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• Science is the great antidote to the poison of enthusiasm and superstition
  Michael I Polkey, Nicolino Ambrosino
  Published on: 8 October 2018
• Absence of evidence is not evidence of absence! Lessons from recent trials of adjunctive IMT in COPD and recommendations for further research: careful selection of candidates, controlling interventions and choosing the most adequate outcomes.
  Daniel Langer, Rik Gosselink and Ghislaine Gayan-Ramirez
  Published on: 8 October 2018

• Published on: 8 October 2018

  Science is the great antidote to the poison of enthusiasm and superstition

  • Michael I Polkey, co-author of the original MS Royal brompton & Harefield NHS Trust
  • Other Contributors:
    • Nicolino Ambrosino, co-author of the original MS

  To the Editor

  Science is the great antidote to the poison of enthusiasm and superstition

  We thank Langer and colleagues for their interest in our editorial. In many ways the title they have chosen for their response confirms our thesis. ‘Absence of evidence’ may not be ‘Evidence of absence’ but it is ……………….. Absence of evidence . Our contention overall is that the relentless search for benefit despite the recently reported negative trials is driven by emotion rather than data.
  Whilst physiological arguments are of interest to physiologists, there remains no convincing evidence in our view either that respiratory muscle fatigue is present in patients with COPD, or that it contributes to exercise limitation. The various suggestions they make in the hope of eliciting a ‘positive result’ for IMT (e.g. changing outcome measure, patient selection) are credible research suggestions and we would not oppose interested investigators pursuing research in this arena, but this does not alter our contention that IMT has no place in current clinical practice.
  Clinically their argument is that IMT alone is beneficial in COPD. We think this argument is specious (irrespective of whether it is correct); pulmonary rehabilitation, in part thanks to the Leuven group, has one of the strongest evidence bases for any therapy in COPD. Therefore the idea that one might drop PR in order to do IMT instead is not one we believe should be taken into the clinical arena....

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  To the Editor

  Science is the great antidote to the poison of enthusiasm and superstition

  We thank Langer and colleagues for their interest in our editorial. In many ways the title they have chosen for their response confirms our thesis. ‘Absence of evidence’ may not be ‘Evidence of absence’ but it is ……………….. Absence of evidence . Our contention overall is that the relentless search for benefit despite the recently reported negative trials is driven by emotion rather than data.
  Whilst physiological arguments are of interest to physiologists, there remains no convincing evidence in our view either that respiratory muscle fatigue is present in patients with COPD, or that it contributes to exercise limitation. The various suggestions they make in the hope of eliciting a ‘positive result’ for IMT (e.g. changing outcome measure, patient selection) are credible research suggestions and we would not oppose interested investigators pursuing research in this arena, but this does not alter our contention that IMT has no place in current clinical practice.
  Clinically their argument is that IMT alone is beneficial in COPD. We think this argument is specious (irrespective of whether it is correct); pulmonary rehabilitation, in part thanks to the Leuven group, has one of the strongest evidence bases for any therapy in COPD. Therefore the idea that one might drop PR in order to do IMT instead is not one we believe should be taken into the clinical arena.
  Lastly we very much hope to be proved wrong by Dr Langer’s future research; if IMT could be shown to confer benefit in a sub-population of COPD patients we entirely accept that it would be a cheap and low risk therapy
  With best wishes

  Michael Polkey and Nicolino Ambrosino

  (Quote from Adam Smith, The Wealth of Nations 1776)

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  Conflict of Interest:
  None declared.

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• Published on: 8 October 2018

  Absence of evidence is not evidence of absence! Lessons from recent trials of adjunctive IMT in COPD and recommendations for further research: careful selection of candidates, controlling interventions and choosing the most adequate outcomes.

  • Daniel Langer, Assistant Professor, Physiotherapist KU Leuven, Department of Rehabilitation Sciences
  • Other Contributors:
    • Rik Gosselink, Full Professor, Physiotherapist
    • Ghislaine Gayan-Ramirez, Full professor

  We support the view of Drs. Polkey and Ambrosino that recommendations for clinical practice should not be based on either positive or negative preoccupation concerning the potential effectiveness of a treatment but rather on an impartial evaluation of the available data. In their editorial entitled ‘Inspiratory Muscle Training in COPD: can data finally beat emotion’ they unfortunately provide a fairly one-sided evaluation of this treatment, based on an incomplete and largely outdated review of the available evidence1. It is unfortunate that they neglect a major part of available data, which could contribute to a more balanced and fair discussion about this intervention. We therefore deemed it necessary to add this missing evidence along with our own interpretation of recent findings to the discussion.
  Complexity of studying add-on interventions to pulmonary rehabilitation
  Based on the results from three recent multicentre trials2-4, Polkey and Ambrosino exclude a role for adjunctive IMT in the rehabilitation of patients with COPD. As emphasized in a previous opinion piece by Dr. Ambrosino5, it is important to distinguish between studies that evaluate the effects of inspiratory muscle training (IMT) as a standalone intervention (i.e. in comparison to no intervention or a sham control intervention) and studies on the effects of IMT added to a pulmonary rehabilitation program (PRP).
  Concerning the first comparison, there is a large amount of data available s...

