE EVENTS, SEPSIS, ARRHYTHMIA, BLEEDING | No significant differences were found in the percentages of patients with serious adverse events, including sepsis, arrhythmia, seizures and bleeding (Additional file | PMC9951410 |
Discussion | EEG-verified, OHCA, hypoperfusion, post-cardiac arrest, cardiac arrest, comatose, Secondary brain injury, reperfusion injury, mitochondrial dysfunction, cerebral ischemia | HYPOPERFUSION, BRAIN HYPOXIA, CARDIAC ARREST, COMATOSE, TRANSIENT CEREBRAL ISCHEMIA, SECONDARY, SEPARATION, MITOCHONDRIAL DYSFUNCTION, HYPERTENSION, CEREBRAL ISCHEMIA | This double-blinded randomized trial compared two blood pressure targets in comatose patients resuscitated from OHCA. Targeting a higher MAP (77 vs. 63 mmHg) did not significantly improve cerebral energy metabolism within 96 h of post-resuscitation care. No secondary outcomes, including cerebral oxygenation (rSOBedside monitoring of global cerebral energy metabolism is a novel technique. It is based on experimental studies in pigs showing that microdialysis of the draining venous cerebral blood gives semi-quantitative information of cerebral interstitial levels of lactate, pyruvate and LP ratio at cerebral ischemia [Secondary brain injury seems to occur in the early period after OHCA and is driven by complex pathophysiological mechanisms such as reperfusion injury with mitochondrial dysfunction, impaired autoregulation and delayed hypoperfusion during the first 12 to 24 h after cardiac arrest [Despite a clinically significant separation between MAP groups (Fig. Compromised cerebral metabolism and brain hypoxia probably depend on several factors. Despite optimized MAP and oxygen delivery, diffusion limitations of oxygen [Interestingly, JBM revealed that jugular bulb lactate, LP ratio, and glycerol correlated negatively to the corresponding MAP in all patients. Moreover, we were able to discriminate specific subgroups (preexisting hypertension), benefiting more from an augmented MAP on cerebral metabolism.Cerebral reperfusion after OHCA is complex and there is a lack of data regarding the first hours after ROSC. In both MAP groups, a majority exhibited severe disturbance in cerebral energy metabolism with markedly increased LP ratio up to 20 h after the start of JBM (Fig. In experimental studies, near-normalization of LP ratio is obtained 60–120 min after recirculation in animals exposed to 30 min of complete cerebral ischemia [Though the LP ratio may return to a near-normal level after transient cerebral ischemia, the insult often causes lasting mitochondrial dysfunction [Although JBM did not start until about 260 min after ROSC, significant differences were obtained between the two outcome groups (CPC 1–2 vs. CPC 3–5) for variables related to oxidative energy metabolism (lactate, pyruvate, LP ratio) (Fig. In the CPC 3–5 group, lactate and pyruvate remained higher than in the CPC 1–2 group for up to 60 h (Fig. Identifying patients bedside suffering from severe mitochondrial dysfunction using JBM might optimize prognostication and individualize (improving oxygen utilization) the treatment of post-cardiac arrest patients and improve outcome.
Moreover, JBM revealed significantly higher pyruvate levels with EEG-verified epileptiform activity during the first 48 h (CPC 3–5).Glycerol was significantly increased in the low MAP group during a prolonged period (Fig. No difference in rSOOn the other side the non-significant difference between MAP groups could reflect an intact cerebral autoregulation. However, irrespective of chronic hypertension, no significant differences in rSO | PMC9951410 |
Limitations | death | SEPARATION, SECONDARY | Our study has several limitations. The assumption for the main study (BOX) 2 × 2 factorial design was that the effects of the MAP and Oxygen interventions were independent (no interaction) in relation to the primary outcome (death or CPC 3–4). However, central factors influencing cerebral metabolism are mainly, e.g., MAP, carbon dioxide and oxygen levels. These main regulators of cerebral metabolism have the potential of important interaction, which justified the exclusion of the “restrictive” oxygen group.
The study is mainly limited by the fact that, due to established clinical routines, it was impossible to start JBM until about 3–4 h after ROSC. The clinical impact of the JBM technique should be re-evaluated when the JBM catheter is positioned within 60 min after ROSC. The blinded MAP intervention was limited to a 20% separation, because the module manufacturer did not support a larger modification without changing the module software. Based on the main BOX trial, we expected significantly higher vasopressor-doses in the high MAP group [Given the known significant limitations of INVOS monitoring to estimate meaningful cerebrovascular physiology, we were not able to state that a higher MAP did not improve brain oxygenation.
