Intraoperative stimulation of the afferences at the surgical site increases the adrenal secretion of catecholamines and cortisol and the pituitary secretion of adrenocorticotropic hormone (ACTH). The response is different for each hormone and for various types of surgical stimulation (1,2). Cortisol, ACTH, epinephrine, and norepinephrine blood levels have been studied to evaluate the effect of different anesthetic techniques on the magnitude of surgical stress response (3–7). Large-dose opioids, together with neuraxial anesthesia, are efficient means to reduce intraoperative stress hormone release (2).
In awake patients, nonpharmacological methods such as mental imagery and therapeutic suggestions can be used to reduce psychological stress. Listening to music in the pre- and postoperative periods has been shown to decrease anxiety related to surgery and to reduce the need for analgesic medications (8,9). In patients under regional anesthesia, music decreases the need for sedation and analgesia, and it also decreases the plasma levels of cortisol, epinephrine, and tissue-type plasminogen activator (10,11).
The effect of music on the neurohumoral response to surgery under general anesthesia has never been studied. Nilsson et al. (12) have shown that hysterectomy patients who listened to music under general anesthesia needed fewer narcotics for postoperative analgesia than patients who did not listen to music. It is then conceivable that perception of auditory stimuli during general anesthesia could result in a modulation of the neurohormonal response. We hypothesized that listening to music under general anesthesia would decrease the release of surgical stress hormones, as measured by epinephrine, norepinephrine, cortisol, and ACTH blood levels.
After IRB approval and written, informed consent, 30 ASA status I–III female patients, aged 18 to 70 yr and scheduled for abdominal hysterectomy, hysterosalpingo-oophorectomy, or salpingo-oophorectomy under general anesthesia, were enrolled in this prospective, randomized, and double-blinded study. Patients with auditory problems, hormonal dysfunction (adrenal, pituitary, or thyroid), steroid use, cocaine abuse, an established diagnosis of severe anxious disorder, uncontrolled hypertension (diastolic blood pressure >105 mm Hg as measured on the ward), or Raynaud syndrome were excluded from the study.
Patients were randomly assigned to the music group or the no-music group. During the preoperative visit, the patients of both groups were asked to choose music that was relaxing to them among a choice of four proposed compact discs (CDs) (classical, jazz, new-age, and popular piano music). The chosen CD was played, and the patients of both groups were asked to adjust the sound volume to a comfortable level. Patients were not premedicated. Standard monitoring was used. After the administration of oxygen, induction was performed with fentanyl 2–3 μg/kg and propofol 1.5–2 mg/kg, and tracheal intubation was facilitated with rocuronium 0.6 mg/kg. After intubation, headphones were placed on the patient’s ears in both groups. The CD was then played in the music group by an anesthesiologist not involved in the study. Nothing was played in the no-music group. The CD player was covered so that the investigator remained blinded to the study group. A 20-gauge arterial catheter was inserted in the radial artery, and a BIS monitor was installed.
Anesthesia was maintained with 50% oxygen in air and isoflurane adjusted (0.3% to 1.5% end-tidal concentration) to maintain a BIS value between 50 and 60. Episodes of hypertension and tachycardia (defined as increases of 20% more than baseline) were first treated with an increase of isoflurane concentration to maintain the BIS target of 50–60. If this was not sufficient or if the BIS value was already in the targeted zone, boluses of fentanyl 0.5–1 μg/kg were added (up to two boluses per episode). In case of persistent hypertension, β-adrenergic blockers were used as rescue medication. Atropine 0.01–0.02 mg/kg was given for episodes of bradycardia (<50 bpm). Hypotension (defined as a decrease of 20% less than baseline) was treated with phenylephrine 0.1 mg IV. Ephedrine was not used. Rocuronium 10–20 mg was given as needed to maintain a single twitch on the neuromuscular monitor.
The sample times were as follows: T1, immediately after arterial line insertion; T2, 5 min after peritoneal incision; T3, at skin closure; and T4, 30 min after arrival in the recovery area. At each sample time, 20 mL of blood was withdrawn for the dosage of epinephrine, norepinephrine, cortisol, and ACTH. Epinephrine and norepinephrine concentrations were determined by using high-performance liquid chromatography with electrochemical detection. Blood samples were collected in prechilled tubes containing EGTA and reduced glutathione (Amersham, Ontario, Canada) and kept on ice. Samples were processed within 30 min of withdrawal, centrifuged at 4°C and 1500 g for 15 min, and stored as aliquots at −20°C until analysis. Analyses were performed in batches, and all samples from a single patient were run in one assay. The extraction procedure was a modification of the technique used by Ganhao et al. (13).
