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Trans-auricular vagus nerve stimulation to reduce perioperative pain and morbidity: protocol for a single-blind analyser-masked randomised controlled trial
Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Established or acquired loss of parasympathetic vagal tone is associated with complications, including pain, after noncardiac surgery. We describe a study protocol designed to test the hypothesis that transcutaneous auricular nerve stimulation may preserve efferent parasympathetic activity to reduce pain and morbidity after noncardiac surgery.
Methods
Participants aged >18 yr scheduled for urgent/elective orthopaedic surgery (n=86) will be randomly allocated to bilateral transcutaneous auricular nerve stimulation or sham protocol for 50 min at the same time of day, before and 24 h after surgery. Holter monitoring, the analysis of which is masked to allocation, will quantify autonomic modulation of HR. The primary outcome will be pain, quantified by absolute changes in VAS 24 h after surgery following sham or stimulation. Secondary outcomes include presence or absence of >10 mm change in the 100 mm VAS (which defines a minimum clinically important change) and postoperative morbidity (Postoperative Morbidity Survey) before and 24 h after surgery. The relationship between the explanatory variable (HR variability), VAS, and morbidity will be examined using a multilevel (mixed-error component) regression model. Safety and complications of the intervention will also be recorded. The study was approved by the NHS Research Ethics Committee (21/LO/0272). As of 25 December 2021, 34/86 participants (mean [standard deviation] age: 48 [19] yr; 14 females [41.2%]) have been recruited, with complete collection of Holter data.
Conclusions
This phase 2b study will explore whether noninvasive autonomic neuromodulation may reduce pain or morbidity using trans-auricular vagus nerve stimulation, providing proof-of-concept data for a non-pharmacological, generalisable approach to improve perioperative outcomes.
Early elevation in plasma high-sensitivity troponin T and morbidity after elective noncardiac surgery: prospective multicentre observational cohort study.
The restoration (or prevention of the loss of) vagal activity may therefore offer a therapeutic target to help improve clinical outcomes after major surgery and potentially limits the use of opioids.
Proof-of-concept studies, chiefly in human volunteers, using noninvasive electrical stimulation of either the auricular branch or the cervical bundle of the vagus nerve suggest that maintenance, or augmentation, of vagal activity is feasible, safe, and associated with minimal side-effects.
International consensus based review and recommendations for minimum reporting standards in research on transcutaneous vagus nerve stimulation (version 2020).
Our systematic review of the proof-of-concept literature has identified specific parameter ranges that appear to be effective in restoring efferent vagal activity.
International consensus based review and recommendations for minimum reporting standards in research on transcutaneous vagus nerve stimulation (version 2020).
We hypothesise that autonomic vagal neuromodulation may improve pain and preserve function in organs that frequently sustain injury after noncardiac surgery (Fig 1). Here, we describe the protocol for a phase 2b study examining whether autonomic neuromodulation can be induced by trans-auricular vagus nerve stimulation (taVNS) and whether the prevention, or reversal, of autonomic dysfunction may reduce pain or morbidity after surgery.
Fig 1Study hypothesis. This figure describes (i) randomisation and treatment allocations, (ii) sham vs active stimulation, (iii) the explanatory variable (cardiac vagal tone, measured via HR variability), and (iv) clinical outcomes (primary outcome is pain; secondary outcomes include postoperative morbidity measures). POMS, Postoperative Morbidity Survey.
This is a single-blind phase 2b randomised-controlled single-centre trial undertaken at The Royal London Hospital, Barts Health NHS Trust, London, UK.