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  We support the view of Drs. Polkey and Ambrosino that recommendations for clinical practice should not be based on either positive or negative preoccupation concerning the potential effectiveness of a treatment but rather on an impartial evaluation of the available data. In their editorial entitled ‘Inspiratory Muscle Training in COPD: can data finally beat emotion’ they unfortunately provide a fairly one-sided evaluation of this treatment, based on an incomplete and largely outdated review of the available evidence1. It is unfortunate that they neglect a major part of available data, which could contribute to a more balanced and fair discussion about this intervention. We therefore deemed it necessary to add this missing evidence along with our own interpretation of recent findings to the discussion.
  Complexity of studying add-on interventions to pulmonary rehabilitation
  Based on the results from three recent multicentre trials2-4, Polkey and Ambrosino exclude a role for adjunctive IMT in the rehabilitation of patients with COPD. As emphasized in a previous opinion piece by Dr. Ambrosino5, it is important to distinguish between studies that evaluate the effects of inspiratory muscle training (IMT) as a standalone intervention (i.e. in comparison to no intervention or a sham control intervention) and studies on the effects of IMT added to a pulmonary rehabilitation program (PRP).
  Concerning the first comparison, there is a large amount of data available supporting the effectiveness of IMT in COPD. The most recent meta-analysis identified 43 randomized controlled trials6. Based on data from more than 1200 patients randomized to either IMT or control interventions authors concluded that IMT improved symptoms of dyspnea (Baseline Dyspnea Index), Quality of life (Saint George's Respiratory Questionnaire), functional capacity (Six minute walking distance, 6MWD) and maximal inspiratory pressure (PImax) in patients with COPD6. A clinically relevant difference of 43m (95%CI: 17m to 69m) in improvements in 6MWD after IMT in comparison to control was reported. The claim that ‘the appeal of IMT in COPD endures in the absence of data’ seems inappropriate in the light of above-mentioned findings. Polkey and Ambrosino further support their conclusions by mentioning that IMT also failed to improve exercise capacity in healthy subjects. They support this statement by citing a single study performed in 20017. In doing so they neglect results from a systematic literature review from 2012 including results from 46 randomized controlled studies. From the meta-analysis it was concluded that ‘respiratory muscle training improves endurance exercise performance in healthy individuals with greater improvements in less fit individuals and in sports of longer durations’8.
  In contrast to studies of IMT as standalone intervention, when evaluating IMT as adjunctive intervention to PRP the evidence base looks different. In these type of studies, the control group already receives a very effective treatment (PRP) that will result in clinically relevant improvements in functional capacity and quality of life9. This makes it challenging to demonstrate additional effects of the adjunctive intervention on functional outcomes. Consequently, study designs are more complex, the database is less comprehensive and conclusions less straightforward6. IMT is not the only intervention that has failed to result in additional improvements in the 6MWD in this context (i.e. studying add-on interventions to PRP). A recent systematic review of RCTs studying the effects of various adjunctive interventions applied during PRP (including non-invasive ventilation, lower limb strength training, upper limb exercise training, oxygen supplementation, and inspiratory muscle training) did not observe additional effects of any of these adjunctive interventions during PR on the 6MWD10. When comparing the results of studies on the adjunctive effects of either lower limb strength training or IMT during PRP the results are of striking similarity. In both cases, the adjunctive interventions result in additional specific improvements in muscle function of the trained muscle groups without resulting in further improvements in 6MWD or quality of life measures10. It is questionable whether additional improvements in health related quality of life are a realistic goal when studying effects of these adjunctive interventions. Control groups participating in comprehensive PRP without adjunctive interventions will already achieve large and clinically relevant improvements in quality of life. It has further been demonstrated that changes in functional exercise capacity correlate poorly with changes in quality of life measures11. The questions should rather be whether in the specific case of IMT the adjunct intervention can (1) further reduce specific symptoms of exertional breathlessness and (2) whether it can optimize the response in functional capacity to PRP in participants who would otherwise achieve a less optimal response. In addition, the most appropriate candidates (i.e. likely responders to the adjunct intervention) and most suitable outcome measures still need to be identified. In order to find out whether the intervention can result in additional effects on functional capacity it will be necessary to strictly control both