Blood samples for ACTH were collected in prechilled tubes containing EDTA and kept on ice. Samples were processed as described previously, and analyses were also done in batches; all samples from a single patient were run in one assay. ACTH was measured by immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA) according to the manufacturer’s instructions. Serum cortisol was performed by using an ADVIA Centaur® automated analyzer (Bayer, Toronto, Ontario, Canada) with chemiluminescent immunometric assay according to the manufacturer’s recommendations.
At each sample time, mean arterial blood pressure (MAP), heart rate (HR), BIS value, end-tidal isoflurane concentration, and total fentanyl dosage were noted. At T4 (recovery room), only MAP and HR were noted. At the end of wound closure and after the last intraoperative blood sample was drawn (T3), the CD player was stopped and the headphones were removed. Residual neuromuscular block was reversed with neostigmine (0.05 mg/kg) and glycopyrrolate (0.01 mg/kg). Isoflurane was turned off, patients were awakened, and the trachea was extubated according to usual criteria. A patient-controlled analgesia (PCA) morphine pump was installed for each patient in the recovery room. Before using their PCA pump, patients received boluses of morphine (3–5 mg IV) until optimal pain relief. No analgesic adjuvant was used for the duration of the study.
The total amount of morphine administered in the recovery room and via the PCA for the first 24 postoperative hours was compiled. Each patient was visited 24 h after surgery, questioned about pain relief, and asked whether she recalled having heard music during the surgical procedure.
Statistical analyses were performed with the S-Plus statistical package, Release 6.1 (Insightful Corp., Seattle, WA). Differences in demographic and intraoperative data between the two groups were sought by using Fisher’s exact test and unpaired Student’s t-tests for nonparametric and parametric variables, respectively. All the comparisons were two tailed. Blood levels of stress hormones were compared within and between groups and in time by using two-way analysis of variance for multiple comparisons. P < 0.05 was considered significant. Assuming an α of 0.05, a posteriori power calculation allowed us to determine that we could detect a 25% reduction of circulating levels of cortisol in the music group when compared with the no-music group, for a power of 85%.
There was no difference between the two groups with regard to demographic and surgical data or the time of day the surgery was performed (Table 1). There was no group difference in terms of MAP, HR, end-tidal isoflurane concentration, BIS value, dose of fentanyl at any time during the procedure (Table 2), or consumption of morphine in the recovery area or via PCA for the first 24 postoperative hours (Table 3). We found no evidence of group differences for the measurements of plasmatic levels of norepinephrine, epinephrine, cortisol, or ACTH at any sample time (Table 4; P values were between 0.4 and 0.7). We found a strong evidence of time effect for all four measurements (P values were 0.01–0.001). At the 24-h postoperative interview, no patient recalled having heard music during the surgical procedure. Six patients in the music group versus two patients in the no-music group needed β-adrenergic blockers as rescue medication for hypertensive episodes (P = 0.13).
Several pharmacological interventions have proven efficient for reducing perioperative stress hormone release under general anesthesia (1–5). In this study, we could not show a similar effect with a nonpharmacological technique—listening to music—in female patients undergoing gynecological surgery. The beneficial effects of music on stress in general and on well-being and the need for sedation during regional anesthesia have already been demonstrated (8–11,14). A few studies have also shown that listening to music, sounds, or therapeutic suggestions during general anesthesia could have a positive effect on postoperative recovery and the need for analgesia (12,15). Some other studies could not duplicate these findings (16,17). This study is the first to investigate the effect of listening to music under general anesthesia on stress hormone release. This study must then be considered a pilot study and as such certainly raises more questions than answers.
Epinephrine, norepinephrine, ACTH, and cortisol are frequently used as markers of surgical stress, particularly in abdominal surgery (1–5,7). Increases in the blood level of these hormones are proportional to the degree of surgical stress, a fact that was clearly duplicated in our study. Wang et al. (18) prospectively studied the effect of preoperative music listening on the anxiety level and stress hormone release of patients undergoing various types of same-day admission surgeries. The patients in the treatment group listened to music for 30 minutes in the hour preceding their surgery, whereas the control group wore headphones with no music or white noise administered. A State-Trait Anxiety Inventory was administered before and after the treatment (listening to music), and levels of cortisol, norepinephrine, and epinephrine were measured at the same times. The authors could not show a difference between the blood level of stress hormones within and between groups before and after treatment. The patients in the music group were, however, significantly less anxious than patients in the control group after the intervention. Rider et al. (19) had already shown that tapes of music, imagery, and relaxation decrease circadian amplitude and mean corticosteroids levels in awake subjects. It therefore seems that the subjective effects of music on anxiety are easy to duplicate but that an objective demonstration of an effect on physiological variables is harder to achieve (20).