Inclusion criteria
The following eligibility criteria must be fulfilled for patients to be considered for the trial:
(i)
Scheduled to undergo major elective or urgent (i.e. not requiring intervention in <24 h) orthopaedic surgery under general or spinal anaesthesia, expected to take >120 min from the induction of anaesthesia
(ii)
ASA Grades 1–3
(iii)
Age 18 yr or over
Exclusion criteria
(i)
Requiring invasive mechanical ventilation or new renal replacement therapy during hospitalisation
(ii)
Cardiac arrhythmia requiring therapy before or during hospitalisation
(iii)
Dementia
(iv)
Cancer requiring active or ongoing therapy
(v)
Postural orthostatic tachycardia syndrome
(vi)
Lower-limb neuromuscular disorders
(vii)
Auricular dermatitis
(viii)
Day-case surgery, not requiring overnight hospital admission
The selection criteria will be applied at initial screening (at a pre-assessment clinic for patients undergoing elective surgery and on admission for patients undergoing urgent surgery) before randomisation and consent. Participants who develop any exclusion criteria after randomisation and intervention will be withdrawn from the trial and included in intention-to-treat analysis.
Recruitment and screening
Eligible patients will be identified by their surgical teams either in preoperative assessment clinics or in intensive care if the surgical procedure is urgent. Potential participants will be given a patient information sheet (PIS) at the earliest opportunity once they are scheduled for surgery, at least 24 h in advance of surgery. Provided that all reasonable efforts have been made to identify a potential participant 24 h in advance of surgery, they will still be eligible for recruitment within a shorter time frame if this has not proved possible. Written informed consent must be obtained before surgery. After eligible participants are identified by the admitting surgical team, two independent members of the research team shall be involved: one will obtain informed consent whilst the other will deliver the interventions (Fig 2). The member obtaining consent (who is considered part of the direct care team) will approach the potential participants and screen them against the eligibility criteria before asking for consent. All eligible patients that undergo screening will be recorded on a screening log on the Investigator Site File, even if they decline the study.
Fig 2Study enrolment and intervention protocol. (a) Consolidated Standards of Reporting Trials (CONSORT) diagram illustrating flow of participants enrolled into the Vagal Augmentation with Transcutaneous Stimulation study. (b) Trans-auricular ear stimulation protocol (performed at the same time of day). VAS is recorded at 0 and 50 min. ECG monitoring records HR throughout the 50 min; baseline HR from 0 to 10 min (10-min period) and HR during recovery from 40 to 50 min (10-min period). Sham or active stimulation is administered between 10 and 40 min (30-min period). HR variability is subsequently calculated offline from analyses of RR intervals.
The principal investigator or suitably qualified nominee will obtain written informed consent from each participant, including provision of a PIS accompanied by the relevant consent form, and an explanation of the aims, methods, anticipated benefits, and potential hazards of the trial. All potential participants are free to refuse to enter the trial or to withdraw at any time during the trial, for any reason. If new safety information results in significant changes in the risk/benefit assessment, the PIS and consent form will be reviewed or amended accordingly. Participants will be informed that, as defined by the UK Policy Framework for Health and Social Care Research, all documentation will be stored for a minimum of 20 yr at the end of the study.
On the morning of surgery, participants will adopt the semi-recumbent position in a hospital bed located in a quiet environment, in which other hospital personnel will not be allowed to enter the bay or communicate with the patient (unless for an urgent or necessary purpose).
Acquired loss of cardiac vagal activity is associated with myocardial injury in patients undergoing noncardiac surgery: prospective observational mechanistic cohort study.
before commencing HR recording using a three-lead Holter ECG monitor (Spacelabs Healthcare, Hertford, UK) that is continued for 50 min (Fig 2). After the first 10 min of resting HR recording, the allocated intervention will be undertaken for 30 min. Participants will be randomly allocated to receive either active or sham taVNS using a CE-marked device (Totally TENS, Well-Life Healthcare Ltd, Taipei City, Taiwan). Two conductive clips are placed securely on the tragus areas of both outer ears. Using parameters we have identified through systematic review, electrical stimulation (pulse width: 200 μs; frequency: 30 Hz) is initiated at 10 mA, until the participant feels a ‘tingling’ sensation within 20 s of commencing (Fig 2). At this point, the current is either reduced to a level just below this threshold (20–60 mA) or switched off (sham group). Participants are unable to see the device settings and are instructed that the stimulation is imperceptible after this initial setting. At the end of the 30 min intervention period, resting HR will be recorded for a further 10 min. The investigator will remain with the patient to ensure compliance and adherence to the protocol. At the end of the 50 min period, participants will score their pain on VAS. The whole process lasts approximately 1 h from start to finish. This intervention is repeated 24 h after surgery at a similar time of day.