adherence with and quality of the adjunctive intervention as well as the symptom-based progression of the general exercise training program in this type of studies. To the best of our knowledge only one of the available studies has so far undertaken this effort4. The absence of evidence from studies on add-on interventions at this point should therefore not be interpreted as evidence of absence. Along these lines, the value of lower limb strength training during PRP in patients with COPD is currently not put into question based on limted available data. It is surprising however that, based on very similar data, it is concluded that there should be no role for IMT in the rehabilitation care of patients with COPD anymore. Instead of interpreting the results of recent studies2-4 as ultimate proof to discourage the use of IMT in COPD, we would rather argue that these findings should be used to optimize the design of future studies in this area. Unfortunately, Polkey and Ambrosino neglect most of the key findings from our recent trial that could be helpful for the design of these future studies. We will discuss these aspects in the final part of our comment. Prior to that we would like to review some of the other arguments that are used by Polkey and Ambrosino to support their statements.
  IMT and the diaphragm in patients with COPD
  They start by citing Leith and Bradleys pioneer work on ‘ventilatory muscle strength and endurance training’ from 1976. According to Polkey and Ambrosino these data, obtained in a handful of young healthy volunteers, support the assumption that inspiratory muscle training improves ‘test performance’ rather than ‘true contractility’12. We are unsure what their definition of ‘true contractility’ is, but it is generally accepted that the principles of specificity of resistance training apply to both training of the peripheral muscles13, and respiratory muscle training14. Results of several randomized controlled studies in patients with COPD have taught us that endurance type training (high flow, low resistance breathing) will specifically improve endurance capacity of the respiratory muscles, while PImax will only improve when subjects perform their breathing training against an external load of sufficiently large magnitude15. We would further like to comment on their statement that the reduction in inspiratory muscle strength in COPD is ‘due to hyperinflation rather than weakness’. While static hyperinflation certainly affects diaphragm contractility, several other etiological factors and biological mechanisms are known to contribute to respiratory muscle dysfunction in COPD16 17. These additional factors, many of which are also involved in peripheral muscle dysfunction, probably also help to explain the large variability in PImax that has been observed for a given level of static lung hyperinflation18.
  It is also noteworthy that, while limitations in diaphragm contribution in patients are acknowledged on the one hand, diaphragm strength evaluated by phrenic nerve stimulation is subsequently put forward as the most relevant measure of changes in inspiratory muscle function in patients with COPD. This seems to be a limited approach especially for patients with COPD in whom, with increasing disease severity, the role of the rib cage muscles becomes more and more important19. As a consequence it seems reasonable that both specific tests of diaphragm strength as well as measures of global inspiratory muscle strength (and endurance) should be used to evaluate the effect of interventions on inspiratory muscle function20. The fact that IMT did not increase diaphragm strength as judged by isolated (artificial) phrenic nerve stimulation (Twitch-Pdi) is used as one of the arguments to support the conclusion that ‘the story of IMT defied data at each stage’. We would like to comment on this. Firstly, the paper that is cited in support of this observation demonstrates a poor relationship between changes in Twitch-Pdi and PImax 21. Secondly, the data, again obtained in a handful of healthy subjects, reveal a high variability between Twitch-Pdi measurements performed before and after an intervention period in a control group that did not perform IMT21. We therefore believe that conclusions with regard to these observations should be formulated more cautiously.
  High fatigue resistance of the diaphragm is subsequently put forward as another argument why respiratory muscles of patients with COPD should not be trained. Indeed, adaptations in the diaphragm towards more fatigue resistance, most likely in response to chronic increased loading during resting breathing, are present in patients16 17. We also agree with Polkey and Ambrosino that it is unclear whether diaphragmatic muscle fatigue typically occurs during exercise breathing in patients with COPD. We would however like to highlight that acute length changes induced by exercise breathing (due to dynamic hyperinflation) will further impair the ability of the diaphragm to contribute to ventilation and will place increasing demands on accessory and rib cage muscles19. It is reasonable to assume that this breathing pattern would promote non-diaphragmatic respiratory muscle fatigue rather than diaphragm fatigue. Notwithstanding the difficulties in reliably assessing non-diaphragmatic muscle fatigue there are indications that fatigue in these muscles can develop