Explicit memory of auditory stimuli, such as words, stories, poems, and music, rapidly disappears under general anesthesia (21). In our study, no patient explicitly recalled having heard music during the surgery. Implicit memory testing is much more complicated, and results vary widely depending on the tests and anesthesia methods used. Some studies show that 0.4–0.45 minimum alveolar anesthetic concentration of isoflurane abolishes both explicit and implicit memory (22).
However, even in the absence of postoperative recall, processing of auditory stimuli still occurs during general anesthesia (23). In this study, we intentionally chose to maintain a light plane of surgical anesthesia (BIS value between 50 and 60, for an average end-tidal concentration of isoflurane between 0.7% and 0.8% in air and oxygen) to increase the likelihood of a normal processing of auditory stimuli. In fact, Nilsson et al. (12), in a study that showed beneficial effects of intraoperative music on postoperative recovery, administered a deeper level of anesthesia. In this study, anesthesia was maintained with at least 0.7% of isoflurane in 70% nitrous oxide. In addition, Kliempt et al. (24), who prospectively studied the effect of hemispheric-synchronized sounds in patients undergoing surgery under general anesthesia, used even larger concentrations of isoflurane. Hemisounds occur when two coherent sounds of nearly similar frequencies are presented to each ear simultaneously. They found that patients listening to these particular sounds required significantly less fentanyl during the surgery compared with patients listening to music or a blank tape. During this study, patients breathed 1.0% isoflurane in 66% nitrous oxide, reinforcing the point that some sort of auditory stimuli processing occurs even during at least a moderate level of general anesthesia. In fact, brainstem auditory evoked response wave forms are quite resistant to both IV and inhaled drugs. Large doses of fentanyl or isoflurane do not increase the latency of the response (25,26).
The decision to use β-adrenergic blockers to treat increases of MAP resistant to fentanyl boluses was based on several assumptions. First, β-adrenergic blockers, when administered perioperatively, do not affect the release of norepinephrine, epinephrine, cortisol, or ACTH (27). Second, we did not want to reach doses of opioids that would likely inhibit neurohormonal response. Studies have shown that doses of fentanyl in the order of 15 μg/kg could effectively suppress the cortisol and glucose responses to lower abdominal surgery (28). In addition, we wished to maintain a light plane of anesthesia (BIS between 50 and 60) to increase the likelihood that the sound processing would be as normal as possible. By design, increasing the volatile anesthetic concentration was not an option when the lower value of the BIS bracket (a BIS of 50) was attained. We made a posteriori comparisons of the release profile of norepinephrine, epinephrine, cortisol, and ACTH of patients who had receive β-adrenergic blockers versus patients who did not. In agreement with the existing literature, we could not find a difference between the 2 subgroups.
There are some limitations to this study. We do not know whether the volume level of music should be different under general anesthesia when compared with awake conditions. Gnadeberg et al. (29) have shown that, depending on the drugs used, the stapedius reflex threshold can be increased or even totally blocked during general anesthesia. We do not have that specific information about the drugs used in our study. In addition, we tried to control the aspect of contamination with surrounding noise by using headphones that covered the entire ear. The level of noise in the operating room was not strictly controlled. It is therefore possible that a certain level of contamination occurred. People who differ in trait anxiety exhibit differential autonomic responsiveness to a stressful situation (20). We did not administer anxiety tests to the patients. It is possible that a subset of patients with a different trait anxiety profile might exhibit some reduction of the release of stress hormones while listening to music during general anesthesia.
In conclusion, this is the first prospective, randomized, and controlled study designed to measure the effects of music on the perioperative hormonal stress response under general anesthesia. We could not demonstrate a positive effect of music on the neuroendocrine response to stress or on the perioperative consumption of opioids. Bearing in mind the above-mentioned limitations, further studies are needed to confirm the results we obtained.
The authors wish to thank the technologists of the biochemistry department at CHUM hospitals for excellent technical assistance and Dr. Marc Martin (responsible for ACTH and cortisol measurement) for his contribution to this study.
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© 2004 International Anesthesia Research Society
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