Outcome measures
The primary outcome will be the absolute VAS pain score 24 h after surgery.
The secondary outcomes are:
(i)
The proportion of participants who achieve a minimum clinically relevant reduction >10 mm using the 100 mm pain VAS will be compared before and after the period of stimulation in each group, before and after surgery.
Absolute changes in pain score before and after the taVNS/sham stimulation will be compared before and after the period of stimulation in each group before and after surgery, stratifying for mild, moderate, and severe pain intensities before the intervention. Pain VAS scores of 30, 70, and 100 indicate the upper boundaries of mild, moderate, and severe pain intensities, respectively.
Vagal autonomic function, as assessed by HR variability during each stimulation session, before and after surgery (Fig 2)20
(iv)
Postoperative morbidity, as defined by the Postoperative Morbidity Survey (POMS) before (preoperative) and after (postoperative Days 3 and 7) surgery. POMS is an 18-item survey that examines nine domains (pulmonary, infection, renal, gastrointestinal, cardiovascular, neurological, haematological, wound, and pain) of postoperative morbidity.
Seventy-two patients are required to have a 90% chance of detecting, significant at the 1% level, a decrease in mean VAS (the primary outcome measure) from 34 mm in the control group to 23 mm in the experimental group after surgery (standard deviation [sd] of outcome 12 mm). Allowing for 10% dropout per group, a final sample size of 86 participants is required, analysed by intention to treat.
Randomisation
Participants are randomly assigned (1:1) by block randomisation to receive stimulation or sham stimulation to ensure a balance in sample size across groups over time (Power Analysis & Sample Size 2021; NCSS Statistical Software, Kaysville, UT, USA). Investigators will log on to a secure web-based randomisation file to obtain a unique patient identification number and allocation to a treatment group.
Bias and blinding
Participants are unable to see the device settings and are instructed by the attending investigator(s) that the stimulation is imperceptible after the initial current setting. Participants and investigators are also masked to the Holter data, which will be analysed offline by a separate investigator not involved with patient recruitment or device application who is masked to the treatment allocation. Interventions are performed at the same time of day (in the morning) before and after surgery to minimise the possible influence of circadian variation.
Data collection
Clinical data and operation type will be recorded (Supplementary data). Participants will complete a pain score assessment (VAS) 10 min before and after the intervention period. Anxiety, an established modifier of pain severity
will be assessed using the General Anxiety Disorder-7 (GAD-7) questionnaire at the time of intervention before and after surgery. In addition, the Amsterdam Preoperative Anxiety and Information Scale
will also be presented for each intervention group but not analysed. HR data will be analysed using Kubios HRV Premium (version 3.5.0, Kuopio, Finland).
Plasma will be stored at –80°C having been obtained after both intervention periods for exploratory analyses of biomarkers related to vagal activation. Postoperative morbidity data, as defined by POMS,
will be collected by a member of the admitting surgical team and analysed by an independent member of the research team; both will be masked to the treatment allocation. Data will be entered electronically on a secure database (Research Electronic Data Capture).
Analyses will be conducted using the intention-to-treat principle, where all patients with a recorded outcome are analysed according to the treatment group to which they were randomised. Baseline patient characteristics will be presented, stratified according to treatment allocation. The primary outcome (VAS for pain) will be analysed using repeat-measures analysis of variance (intervention allocation × intervention period [before vs after stimulation/sham]). For secondary outcomes, the proportion of patients in each group with >10 mm change in the 100 mm VAS 24 h after surgery, which signifies a minimum clinically important improvement or deterioration, will be assessed (Fisher's exact test).
