Effect of Preoperative Music on Sterile Inflammation Induced by Laparoscopic Surgery
Effect of Preoperative Music on Sterile Inflammation Induced by Laparoscopic Surgery
Surgery induced sterile inflammation leaves behind a biomolecular footprint measurable by
 various pro-inflammatory markers e.g. IL-6, CD(Cluster of differentiation)19B,
 HsCRP(High-sensitivity CRP) etc. Music is a non-pharmacological means in attenuating this
 inflammatory pathway thereby improving Health related quality of life measurable by improved
 postoperative convalescence. Correct timing of music application is a lacuna in the
 knowledge. This research aims at evaluating the effect of preoperative music on sterile
 inflammation induced by index Laparoscopic Surgery (Laparoscopic Cholecystectomy) and its
 proposed beneficial effects on patient reported outcomes. A total of 50 patients divided into
 2 groups (test and control) will be evaluated in this triple blind randomized controlled
 study aiming at evaluating the biomolecular signatures of sterile inflammatory response and
 its correlation with improved postoperative convalescence. All the patients will be followed
 up for a period of 1 month postoperatively to assess for overall improvement in health
 related quality of life. Collected data will be analysed using updated SPSS software and a p
 value of less than 0.05 will be taken as statistically significant in support of the measured
 indices.
INTRODUCTION Historically, surgery was seen as the last resort to preserve life. Even today,
 the popular acceptance of surgery is premised upon it being either as the only treatment
 option or as the last option after all nonsurgical treatments have been unsuccessful. This is
 attributable to the patient anxiety about the protracted convalescence, besides its clinical
 morbidity. Over last two centuries, surgery has evolved from being misery alleviating to
 being life-saving and then to being limb-preserving and finally function preserving as well.
 Last 30 years have witnessed the introduction of minimally invasive surgery (MIS) into
 surgical practice. Application of MIS in various surgical domains has achieved clinical
 equivalence with the established benchmarks of the conventional surgery. The spectrum of
 clinical equivalence besides positive outcomes includes the whole spectrum of the established
 various morbidity indicators like procedure specific complications, length of hospital stay
 and long-term morbidity. The focus for further evolution in surgery has marched from being
 clinical outcome based on the patient-reported outcome (PRO) specific. The improvement in
 PRO's has been attributed to attenuated postoperative inflammatory response, which has been
 studied by the changes in cytokine pathways. This cytokine-mediated inflammatory response is
 shown to be subdued after MIS as compared to conventional surgery.

 Parallel to emphasis on PROs, surgery evolved with considerations for early and speedier
 convalescence. This led to the concept of enhanced recovery after surgery (ERAS) being the
 current stated objective. Postoperative convalescence (POC) is a function of the inflammatory
 response following surgery. This postoperative inflammatory response consists of a sterile
 inflammation apart from classical inflammation if any infection coexists. Sterile
 inflammation determines outcomes like postoperative fatigue (POF), postoperative pain (POP),
 postoperative nausea and vomiting (PONV) and circadian disturbances leading to compromised
 quality of sleep. All these factors directly influence postoperative convalescence as well as
 PROs. Patient perspective has been classically described by the aphorism "Surgery leaves
 scars on the mind as well". This sentiment now has scientific resonance, as now it is
 understood that the mediators of sterile inflammation are influenced temporarily and by
 neurohumoral pathways. Sterile inflammation is mediated by various cytokine and
 immunosuppressive pathways. It is primarily driven by danger associated molecular proteins
 (DAMP), also known as alarmins. These alarmins trigger a biocellular response by expansion of
 many cell lines. The CD19B cell line is known to expand the most. These biocellular responses
 then initiate a cascade of cytokines of which IL6 is the most dominant. It is the balance of
 these two, that determines the severity of sterile inflammation hence the POC. Current
 scientific discourse is on modulating this sterile inflammatory pathway. Pharmaceutical
 interventions by anti-inflammatory drugs are already known to attenuate this pathway and make
 the patient feel better but are not free of side effects. Non-pharmaceutical interventions
 have recently been studied for the same effect with an additional benefit of avoiding side
 effects of drugs. Perioperative music has been shown to improve both POC as well as PROs.
 However, this benefit has been reported for preoperative & peroperative music for surgeries
 under local or locoregional anaesthesia. Effect of preoperative music has not been studied
 for outcomes of surgeries done under general anaesthesia. The biocellular and biomolecular
 basis of this effect of music has not been clearly established. The most beneficial timing of
 music i.e. preoperative or peroperative is also not scientifically clear. The studies showing
 benefits of preoperative music are based upon surgeries under local-locoregional anaesthesia
 In a recent study done at our institution, study, peroperative music has been found to be
 beneficial. This study was done on the index MIS i.e. laparoscopic cholecystectomy (LC)under
 general anaesthesia (GA). Peroperative music was found to have a biocellular as well as
 biomolecular signature. It causes attenuation of sterile inflammation by controlling the
 expansion of CD19 cell population&, limiting the suppression of NK cell population and
 moderating the IL6 surge. Music-induced fall in IL6 as the beneficial biomolecular response
 has already been known.