selectively and separate from diaphragm fatigue, depending on the breathing pattern that is maintained22-24. The reluctance of Polkey and Ambrosino to acknowledge that the stimulus of exercise hyperpnea, as a consequence of further acute shortening of respiratory muscles and increased elastic loads due to dynamic hyperinflation, can result in acute disturbances in the load – capacity balance of the respiratory muscles of patients with COPD is surprising to say the least25 26. Especially given the fact that in an earlier opinion piece Dr Polkey highlighted the ‘specific relevance of [breathing close to] end inspiratory lung volume’ in patients with COPD, supported ‘by the observation that augmenting inspiratory muscle action at high lung volumes […] can extend exercise duration and increase peak work load27.’ It remains his secret as to why he would not appreciate a role for inspiratory muscle training in augmenting inspiratory muscle performance at high lung volumes during exercise breathing. In this context we would like to refer to a recent study28, in which we were able to demonstrate dyspnea relief during a constant work rate cycling test in response to IMT in patients with COPD. The effects of IMT were observed in patients with static and dynamic hyperinflation. Dyspnea reduction was observed in conjunction with a reduced activation of the diaphragm relative to maximum and in the absence of significant changes in ventilation, breathing pattern and operating lung volumes during cycling exercise 28. These data support previous findings of reduced diaphragm fatigability after IMT in patients with COPD29.
  Choosing adequate outcomes to evaluate the effects of adjunctive IMT
  As mentioned earlier it is a pity that some important results from our recent trial (IMT as adjunctive intervention during PRP)4, along with suggestions to improve the design of future studies have not been addressed by Polkey and Ambrosino. We would therefore like to highlight some of our key findings. In the absence of an additional effect of IMT on the 6MWD, we were able to demonstrate a significant improvement in the ability to sustain a submaximal effort during a constant work rate endurance-cycling test, as well as a reduction in symptoms of dyspnea at a standardized timepoint during this test4. The absence of evaluating symptoms at standardized levels of exertion has been identified as one of the shortcomings in one of the studies published earlier this year30. In our opinion these iso-time evaluations should be performed with the multidimensional dyspnea profile (MDP) in addition to Borg-CR 10 scale dyspnea scores in future studies. The higher sensitivity of submaximal constant work rate endurance exercise tests in comparison with the 6MWD has consistently been documented in pharmacological and non-pharmacological interventions in patients with COPD 31-33. The constant work rate endurance test therefore seems to be an optimal choice as a primary outcome for evaluating the effects of adjunctive interventions during PRP on functional capacity in future studies.
  Optimization of patient selection
  Furthermore, our recent findings also offer some food for thought with regard to selecting appropriate candidates for the adjunct intervention (IMT). While for peripheral muscle strength training it is reasonable to assume that the subjects with most pronounced weakness will benefit the most from the intervention, this might not be the case when selecting patients with respiratory muscle weakness. In our study we selected patients with pronounced weakness. This resulted in a sample of severely hyperinflated subjects (average RV >200%pred). The mechanical disadvantage of the respiratory muscles in these severely hyperinflated participants is probably a major contributor to the reduction in respiratory muscle pressure generating capacity. It has also been demonstrated that some of these severely hyperinflated patients are unable to dynamically hyperinflate during exercise34. These patients would consequently not undergo additional functional weakening of their inspiratory muscles due to further acute shortening during exercise. These patients will also not experience a great deal of additional loading on their respiratory muscles during exercise breathing due to both their inability to achieve major increases in tidal volume expansion, minute ventilation and their inability to dynamically hyperinflate during exercise breathing. Both factors (the large impact of mechanical disadvantage on weakness and the absence of acute disturbances in the load-capacity balance during exercise hyperpnoea) might render IMT less effective in these patients. Measurements of dynamic hyperinflation during exercise (which were not available in our study) would be needed to explore these issues further in order to identify participants who are potentially less likely to benefit from adjunctive IMT. In a further step one might choose to either exclude these patients from participation or to stratify randomization for this criterion.
  Improving control of interventions