Interpretation of the biochemical patterns is based on experiences from intracerebral microdialysis. Further investigations regarding the relationship between global brain 18-FDG-PET (cerebral metabolic rate of glucose) and levels of biochemical variables in cerebral tissue and the draining venous blood are necessary. We did not measure CBF during the study periods to demonstrate coherent findings in cerebral blood flow and JBM. However, our results reflect the complex pathophysiologic mechanisms underpinning secondary brain injury, and combined JBM, CBF measurements (e.g., brain | PMC9951410 |
Conclusions | ROSC, comatose | COMATOSE | In comatose patients resuscitated from OHCA, targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism within 96 h of post-resuscitation care. Patients with a poor clinical outcome exhibited significantly worse biochemical patterns documenting that inadequate tissue oxygenation and reperfusion instantly after ROSC is an essential factor determining neurological restoration. | PMC9951410 |
Acknowledgements | We thank the critical care healthcare professionals at the Department of Anesthesiology and Intensive Care, Odense University Hospital, who each and collectively made this study possible. | PMC9951410 |
||
Take-home message | ROSC, comatose | COMATOSE | Among comatose patients resuscitated from OHCA, targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism and oxygenation. Initial cerebral reperfusion in most patients is insufficient to restore cerebral energy metabolism, potentially influencing neurological outcomes. | PMC9951410 |
140-character tweet | ROSC, comatose | CARDIAC ARREST, COMATOSE | Targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism among comatose patients resuscitated from cardiac arrest. | PMC9951410 |
Author contributions | SIM, CH, JK, PT, CHN, THN and HS contributed to conceptualization. SIM, AF, CH, JK, PT, CHN, THN, AT, TK, and HS provided methodology. SIM and SM carried out formal analysis. SIM, SV, DM, and TT performed investigation. SIM and HS performed project administration. THN, AF, CH, JK, HS, and PT provided resources. AT and TK performed validation. SIM performed writing—original draft. All authors performed writing—review and editing. PT, JK, CH, and HS performed supervision. All authors read and approved the final manuscript. | PMC9951410 |
||
Funding | This study was sponsored by non-profit organizations, including the University of Southern Denmark, Region of Southern Denmark, and the Department of Anesthesiology and Intensive Care, Odense. Moreover, the study received independent grants from A.P. Moeller Foundation for the Advancement of Medical Science; Intensive Symposium Hindsgavl; Danish Society of Anesthesiology & Intensive Care Medicine; The Board of Physicians’ Legacy Committee, Odense University Hospital. The funding organizations did not affect the trial’s design, administration, or reporting. | PMC9951410 |
||
Availability of data and materials | Deidentified data are available for sharing. The dataset analyzed in the present manuscript is available from the corresponding author on reasonable request. Any proposal will need approval from the ethics committee before sharing any patient data. A signed data transfer agreement will be required if a proposal is approved before data sharing. | PMC9951410 |
||
Declarations | PMC9951410 |
|||
Ethics approval and consent to participate | HLP, comatose | COMATOSE | The Danish Regional Committee on Health and Research Ethics approved the protocol (MICA-S-20150173 HLP, 01/01/2017). Danish legislation permits immediate inclusion of patients who are unable to provide consent in nonpharmaceutical trials and mandates that consent should be obtained at the first given opportunity after inclusion in the trial. Consent for the inclusion of comatose patients was obtained from a legal representative and a physician with expertise in the clinical area but no affiliation with the trial. A physician obtained proxy consent at the earliest possible opportunity. Informed consent from the patient was obtained if the patient regained consciousness. | PMC9951410 |
Consent to publish | Not applicable. | PMC9951410 |
||
Competing interest | None of the authors has any conflict of interest to declare. | PMC9951410 |
||
References | PMC9951410 |
|||
Introduction | EOS | Pain-reducing effects of music listening are among the most widely studied and most replicable effects of music in clinical settings [The lack of research comparing pain-reducing effects between these two forms of music listening (i.e active vs. passive) is noteworthy because recent advances have proposed that active sensorimotor synchronization to music is associated with the activation of the endogenous opioid system (EOS), including the release of endorphins [Details on the study sample are shown in | PMC10381080 |
|
Consort flow diagram on the study sample. | The experimental design is illustrated in | PMC10381080 |
||
Experimental design. | The experiment used a 2x2 design with the within-subject factors In accordance with the well-established pain-reducing effects of music listening in clinical settings [ | PMC10381080 |
||
Materials and methods | PMC10381080 |
|||