 With this background of established benefits of perioperative music but no study having
 tested preoperative music for surgery under GA, and an established known biocellular -
 biomolecular basis of peroperative / postoperative music for surgeries done under GA
 benefits, the investigator hypothesize that preoperative music could also have similar
 benefits for surgeries done under and GA, and a biomolecular basis for the same.

 REVIEW OF LITERATURE Historically, practice of surgery started as the last resort for
 preservation of life. Over the last two centuries it has improved with progressive reduction
 in not only mortality but and significant improvements in clinical morbidity. With the advent
 of MIS, not only the clinical benchmarks of the conventional era were expected to be achieved
 matched with heightened community expectations. The practice of MIS was initially driven by
 its popular appeal despite the absence of any supportive level I evidence. The benefits of
 MIS were primarily based upon PROs. The benefits included reduced wound morbidity both in
 short-term (wound infections) as well as long-term (an incisional hernia). Other popular
 advantages included shorter hospital stay, less postoperative pain, lesser analgesia usage,
 early return to activity and better patient-reported health-related quality of life (HrQoL).
 All these made MIS popular both with society as well as with profession.

 Application of MIS to most of the surgical domains was aided by paralleled advances in
 technological technology advances and innovations. In last 30 years of MIS experience, the
 clinical and PRO outcomes have stabilized. Current scientific discourse is on improving POC.
 Postoperative convalescence is akin to side effects of medicines in non-surgical practice.
 Postoperative convalescence is dependent upon various factors. Postoperative pain, PONV, POF,
 sleep disturbances and analgesia required are some of these factors. Postoperative
 convalescence is variable for similar surgeries. Prolonged POC leads to personal suffering,
 functional impairment, delayed return to work, and significant societal and economic costs.
 Postoperative convalescence has been defined as the "process to regain control over physical,
 psychological, social and habitual functions, and return to preoperative levels of
 independence and psychological well-being". It marks a shift from conventional recovery
 indicators e.g. length of hospital stay, to PROs like the absence of symptoms, the ability to
 perform regular activities, return to work, and regain quality of life. Major determinants of
 slow POC are fatigue, pain and resulting functional impairment. Fatigue is the key sickness
 behaviour fined as "an indefinable weakness throughout the body requiring sitting or lying
 down after minor tasks". The POC delaying factors are a clinical manifestation of an
 inflammatory process induced by surgery and stress of surgery. This inflammatory process
 happens in absence of any infective agent hence is called 'Sterile inflammation'. This
 sterile inflammation is a result of various cellular, biomolecular, immune changes induced by
 surgery. These are mediated by signalling that involves the production of cytokines,
 expansion of certain cell populations and contraction of some cell population. These changes
 happening within 24 hrs and are strongly associated with the speed of POC. Surgery induces a
 local immune response which leads to systemic proinflammatory and immunosuppressive phases
 which are temporally related and proportionate in magnitude. This response is mediated by a
 battery of cytokines of which IL6 is not only the beginner but also most dominant. Tissue
 injury is sensed by a group of protein receptors known as pattern recognition receptors
 (PRR). These PRRs can be activated by pathogen-associated molecular pattern (PAMP) and DAMP.
 The surgery induced sterile inflammation has no PAMP hence the DAMP is primary driver of the
 inflammatory cascade. Various pharmaceutical interventions (anti-inflammatory agents) have
 been used to attenuate or abort this sterile inflammation towards the goal of enhancing POC,
 but they are not free of side effects & contraindications. Music has been shown to have a
 positive influence on POC and PROs with supportive robust Level 1 evidence. Yet there is
 debate on many issues-

 -  Relative efficacy of preoperative music under general anaesthesia.

 -  Choice of music, whether patients or surgeons.

 -  Type of music, classical or otherwise.

 -  The timing of music, whether preoperative or peroperative or both.