Absolute pain scores will also be analysed controlling for mild, moderate, and severe pain intensities before the intervention before and after surgery; VAS scores of 30, 70, and 100, respectively, indicate the upper boundaries of mild, moderate, and severe pain intensities.
before and after the taVNS will be compared in each group before and after surgery (repeated-measures analysis of variance [intervention allocation × intervention period × before/after surgery]). A pre-specified exploratory analysis will examine the relationship between pain and vagal measures of cardiac autonomic modulation by logistic regression analysis, taking into account age, sex, anxiety (GAD-7), time, and allocation arm of the intervention. Sensitivity analyses for variables that may affect pain or autonomic measures will also be conducted, including use of beta blockers, chronic pain and analgesic technique. Absolute and categorical measures of cardiac parasympathetic activity (divided into tertiles, where each tertile is treated as a categorical value) will be used in this model. The significance level will be set at 0.05. A full statistical analysis plan will be developed before analysis and the end of the study, published online at https://www.qmul.ac.uk/ccpmg/sops--saps/statistical-analysis-plans-saps.
Trial management and data monitoring
The sponsor organisation is Queen Mary University of London. Daily trial management will be coordinated by a trial management group consisting of the chief investigator and his/her support staff. An independent study committee will oversee the trial, including assessing the safety of the intervention, reviewing relevant new external evidence, and monitoring the overall conduct of the trial. This committee consists of an independent clinical trialist, lay representative, and an independent chair.
Adverse events
Pre-specified and any other adverse events directly related to the trial intervention will be recorded (Supplementary material).
Confidentiality
Information related to participants will be kept confidential and managed in accordance with the Data Protection Act (UK), NHS Caldicott Principles (UK), Research Governance Framework for Health and Social Care (UK), and the conditions of Research Ethics Committee Approval or corresponding legislation or approvals for a particular participating country or site. The principal investigator will maintain in strict confidence trial documents (e.g. patients' written consent forms) and patients' confidentiality. Representatives of the trial management team will require access to patient notes for quality assurance purposes and source data verification.
Patient/public involvement
Our ongoing National Institute for Health and Care Research (NIHR) programme of Patient and Public Involvement (PPI) has helped inform on every aspect of the study, which addresses key research priorities identified by the James Lind Alliance, including, ‘What can we do to stop patients developing pain after surgery?’ and ‘How can we improve recovery from surgery for elderly patients?‘.
Identifying research priorities in anaesthesia and perioperative care: final report of the joint national Institute of academic anaesthesia/james Lind alliance research priority setting partnership.
An appointed lay representative will co-author a detailed scientific report, which will be submitted to a widely accessible scientific journal.
Auditing
The sponsor will have oversight of the trial conduct. The trial team ensures compliance with the requirements of Good Clinical Practice, including data quality control and safety reporting.
Study progress
As of 25 December 2021, 34/86 participants (mean [sd] age: 48 [19] yr; 14 females [41.2%]) have been recruited, with 100% complete collection of Holter data.
Discussion
Several contributory mechanisms may explain the relationship between the severity of pain early after noncardiac surgery and subsequent complications. Acute pain impairs mobilisation, promotes alveolar collapse and pulmonary infection, prolongs urinary catheterisation, and delays restoration of bowel function.
Autonomic dysregulation is a pivotal feature of acute pain, impacting on a wide range of interconnected neurohormonal and immune pathways that limit organ injury and resolve inflammation and promote organ repair.
Our phase 2b study aims to provide data to demonstrate the feasibility and efficacy of the taVNS in reducing pain by boosting autonomic function and potentially accelerating functional rehabilitation (Fig 2).
Studies of indirect vagal neuromodulation have usually been conducted in healthy volunteers and are susceptible to bias.