Participants | A random sample of 59 participants, who were naïve with regard to the hypotheses, was included in the data analysis (age range 19 to 35 years, | PMC10381080 |
||
Stimuli | Music stimuli were presented with an average sound pressure of approximately 60 dB SPL over Beyerdynamic DT 770-PRO 250 Ohm headphones. 10 instrumental music experts were selected, each 30 seconds long (song characteristics are provided in | PMC10381080 |
||
Pressure algometry | Pain | Pain was applied by the experimenter during each trial using a Wagner Force One Pressure Algometer (Wagner Instruments, Greenwich, USA). The equipment head (used to apply the pressure) had a diameter of 12mm and a surface area of 113mm | PMC10381080 |
|
Procedure | The investigation took place in a laboratory room at the department of biological and medical psychology of the University of Bergen. 40 experimental trials were delivered, 10 for each experimental trial type (Music Active, Music Passive, Silence Active, Silence Passive). The experimenter was blinded during the entire experimental procedure. Each trial started with an instruction screen where participants were either instructed to tap their right foot like a metronome (active tapping task) or to relax (passive control task). For exact experimental instructions see | PMC10381080 |
||
Experimental design & data analysis | Data analysis was computed using R (version 4.0.4) including the R Stats, R Base, and ggplot 2 (version 3.3.3) [ | PMC10381080 |
||
Within-subjects perceived pain per experimental condition. | pain | The violin plots show the distribution density of the perceived pain (rated on a scale ranging from 1 to 9) during music (red) or silence (blue) while performing either an active tapping task (darker colors) or a passive control task (lighter colors). The embedded box-and-whisker plots represent the 25th and the 75th percentiles of the distributions, respectively. Upper and lower whiskers extend from the hinge to the largest/smallest value no further than 1.5 * inter-quartile range. The vertical lines in the boxes indicate median values, and the white disks indicate the means. The black dots show the jittered data points, and the dashed grey horizontal lines in the background represent the mean difference of the perceived pain between music with tapping and silence without tapping. Note here that the pain-reducing effect of music with tapping (Music Active, dark red) compared with silence without tapping (Silence Passive, light blue) has a large effect size (Despite the observation of the strongest pain-reducing effect of tapping to music in the descriptive analysis, the LME analysis failed to reveal a significant interaction. However, it is important to note that the absence of a significant interaction does not necessarily imply that the tapping was not effective. From a clinical perspective, the absence of statistically significant differences must be carefully scrutinized [ | PMC10381080 |
|
Emotional mechanisms underlying the pain-reducing effect of sensorimotor synchronization to music | To test our assumption that the mechanisms driving the pain-reducing effect of sensorimotor synchronization to music include emotion, we computed two additional LME analyses. For detailed information on the experimental design and data analysis for both analyses see | PMC10381080 |
||
Preference effect on the perceived pain for the music trials. | pain | Data are shown separately for the active tapping task and the passive control task. Perceived pain (rated on a scale ranging from 1 to 9) was reduced with increasing preference (rated on a scale ranging from 1 to 9 and mean-centered) and while performing the active tapping task (solid black line) compared to the passive control task (dashed black line). Blue shaded areas represent the respective 95% Confidence Intervals (CIs) and their overlapping area.The second LME analysis on involved emotional mechanisms examined the effect of | PMC10381080 |
|
Within-subjects felt pleasantness per experimental condition. | The violin plots show the distribution density of the felt pleasantness (rated on a scale ranging from 1 to 9) during music (red) or silence (blue) while performing either an active tapping task (darker colors) or a passive control task (lighter colors). Note that pleasantness ratings were descriptively highest for trials in which participants were tapping to the music. The embedded box-and-whisker plots represent the 25th and the 75th percentiles of the distributions, respectively. Upper and lower whiskers extend from the hinge to the largest/smallest value no further than 1.5 * inter-quartile range. The vertical lines in the boxes indicate median values, and the white disks indicate the means. The black dots show the jittered data points, and the dashed grey horizontal lines in the background represent the mean difference of the felt pleasantness between music with tapping and silence without tapping. | PMC10381080 |
||
