1. Sign our petition calling on Cochrane to withdraw their review of Exercise Therapy for CFS here.
    Dismiss Notice
  2. Guest, the 'News in Brief' for the week beginning 18th March 2024 is here.
    Dismiss Notice
  3. Welcome! To read the Core Purpose and Values of our forum, click here.
    Dismiss Notice

[Protocol] Trans-auricular vagus nerve stimulation to reduce perioperative pain and morbidity

Discussion in 'Other health news and research' started by SNT Gatchaman, Jun 29, 2022.

  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

    Messages:
    4,256
    Location:
    Aotearoa New Zealand
    Trans-auricular vagus nerve stimulation to reduce perioperative pain and morbidity: protocol for a single-blind analyser-masked randomised controlled trial
    Amour B.U. Patel, Phillip P.W.M. Bibawy, Zehra Majeed, Weng Liang Gan, Gareth L. Ackland

    Background
    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.

    Link (open access)
     
    Peter Trewhitt and Trish like this.
  2. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

    Messages:
    4,256
    Location:
    Aotearoa New Zealand
     
  3. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,534
    Location:
    Aotearoa New Zealand
    I'm not sure why you put this study in Research methodology @SNT Gatchaman. Is it because you think the study design is a good one? Or a bad one?

    The approach to the sham treatment looks good, with both treatments getting an initial burst of sensation, and then the treatment stimulation being set at a level that reportedly is imperceptible. The content and clarity of the protocol looks good, including the commitment to record the numbers of participants at each point in the study.

    The study aims to administer the treatment one time prior to an operation and 24 hours after the operation. This is probably different to what would be done for ME/CFS. The primary outcome is after surgery: the difference in reported pain prior to the treatment and reported pain after the treatment, which takes 1 hour all up. As such, it is a very momentary measure. Unless people are going to remain hooked up to the device all day, I can't see how this provides a measure of clinical utility. I guess, though, that even if they can show there is some change as a result of the stimulation, then it suggests more study is warranted.

    At the time that the protocol was written, they had already recruited nearly half of the planned number of participants and, it seems, had administered the treatment to these people. Although it says that the analysis of the holter data was blinded to allocation, that order of things - recruitment, study execution, then protocol publishing is not ideal.

    Participants are subgrouped according to their pre-operative pain levels: mild, moderate and severe. There is nothing saying that the the researchers were blinded to participants' reported pain levels prior to finalisation of the protocol. Therefore, with a protocol published after half of the pain reports has been collected, there was scope for choosing definitions of pain levels that give a significant result.

    With the subgroups and a lot of combinations of comparisons before and after treatment and before and after surgery, as well as absolute values, there are quite a lot of opportunities for something to show a positive result. They are recruiting males and females, and they plan to analyse on gender and on age, and a variable called 'time', which might be how long the surgery takes?.

    There's also some optionality around whether a clinically relevant result is achieved (defined as a reduction of 1 or more on a 10 point scale of pain - a binary result) and the actual reduction in pain (in units of 1 on the 10 point scale).

    There is also the Post-operative Morbidity survey, to be done before and 3 and 7 days after the operation. This survey has 9 domains, multiplying the number of measures and possibilities for cherry-picking still further. And there's a survey on anxiety, as they think anxiety modulates the experience of pain - so there are more opportunities for analysis. Two lots of plasma are collected for analysis of biomarkers related to vagal activation. Having such a big number of measures of course isn't bad in itself - it makes sense to get as much useful data during a trial as possible. It just creates a bias hazard if the researchers don't approach the study in a state of equipoise.

    The study is described as single-blinded. The participants don't know what treatment they are getting. The investigator who is responsible for delivering either the real or sham treatment remains with the participant throughout the treatment and the scoring of pain. There is therefore a chance that the investigator consciously or unconsciously influences what pain level the participant chooses. This is particularly a concern given the uncritical reporting of the results of previous studies on vagal stimulation in the protocol - the researchers clearly have an opinion about the utility of vagal stimulation.

    They do consider circadian variation - planning to undertake the studies at the same time of day - that's good.

    They say
    but surely this will be a major confounder? Surely whether a person is receiving pain-controlling drugs will overwhelmingly influence the outcomes of the study? Again, with the researchers clearly expecting to find a positive result, I am concerned that there is scope for bias in how carefully pain medication is recorded (and even perhaps what pain medication is offered and delivered).

    Importantly, there is a conflict of interest, in that the senior author, Gareth Ackland, has a UK patent application titled "Neuromodulation for the treatment of critical illness". He is also the editor of the British Journal of Anaesthesia - so he will be able to ensure that any papers are easily published, including examination by friendly peer reviewers. He's a professor of peri-operative medicine and a consultant in anaesthesia in the hospital that the study is being done in.

    It all could be fine if the study is done with integrity, with a genuine aim of finding the truth. And perhaps it will be. It's just that, if there is a lack of integrity, then there is a lot of scope for finding a predetermined outcome. I suppose that's true of most studies.
     
    Last edited: Jun 30, 2022
    Michelle, alktipping, Lilas and 3 others like this.
  4. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

    Messages:
    4,256
    Location:
    Aotearoa New Zealand
    Sorry @Hutan I thought this subforum might be a reasonable holding bay, for "not-a-study" but still potentially of interest and something to keep an eye out for. I was also interested in their approach to shamming on the control arm. If you remember I thought sham HELP apheresis might be too hard to devise, so this seemed a good example of how the problem can be approached.

    When I looked, I saw the Research quality and methodology forum which indicated to me it was separate from discussions purely about methodology strengths and weaknesses. On balance this seemed like a good forum, given those points. I am conscious that I might be submitting too many papers and creating noise for potential readers and work for others (as you have generously done above), which was another reason I thought to separate it a bit from people's notifications.

    Would you be kind enough to move it to eg Other health news and research?
     
    alktipping and Peter Trewhitt like this.
  5. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,534
    Location:
    Aotearoa New Zealand
    Sure. And no, re the possibility of posting too many papers, as far as I am concerned, please keep posting.

    I'm interested in this vagal stimulation idea as it seems to have a lot of support among ME/CFS advocates and clinicians, and it's being promoted quite strongly for all manner of health problems, but I'm not yet convinced that the purported problem is valid for ME/CFS, let alone that a clip round the ear is a good way to fix the problem.

    I found it interesting to consider what would make for a good study of trans-cutaneous vagal stimulation. Having a good sham treatment is part of it, but what I concluded was that there's a lot of other points where research could go wrong. I think potentially a trial design could be robust and safe in the hands of researchers with equipoise, with exactly the same trial design being unsafe in the hands of researchers with a conflict of interest. I did conclude my last post saying 'safe in the hands of people with integrity and unsafe in the hands of people without', but I think bias can be very subtle, and even people with integrity but with a reason to want to find a positive result will probably produce a biased result.

    I'm not sure where that leaves us, beyond not trusting any result much until replicated by people with absolutely no incentive to find in favour of the treatment, which obviously isn't very helpful given the low levels of replication by disinterested parties in ME/CFS research.
     
    Last edited: Jun 30, 2022
    Michelle, alktipping, Lilas and 4 others like this.
  6. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    13,278
    Location:
    London, UK
    This looks very problematic.

    To be robust the method has to make sure there is no way attitudes can influence. If bias is possible it will almost certainly occur, or at least one has to assume it may well have done.
     
    Mithriel, shak8, alktipping and 6 others like this.

Share This Page