 -  Whether patient alone or the entire OT team. These issues are pertinent because some
 surgeons accept the benefits to their patients but distracting to their staff. Some
 colleagues demand evidence better than the available Level 1 A evidence and consider it
 potential disruptor of communication& dangerous for patient safety. They find support
 from studies giving a scientific camouflage in concluding that music may contribute to
 decreasing in auditory processing function see music as noise in the OT. These naysayers
 have had robust rebuttals from other colleagues. Giving the choice of music to the
 patient has been shown to increase add to preoperative anxiety and compromise its
 benefits but some studies have advocated patient choice. But none of the studies has
 tested preoperative music for surgery done under GA. The investigator has earlier
 studied the effect of peroperative music and found it to be beneficial. It is not known
 whether preoperative music will have similar benefits or not? Hence, the investigator
 hypothesized to study this.

 The benefits of music are related to attenuation of sterile inflammation and the inflammation
 is measurable with cytokine - immunosuppressive pathways. These pathways need to be studied
 for the effect of DAMPS. Thermal energy has a specific DAMP known case of heat called heat
 shock protein (HSP). The thermal energy specific sterile inflammation and its impact on PROs
 / POC have been reported earlier. This HSP related inflammatory component and its attendant
 cytokine response have also been studied and reported. As thermal component has its specific
 signature, any study of sterile inflammation induced by non-HSP DAMPs requires the surgery to
 be done without application of thermal energy. Hence an MIS procedure that is done without
 energy has to be subject to study. Laparoscopic cholecystectomy can be done safely, without
 an application of energized dissection by thermal energy. Laparoscopic cholecystectomy is an
 index MIS surgery for any innovations or PRO based studies.

 A study of biomolecular changes and their effect on PROs, and POC in a setting of an HSP
 milieu, is thus an appropriate model to study the effect of preoperative music. Hence, the
 investigator proposes to study the biomolecular (IL6, TNF alpha, HSCRP, procalcitonin) and
 PROs (POP, PONV, POF, postoperative sleep quality, HrQoL and quantitative analgesia usage) in
 an HSP DAMP driven surgical milieu of an index MIS i.e. LC without the usage of surgical
 energy.

 What is already known?

 -  Perioperative Peroperative and postoperative music are beneficial in improving
 'postoperative convalescence' and 'patient reported outcomes' following surgery under
 all kinds of anaesthesia.

 -  These benefits are demonstrable in unaware (under GA) peroperative phase.

 -  The peroperative music related benefits have a quantitative biomolecular footprint.

 Lacunae in our knowledge

 -  Effect of preoperative music on 'postoperative convalescence' and 'patient reported
 outcomes' following surgery under GA has not been studied.

 -  Biomolecular response specific to preoperative music in surgeries done even under
 locoregional anaesthesia (without GA) has not been studied.

 HYPOTHESIS • Preoperative music could have beneficial effects on 'postoperative
 convalescence' and 'patient reported outcomes' following laparoscopic surgery under general
 anaesthesia GA.

 AIMS AND OBJECTIVES

 Primary objective:

 • To study the effect of preoperative music on 'postoperative convalescence' and 'patient
 reported outcomes' following laparoscopic surgery under general anaesthesia'

 Secondary objective:

 • To study the biomolecular response specific to preoperative music.

 MATERIALS AND METHODS

 -  STUDY SITE- Sir Ganga Ram Hospital, New Delhi.

 -  TIME & Duration of the study- From October 2017 until January 2019

 -  STUDY DESIGN-Triple-blinded Randomized Study

 -  SAMPLE SIZE - A reduction in pain scores (between 6-24 hours after surgery) from 48.04
 (SD 11.07) to 26.54[16] (10.03) with a p-value of 0.000 has been seen in the
 investigator's previous study on the effect of peroperative music in the similar study
 population. To study the similar benefit of preoperative music with a confidence
 interval of 99% and an alpha error of 0.01 and power of 90%, a sample size of 16 i.e. 8
 patients in each arm is required. With possible trial deviates attrition of 33%, the
 sample size required will be 24 (12 in each group). Given the window of time available,
 a minimum of 24 patients (12 in each group) but the desirability of population size
 similar to our last study with peroperative music, the investigator intends to have a
 sample size of 50 (25 in each group). An intention to treat analysis will be done.

 -  RANDOMIZATION- Computer generated randomization by an independent external research
 coordinator and will be telecommunicated to the nurse in preoperative area.

 All participants found eligible and compliant with inclusion criteria will be enrolled for
 the study. Demographic and clinical data of the participants will be recorded in a standard
 proforma (Annexure II). A standard protocol for perioperative medicines including
 Anaesthesia, antibiotics, chemoprophylaxis and analgesia etc. will be followed.

 The participants will be allocated to either study or control group by an independent
 external research co-coordinator (based upon a random sequence computer generation). The
 external coordinator will inform about the group allocation to the nurse in preoperative hold
 area (POHA), by phone or any web-based media network (SMS and/or WhatsApp).