Discussion | pain | Our results show that participants felt less pain while actively tapping to music, compared with merely listening to music. This finding indicates that sensorimotor synchronization to music has analgesic effects. Compared to music listening without tapping, tapping to music elicited a moderate pain-reducing effect, and compared to the silent control condition without tapping, tapping to music elicited a large, clinically significant [Notably, our findings are consistent with the hypothesis that sensorimotor synchronization to music reduces pain by virtue of EOS activation [We also investigated potential mechanisms underlying the analgesic effects of sensorimotor synchronization to music. So far, the (causal) mechanisms underlying the pain-reducing effects of (passive) music listening are not fully understood, but previous work has implicated attentional and emotional mechanisms as the two main candidates [Additionally, since pain-reduction is commonly used as a proxy of EOS activation [ | PMC10381080 |
|
Limitations | pain | Our behavioral approach only provides an indirect measure of the activation of the EOS. This limitation warrants further discussion because the mixed-trial design of our study poses the question as to whether the level of endogenous opioids can vary every minute, forty times in a row, without contaminating the subsequent trial. We believe that our results are physiologically plausible, because in a previous functional magnetic resonance imaging (fMRI) study, also using a mixed-trial design, we showed that 30 seconds of pleasant vs. unpleasant music (corresponding to the length of the musical stimuli used in the present study) are sufficient to elicit activity changes in the hippocampus [Another limitation of our study is that our four experimental conditions (especially music with tapping vs. silence with tapping) might have differed in their task difficulty. Thus, we cannot exclude the possibility that our results are confounded by effects of task difficulty. However, our results indicate that pleasantness and familiarity contributed to the modulation of pain (see above), and therefore the pain-reducing effects of sensorimotor synchronization to music cannot be explained by task difficulty only. Nevertheless, it remains a matter of future studies to elucidate the influence of task difficulty on pain-reducing effects of sensorimotor synchronization to music. | PMC10381080 |
|
Conclusion | EOS, pain | Results demonstrate that sensorimotor synchronization to music significantly impacts pain perception and can amplify the well-established pain-reducing effect of merely listening to music. Our results shed new light on the mechanisms underlying pain reduction with music, suggesting that such effects are driven by social bonding, attention, emotion, and preference. Our findings support the recent hypothesis that social bonding emerges with music due to the activation of the endogenous opioid system (EOS) with sensorimotor synchronization [ | PMC10381080 |
|
Supporting information | (DOCX)Click here for additional data file.(DOCX)Click here for additional data file.(DOCX)Click here for additional data file. | PMC10381080 |
||
CONSORT checklist. | (DOC)Click here for additional data file. | PMC10381080 |
||
Music excerpts played during the experiment. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Descriptive statistics of the applied pressure and duration of the applied pressure. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Inferential statistics of the LME analysis on single trial perceived pain. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Paired-Samples t-tests (one-tailed) on the perceived pain between all four experimental conditions. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Inferential statistics of the LME analysis on the single trial perceived pain for music trials. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Inferential statistics of the LME analysis on the single trial felt pleasantness. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Descriptive statistics of the felt arousal per experimental condition. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Supplementary methods for the pressure data. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Experimental instructions. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Supplementary methods: Experimental design and data analysis on emotional mechanisms underlying the pain-reducing effect of sensorimotor synchronization to music. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Data analysis & results on the pain-reducing effect of sensorimotor synchronization to music including the mean-centered EHI as a covariate to test for confounding effects of handedness. | (DOCX)Click here for additional data file. | PMC10381080 |
||
Data analysis & results on the pain-reducing effect of sensorimotor synchronization to music including gender as a covariate to test for confounding effects. | (DOCX)Click here for additional data file. | PMC10381080 |
||
