Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03429478 |
| Other study ID # |
EC/10/17/1281 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 1, 2017 |
| Est. completion date |
December 1, 2019 |
Study information
| Verified date |
December 2019 |
| Source |
Sir Ganga Ram Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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.
