Effect of Preoperative Music on "Sterile Inflammation" Induced by Laparoscopic Surgery-A Randomized Study

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-