1. Introduction | DOMS, skeletal muscle, inflammation, EIMD, muscle damage | INFLAMMATION, OXIDATIVE STRESS | Unaccustomed eccentric exercise results in muscle damage limiting physical performance for several days. This study investigated if Greenshell™ mussel (GSM) powder consumption expedited muscle recovery from eccentric exercise-induced muscle damage (EIMD). Methods: Twenty untrained adult men were recruited into a double-blind, placebo-controlled, cross-over study and were randomly assigned to receive the GSM powder or placebo treatment first. Participants consumed their allocated intervention for four weeks then completed a bench-stepping exercise that induced muscle damage to the eccentrically exercised leg. Muscle function, soreness and biomarkers of muscle damage, oxidative stress and inflammation were measured before exercise, immediately after exercise and 24, 48 and 72 h post exercise. GSM powder promoted muscle function recovery, significantly improving (Unaccustomed and prolonged eccentric exercise leads to muscle damage, resulting in reduced muscle strength and mobility [While the mechanisms underpinning EIMD and associated symptoms such as DOMS are not precisely known, reduced muscle function from muscle damage is attributed to the disturbance of the highly ordered sarcomere structure of skeletal muscle [There is increasing demand for nutritional strategies to reduce the severity of muscle damage or to expedite muscle recovery from EIMD. A variety of plant- and marine-derived foods to support muscle recovery following EIMD have been researched, and variable efficacy of polyphenol-rich foods and marine oils in various formats in accelerating the recovery of muscle performance and reducing DOMS following EIMD has been reported [New Zealand green-lipped mussel (The benefits of GSM oil in supporting muscle recovery from EIMD have been attributed to the anti-inflammatory properties of bioactive constituents including in the ω-3 polyunsaturated fatty acids (PUFAs) (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), sterols, sterol esters and polar lipids [Although there is compelling clinical evidence supporting the efficacy of GSM oil for muscle recovery following EIMD, it is unclear whether supplementation with GSM powder is equally beneficial. PernaUltra™ is a flash-dried powder of GSM whole meat, prepared using a standardised proprietary manufacturing process. It is a complex blend of bioactive lipids, polysaccharides and proteins [ | PMC10221610 |
2. Materials and Methods | PMC10221610 |
|||
2.1. Study Participants | A total of 22 healthy male volunteers between 21 and 45 years old who were not undergoing any form of exercise training and had similar fitness characteristics based on the Baecke habitual questionnaire [ | PMC10221610 |
||
2.2. Study Design | muscle damage, pain | CONTRACTIONS | This was a randomised, double-blind, placebo-controlled, cross-over intervention study. Eligible participants attended a familiarisation session at least one week prior to commencing the study. In this session, they were instructed on how to perform the bench-stepping exercise that they would be required to complete on their exercise trial day and the muscle function assessments on an isokinetic dynamometer (Biodex Medical Systems Inc., New York, NY, USA) that they would be required to undergo during their exercise trial and recovery days.All participants underwent a six-week dietary washout period where they omitted foods containing New Zealand GSM and supplements and foods high in omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Participants were randomised into either the PernaUltra GSM powder or placebo intervention group for the study’s first arm and asked to consume their allocated intervention daily for four weeks. Participants arrived on location within 24 h of their final supplementation day to complete their exercise trial day.Participants avoided strenuous exercise 48 h prior to their scheduled trial day. Upon arrival at the laboratory, participants completed the short-form McGill pain questionnaire (SF-MPQ) [Participants returned to the facility 24, 48 and 72 h post exercise for recovery assessments. On each visit, participants completed the SF-MPQ before donating a venous blood sample. After completing a five-minute warmup on a cycle ergometer, muscle function was assessed with the Biodex isokinetic dynamometer as well as perceived pain during the first eccentric and isometric contractions. During the 72 h recovery period, participants avoided strenuous exercise and continued to omit New Zealand GSM and foods and supplements that contained high concentrations of EPA and DHA from their diet.Before the beginning of the second trial arm, participants underwent another six-week dietary washout period. In the second trial arm, participants were supplemented with the dietary intervention that they were not allocated to during the first trial arm. Participants underwent the same muscle damage and recovery protocols but with the opposite leg to the one that had undergone eccentric muscle damage during the first trial arm. The participants’ progress through the phases of this randomised, cross-over study is illustrated in the Consolidated Standards of Reporting Trials (CONSORT) flow diagram ( | PMC10221610 |
2.3. Dietary Intervention | The GSM and placebo interventions used in this study and the methods to characterise their composition have previously been described [ | PMC10221610 |
||
2.4. Exercise Protocol | The bench-stepping exercise protocol used in this study was modified from Newham et al. [ | PMC10221610 |
||