Our study addresses the lack of specific focus on perioperative patients, for whom multiple morbidities after surgery may benefit from autonomic neuromodulation. The use of sham stimulation is critical, as meta-regression analyses indicate that physical placebo interventions and patient-reported outcomes in pain are more likely to reveal significant placebo effects.
However, the effect of placebo on pain appears to vary even in trials deemed to have a low risk of bias, ranging from negligible to clinically important. Variations in the effect of placebo are partly explained by variations in how trials are conducted and how patients are informed. Larger effects of placebo have been found in trials that did not inform patients about the possible placebo intervention, which is in contrast to our approach. The use of VAS to evaluate postoperative pain is consistent with consensus guidelines.
although we acknowledge that in acute pain, minimum clinically important difference appears to vary between studies, is influenced by baseline pain, and is context-specific.
Because of the unanticipated ongoing disruption of COVID-19 on elective surgery throughout 2021, we have focused on orthopaedic trauma surgery to ensure timely completion of the study. Although some patients may have pain before their operation, each participant serves as his/her own control. Examining the response of the taVNS on autonomic regulation in this population is widely generalisable to a broader surgical population, including those reporting preoperative pain. Provided that we can confirm in the acute care setting that autonomic changes after vagal neuromodulation occur by measuring HR variability, the low-cost, noninvasive device we are using suggests a very low potential risk-to-benefit ratio. Our systematic review identified the taVNS stimulation parameters that alter HR variability,
although we cannot be certain that there may be minimum thresholds for the duration or intensity required to be clinically effective in the surgical population. The emphasis in this study on acute effects does not rule out any putative benefit of a longer course of treatment after surgery. Nevertheless, the 30-min period of daily stimulation via cutaneous innervation of the outer ear has not been associated with harm. Mapping pain and morbidity outcomes to alterations in autonomic function (which are analysed by an investigator masked to treatment allocation) will enable the hypothesis to be examined whilst minimising bias.
In summary, this phase 2b perioperative study will explore whether noninvasive autonomic neuromodulation may reduce pain or morbidity using the taVNS. This non-pharmacological approach may be broadly generalisable to help improve outcomes after noncardiac surgery.
Dissemination plans
This is an investigator-led study sponsored by the chief investigator's substantive employer, Queen Mary University of London. The data collected will not be used to license/register any pharmaceuticals. Data arising from the research will be made available to the scientific community in a timely and responsible manner. An appointed lay representative will co-author a detailed scientific report, which will be submitted to a widely accessible scientific journal. Our ongoing NIHR programme of PPI will help disseminate the findings. Authorship of the final paper(s), interim publications, or abstracts will be decided according to active participation in the design, accrual of eligible patients, and statistical analysis. Contributing/participating investigators will be acknowledged in the final paper.
Authors' contributions
Study protocol design: ABUP, GLA.
Drafting of paper: all authors.
Subsequent revising of paper: all authors.
Declarations of interest
GLA is editor of the British Journal of Anaesthesia, has UK patent application 2011523.4 (Neuromodulation for the treatment of critical illness), and performs consultancy work for GlaxoSmithKline unrelated to this work. The other authors declare no competing financial interests.
Funding
National Institute for Health and Care Research Advanced Fellowship (NIHR 300097) to GLA; King Edward VII Hospital clinical research fellowship to ABUP.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Early elevation in plasma high-sensitivity troponin T and morbidity after elective noncardiac surgery: prospective multicentre observational cohort study.
International consensus based review and recommendations for minimum reporting standards in research on transcutaneous vagus nerve stimulation (version 2020).
Acquired loss of cardiac vagal activity is associated with myocardial injury in patients undergoing noncardiac surgery: prospective observational mechanistic cohort study.
Identifying research priorities in anaesthesia and perioperative care: final report of the joint national Institute of academic anaesthesia/james Lind alliance research priority setting partnership.
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