 A standard post-operative recovery clinical pathway compatible with ERAS and protocol for
 'fast track surgery', will be followed by the discharge ability.

 At the time of shifting of the patient, from the ward to POHA, a Bluetooth Headphone will be
 applied put on the participants. Once in POHA, an independent nurse will either start the
 music or not, as per the random group assigned. The participants will stay for 60 to 90
 minutes in POHA. They will be shifted with the headphones to the operation theatre. The
 headphones will be removed at the time of induction of anaesthesia.

 An EEG will be done in the ward before transfer to POHA, during surgery and 24 hours after
 surgery.

 Blood samples will be drawn at the time of transfer from the ward to POHA i.e. prior to
 application of headphones (HT0), at the time of before induction of anaesthesia (TH1), at 6
 hours after surgery (TH2) and at 24 hours after surgery (TH3).

 • Premedication- All participants will receive premedication with alprazolam (0.25 mg) the
 night before surgery and ranitidine (150 mg per oral, the night before surgery and 120 min
 before surgery).

 Anaesthesia Technique:

 All participants will receive pre-induction fentanyl citrate 2 micrograms /kg. Routine
 monitoring (Pulse Oximetry, EKG, NIBP) will be applied. A bi-spectral index (BIS) sensor for
 monitoring the depth of Anaesthesia, using the BIS monitoring module, will also be applied
 over the participant's forehead according to the manufacturer's instructions prior to the
 induction of anaesthesia. After pre-oxygenation, anaesthesia will be induced with propofol up
 to 2.0mg/kg body weight to the point of loss of verbal contact. Atracurium besylate will be
 administered 0.5mg/kg to facilitate tracheal intubation. General Anaesthesia will be
 maintained with sevoflurane (1-2%) and 50% nitrous oxide in oxygen titrated to maintain a BIS
 value between 40-60. Fentanyl citrate 0.5 microgram/kg will be administered every 30 minutes
 intraoperatively.

 Postoperatively, paracetamol 1 gm I.V. will be administered if the visual analogue scale
 (VAS) score is >30.

 The hemodynamic markers of the depth of Anaesthesia like pulse, blood pressure, saturation of
 peripheral oxygen (SpO2), and end-tidal carbon dioxide (EtCO2) concentration will be recorded
 in a standard proforma (Annexure III). Standard four-port technique of LC without energized
 dissection will be followed [35].

 The surgical procedure will be video-recorded for prospective anatomical analysis and
 retrospective reference. Duration of surgery will be recorded with reference to the different
 stations of intervention i.e. induction of anaesthesia, first surgical incision, complete
 separation of GB from liver bed and extubation. Peroperative surgical data will be recorded
 in a standard proforma.

 Operative clinical data will be recorded in a standard proforma. This post-operative protocol
 will be followed by the surgical nurses in the common post-operative area where all the
 operated cases are managed. Standard criteria based discharged protocol will be followed.

 Participants will be discharged after clearance from with protocol-based consensus of the
 anaesthesia team, nursing team and surgical team. A standard discharge advice will be given
 to the participants incorporating the various post-operative diary protocols.

 The PRO's and the clinical outcome will be analyzed by Clavien and Dindo classification of
 surgical complication.

 Statistical Analysis The prospectively collected data will be entered into an excel sheet
 (Windows Microsoft 8 or higher version). The data will be analyzed using the latest version
 of SPSS (statistical package for social science). Qualitative data will be compared using
 Chi-square test and quantitative data using Student's t-test, or any other appropriate
 statistical tool. A p-value less than 0.05 will be considered significant. An intention to
 treat analysis will be done.
Inclusion Criteria:

 1. Age more than 18 years.

 2. Should be able to understand and sign an informed consent.

 3. Consent for surgery, anaesthesia and the use of standardized music before surgery.
 (Appendix I)

 4. Fitness for General Anesthesia (GA)

 5. Ability to maintain & communicate a PRO diary.

 6. Ability to communicate via telephone or email or SMS or WhatsApp.

 Exclusion Criteria:

 1. Fitfor GA but higher than ASA Grade I.

 2. Uncontrolled coagulopathy

 3. Suspicion of carcinoma gallbladder on USG

 4. Any suspicion of common bile duct (CBD) stones or pancreatitis.

 5. Patient using chronic anti-inflammatory drug.

 6. Concomitant common bile duct (CBD) stone or any CBD intervention/pancreatitis in the
 preceding 6 weeks.

 7. Patient on immunosuppressive / cytotoxic/ steroid therapy.

 8. Documented or known sensitivity to any drug to be used in the study protocol.

 9. Pregnant or lactating ladies.

 10. Any concomitant surgery