2.5. Muscle Function Assessment | CONTRACTION, CONTRACTIONS | Participants were seated on a Biodex isokinetic dynamometer at a position where the femoral epicondyle of the tested leg was aligned with the machine’s axis of rotation. The ankle strap of the machine was positioned 5 cm proximal to the test leg’s medial malleolus, and the ankle and thigh of the test leg were strapped firmly to the machine to isolate the movement of the quadriceps. The range of motion of the test leg was set at 60° for concentric and eccentric contractions and fixed at 75° for isometric contractions using the dynamometer’s goniometer. Participants performed five maximal eccentric, isometric and concentric contractions with each contraction type separated by one minute of passive rest. Participants maintained five seconds of maximal effort during each isometric contraction. The torque during concentric contractions was measured at an angular velocity of 30°/s. The absolute peak torque from the five contractions for each movement was recorded. | PMC10221610 |
|
2.6. Subjective Pain Assessments | muscle soreness, affective pain, pain | CONTRACTIONS | Perceived muscle soreness during muscle function assessments was determined during the exercise trial and recovery (24, 48 and 72 h post exercise) days. Participants rated the severity of soreness of the exercising leg during the first maximal eccentric and isometric contractions on a 5-point Likert scale ranging from 1 to 5 (1 = no soreness; 5 = worse possible pain).The muscle soreness of the resting eccentrically exercised leg was assessed with the SF-MPQ before the bench-stepping exercise and at selected post-exercise timepoints (0, 24, 48 and 72 h post exercise). The questionnaire comprised 15 pain-related adjectives, and participants rated each adjective on scale of 0 (none) to 3 (severe). The sum from each adjective score was calculated to give the total pain measure. The pain descriptors in the SF-MPQ included 4 affective pain and 11 sensory pain adjectives, allowing for the specific assessment at these 2 pain dimensions. In addition, the SF-MPQ included a VAS scale anchored by descriptors “no pain” and “worse possible pain” at the opposite ends of the 10 cm scale to assess average pain experienced by participants. | PMC10221610 |
2.7. Blood Sampling | OXIDATIVE STRESS, LYSIS | Venous blood samples were collected into heparin and ethylenediaminetetraacetic acid (EDTA) vacutainer tubes and centrifuged at room temperature. The plasma layer and erythrocytes were collected, aliquoted and stored at −80 °C until measurement of creatine kinase (CK), cartilage oligomeric matrix protein (COMP), oxidative stress, antioxidant capacity and cytokine concentrations.For isolation of peripheral blood mononuclear cells (PBMC), the buffy coat interface containing mononuclear cells following centrifugation was collected and washed with Dulbecco’s phosphate-buffered saline (DPBS). Following incubation in erythrocyte lysis buffer (Sigma; Cat. No. R7757, St. Louis, MO, USA), cells were washed and suspended in DPBS for subsequent cell staining. | PMC10221610 |
|
2.8. Creatine Kinase | Plasma CK collected pre and immediately post exercise and 24, 48 and 72 h post exercise was measured at a commercial laboratory (Canterbury Health Laboratories, Christchurch, New Zealand). The analysis of CK was quantified by spectrophotometry, which measured the rate of nicotinamide adenine dinucleotide (NADH) formation from an enzymatic reaction using an automated Beckman Coulter AU5822 analyser. Plasma, and not serum, was the preferred analyte by the laboratory, and the reference intervals for plasma CK in males were reported to be between 60 and 22 U/L. | PMC10221610 |
||
2.9. Immune Measures | PMC10221610 |
|||
2.9.1. Plasma Cytokine | TUMOUR NECROSIS | Plasma cytokine concentrations were analysed by bead array using Biolegend Legendplex™ 13-plex Human Essential Response panel (Cat. No. 740930, San Diego, CA, USA) according to the manufacturer’s instructions. The simultaneous quantitation of 13 cytokines (interleukin (IL)-4, IL-2, C-X-C motif chemokine ligand (CXCL)10 (IP-10), IL-1β, tumour necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, IL-17A, IL-6, IL-10, interferon (IFN)-γ, IL-12p70, CXCL8 (IL-8), and transforming growth factor (TGF)-β1) in plasma samples was measured using a BD FACSverse™ flow cytometer (BD Biosciences, San Jose, CA, USA). | PMC10221610 |
|
2.9.2. Immune Cell Phenotyping | Isolated PBMC were first stained with Biolegend “zombie NIR” fixable viability dye (Cat. No. 423106; San Diego, CA, USA) according to the manufacturer’s instructions for 15 min at room temperature. Cells were washed in DPBS before being stained with fluorescently labelled cell surface markers at 4 °C for 15 min. The Biolegend antibodies used were PE-Fire700 CD45 (Haematopoietic cell marker); BV605 CD3ε (T cells/natural killer T (NKT) cells); BV510 CD4 (T helper/Treg); BV650 CD8a (Cytotoxic T cells/NKT cells); BV711 CD25 (Treg/activated T cells); APC-Fire750 CD127 (Treg); PerCP CD38 (Activated NKT cells/Activated T cells/B cells); BV421 CD68 (Myeloid cells); BV570 CD56 (NK cells/NKT cells/T cells); PE-Cy7 CD16 (natural killer (NK) cells/monocytes/neutrophils); AF488 CD14 (Monocytes/neutrophils); PE-Cy5 CD15 (Neutrophils); AF647 CD11b (monocytes/macrophages); PE CD11c (monocytes/dendritic cells); BV750 HLA-DR (activated monocytes/DCs). The PBMCs were fixed in 4% formalin and then suspended in fluorescence-activated single cell sorting (FACS) buffer and analysed on a Cytek Aurora Spectral 3 laser flow cytometer (Cytek Biosciences, Fremont, CA, USA) with live spectral unmixing. Cell phenotype subpopulations were identified from Flow Cytometry Standard (FCS) files using the FlowJo software (BD Biosciences, San Jose, CA, USA). | PMC10221610 |
||
2.10. Statistical Analysis | Statistical analysis of data was conducted using analysis of variance (ANOVA), based on linear mixed effect models with fixed effects for trial arm, treatment and time × treatment interaction and random effects for participant, participant × trial arm and participant × time. Residuals were inspected to check that the assumptions of the model were satisfied; for many of the antioxidant and cytokine measures, data were log-transformed before analysis to stabilise the variance. For most data, raw means are presented; for antioxidant and cytokine measures, there were a few missing samples which influenced the raw data means. For these measures, predicted means were calculated, and where the data had been log-transformed, the predicted means were back-transformed. Models were fitted with the R package Imer Test, and post-hoc tests were performed using the predict means package. | PMC10221610 |
||
3. Results | PMC10221610 |
|||
3.1. Physical Characteristics of Participants | The variation in age, height and weight of participants recruited in this study is presented in Anthropometric measures of each volunteer were measured using manual scales, and habitual activity was determined using the Baecke Physical Activity Questionnaire. Vest weight worn by participants was equivalent to 15% of their bodyweight, and the bench height was set at 110% of participants’ lower leg length. Data are mean ± SD. | PMC10221610 |
||
3.2. Muscle Function | Eccentric exercise from bench-stepping exercise induced a significant decline (time effect; For peak concentric torque, there was a significant reduction (time effect; | PMC10221610 |
||
3.3. Subjective Pain Assessments | DOMS, muscle soreness, Muscle damage, pain | CONTRACTIONS | Muscle damage from repeated eccentric contractions is typically accompanied by DOMS that persists for several days after exercise. The post-exercise sensory, affective, total and VAS-assessed pain of the eccentrically exercised leg at rest significantly increased (Total pain scores of the resting eccentrically exercised leg significantly increased in both treatment groups post exercise (time effect; When muscle soreness during maximal voluntary contractions was assessed, a significant ( | PMC10221610 |
3.4. Creatine Kinase | The bench-stepping exercise induced a significant change in plasma CK (time effect: | PMC10221610 |
||
3.5. Immune Measures | A significant time effect (No time, treatment or time × treatment interactions were measured for circulating total and sub populations of T cells, monocyte and neutrophils, indicating that exercise and GSM supplementation had no effect on the circulating populations of these immune cells post exercise ( | PMC10221610 |
||
4. Discussion | DOMS, Reduced muscle function, muscle soreness, EIMD, muscle damage, muscle [Muscle damage | INFILTRATION, CONTRACTIONS, INFLAMMATORY RESPONSE | The current study investigated the effectiveness of daily supplementation with GSM powder for four weeks to accelerate muscle recovery after EIMD in untrained males. Our findings show that GSM powder supplementation expedited muscle recovery following exercise-induced damage as determined by faster recovery of muscle function, reduction in plasma CK concentrations and decreased soreness of target muscle groups. The potential mechanism of action for GSM powder in supporting muscle recovery may be partially through modulating the post-exercise immune responses to facilitate muscle repair. Together, these results support our hypothesis that consuming GSM powder supports muscle recovery in untrained males following EIMD to the quadriceps. To our knowledge, this is the first study demonstrating the benefits of GSM powder as a functional food for supporting muscle recovery after exercise.Reduced muscle function following prolonged unaccustomed eccentric exercise is a classic indicator of muscle damage. Previous studies using a bench-stepping paradigm have reported up to a 20% reduction in peak isometric torque that persisted for 48 h post exercise in untrained cohorts [Previous nutrition intervention studies have investigated the benefits of supplementing with GSM and other marine-derived lipids in attenuating eccentric EIMD. Using a downhill running protocol to induce muscle damage to the quadriceps, supplementation with a GSM-derived lipid blend did not attenuate exercised-induced reductions in peak concentric and isometric torque of the quadriceps in trained and untrained runners [Delayed onset muscle soreness (DOMS) is a common outcome of unaccustomed physical activity, typically occurring between 24 to 72 h after exercise and gradually subsiding thereafter. The discomfort caused by DOMS adversely affects the execution of daily activities and athletic performance [Eccentric exercise can disrupt the highly arranged structure of skeletal muscle, releasing CK into circulation, which is a recognised biomarker of EIMD. Bench-stepping exercise has been reported to induce a delayed increase in plasma CK, peaking at 48 to 72 h post exercise and returning to baseline concentrations after 7 days of recovery [The functional benefits of GSM supplementation for supporting muscle recovery are largely attributed to the anti-inflammatory bioactivity of GSM constituents. Exercise-induced muscle damage signals the increased release of cytokines by skeletal muscle and resident immune cells, resulting in an acute dynamic inflammatory response. Of the cytokines measured in this study, only MCP-1 was significantly upregulated after exercise, and the significant increase in MCP-1 observed immediately post exercise was mitigated in the GSM powder group. MCP-1 is a potent chemokine that regulates the migration and infiltration of monocytes into damaged muscle tissue, where they differentiate to macrophages and clear damaged myofibers, facilitating the remodelling and repair of damaged muscle [Muscle damage protocols, such as repeated eccentric quadriceps maximal voluntary contractions and bench stepping, induce an increase in IL-6 that peaks 6 h post exercise then returns to pre-exercise concentrations following 24 h recovery [An interesting finding in this study was the intervention effect on post-exercise circulating NK cell populations. Acute exercise has been shown to lead to an immediate increase in circulating NK cell numbers post exercise that returns to pre-exercise levels within 24 h of recovery [Previous intervention studies have postulated that the anti-inflammatory and analgesic effects of GSM may only be partially explained by the bioactive properties of EPA and DHA [It is important to acknowledge that the present study had limitations. Participants were solely untrained men; therefore, the findings in this study may not be extrapolated to women or trained individuals. Training status has a significant influence on the physiological and biological parameters of muscle damage due to the highly adaptable nature of skeletal muscle to repeated exercise [ | PMC10221610 |
5. Conclusions | DOMS, EIMD | The present study demonstrates that long-term supplementation with New Zealand GSM powder expedited the recovery of muscle function, reduced the severity of DOMS and facilitated the dissipation of DOMS and CK to baseline during recovery following EIMD to the quadriceps. These findings support the potential benefits of GSM powder as a functional food for supporting muscle recovery in untrained men. Further research is required to investigate whether GSM confer similar benefits in untrained women and trained athletes. Future research to characterise whether the efficacy of GSM powder in supporting muscle recovery is mediated by the immune-modulatory properties of GSM powder constituents is recommended. | PMC10221610 |
|
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10221610 |
||
Author Contributions | Conceptualization, D.L., M.B., M.R.M. and H.S.T.; methodology, D.L., M.B. and O.S.; validation, D.L., M.B. and O.S.; formal analysis, D.H.; investigation, D.L., N.N., G.S., O.S., N.B., A.K., T.B., K.B.-H. and A.C.; data curation, D.L., N.N., N.B. and D.H.; writing—original draft preparation, D.L.; writing—review and editing, M.B., O.S., M.R.M., N.N., G.S., H.S.T. and D.H.; supervision, D.L. and M.R.M.; project administration, D.L., N.N., G.S. and M.R.M.; funding acquisition, D.L., M.R.M. and H.S.T. All authors have read and agreed to the published version of the manuscript. | PMC10221610 |
||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki, and approved by New Zealand’s Southern Health and Disability Ethics Committee (20/STH/75; 14 July 2020). | PMC10221610 |
||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from all subjects involved in the study to publish this paper. | PMC10221610 |
||
Data Availability Statement | The data presented in this study are available on request from the corresponding author. The data are not publicly available due to ethical guidelines to protect the privacy of participants in this study. | PMC10221610 |
||
Conflicts of Interest | The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. | PMC10221610 |
||
References | Muscle soreness, Pain | Consolidated Standards of Reporting Trials (CONSORT) diagram illustrating the flow of participants through each stage of the randomised crossover trial.Muscle function assessments after bench-stepping exercise. Peak quadriceps isometric (Pain assessment of eccentrically exercised leg at rest after bench-stepping exercise. Total (Muscle soreness scores during eccentric (Plasma creatine kinase concentrations pre-exercise (Pre) and 0 (Post), 24, 48 and 72 h post exercise following 4 weeks of placebo or Greenshell™ mussel (GSM) supplementation. Data are means ± SEM and expressed as % change from pre-exercise concentrations. * indicates significant difference from baseline concentration (Plasma monocyte chemoattractant (MCP-1) concentration (Physical characteristics and habitual activity scores of recruited participants ( | PMC10221610 |