  In addition, we were the first to show a relationship between quality and quantity of the performed IMT sessions and improvements in PImax4. We were able to control training parameters by using an electronic training device that stored training parameters recorded during home based IMT sessions35. We also observed that changes in PImax were significantly related to increases in the symptom-based progression of the intensity of the general exercise-training program and to improvements in functional exercise capacity4. This highlights the importance of monitoring and controlling both adherence to and quality of the adjunctive intervention, as well as the symptom based progression of the general exercise training components of the PRP in future studies. Sufficient time also needs to be allowed to establish the effects of IMT on symptom perception during exercise. This will enable patients to achieve larger increases in symptom based progression of the general exercise program. These increases in training intensity are a prerequisite to achieve additional benefits in functional capacity. Of the three studies of adjunctive IMT in COPD published this year2-4, ours was the only one that made an attempt to control for these parameters and we strongly encourage the use of these measures in future work in this area.
  Conclusions
  In summary, we feel that formulating strong statements to either discourage or recommend the use of IMT for patients with COPD in clinical practice is inappropriate at this stage. The results of recently published studies should in our opinion rather be regarded as a call for further research on the effects of IMT as an adjunct to PRP in patients with COPD. These studies will be needed to identify the best candidates for this adjunctive treatment. Based on the existing evidence and our own experience we formulate the following recommendations for further research:
  1. Select patients with respiratory muscle weakness and possibly exclude or stratify those patients who are unable to dynamically hyperinflate due to severe static lung hyperinflation.
  2. Tightly control adherence with and quality of the adjunct IMT intervention.
  3. Tightly control symptom based progression of general exercise training intensity during the PRP and preferably allow enough time (> 8 weeks) for effects of IMT on symptom perception to establish.
  4. Have general exercise training intervention executed and monitored by highly trained professionals who are blinded to group allocation.
  5. Select changes in symptoms of dyspnea (MDP scores or Borg CR-10 Scale dyspnea score) at standardized levels of exertion during constant work rate endurance exercise tests as the primary outcome of these studies30 36.
  References
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  2. Beaumont M, Mialon P, Le Ber C, et al. Effects of inspiratory muscle training on dyspnoea in severe COPD patients during pulmonary rehabilitation: controlled randomised trial. Eur Respir J 2018;51(1) doi: 10.1183/13993003.01107-2017 [published Online First: 2018/01/27]
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  11. Puhan MA, Mador MJ, Held U, et al. Interpretation of treatment changes in 6-minute walk distance in patients with COPD. Eur Respir J 2008;32(3):637-43. doi: 10.1183/09031936.00140507 [published Online First: 2008/06/14]
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  22. Fitting JW, Bradley TD, Easton PA, et al. Dissociation between diaphragmatic and rib cage muscle fatigue. J Appl Physiol (1985) 1988;64(3):959-65. doi: 10.1152/jappl.1988.64.3.959 [published Online First: 1988/03/01]
  23. Hershenson MB, Kikuchi Y, Tzelepis GE, et al. Preferential fatigue of the rib cage muscles during inspiratory resistive loaded ventilation. J Appl Physiol (1985) 1989;66(2):750-4. doi: 10.1152/jappl.1989.66.2.750 [published Online First: 1989/02/01]
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  28. Langer D, Ciavaglia CE, Faisal A, et al. Inspiratory muscle training reduces diaphragm activation and dyspnea during exercise in COPD. J Appl Physiol (1985) 2018 doi: 10.1152/japplphysiol.01078.2017 [published Online First: 2018/03/16]
  29. Dekhuijzen PN, Folgering HT, van Herwaarden CL. Target-flow inspiratory muscle training during pulmonary rehabilitation in patients with COPD. Chest 1991;99(1):128-33.
  30. Ekstrom M, Elmberg V, Lindow T, et al. Breathlessness measurement should be standardised for the level of exertion. Eur Respir J 2018;51(5) doi: 10.1183/13993003.00486-2018 [published Online First: 2018/06/01]
  31. Puhan MA, Schunemann HJ, Frey M, et al. Value of supplemental interventions to enhance the effectiveness of physical exercise during respiratory rehabilitation in COPD patients. A systematic review. Respir Res 2004;5:25. doi: 10.1186/1465-9921-5-25 [published Online First: 2004/12/04]
  32. Laviolette L, Bourbeau J, Bernard S, et al. Assessing the impact of pulmonary rehabilitation on functional status in COPD. Thorax 2008;63(2):115-21. doi: 10.1136/thx.2006.076844 [published Online First: 2007/09/29]
  33. Pepin V, Brodeur J, Lacasse Y, et al. Six-minute walking versus shuttle walking: responsiveness to bronchodilation in chronic obstructive pulmonary disease. Thorax 2007;62(4):291-8. doi: 10.1136/thx.2006.065540 [published Online First: 2006/11/14]
  34. Guenette JA, Webb KA, O'Donnell DE. Does dynamic hyperinflation contribute to dyspnoea during exercise in patients with COPD? Eur Respir J 2012;40(2):322-29.
  35. Langer D, Charususin N, Jacome C, et al. Efficacy of a Novel Method for Inspiratory Muscle Training in People With Chronic Obstructive Pulmonary Disease. Phys Ther 2015;95(9):1264-73. doi: ptj.20140245 [pii];10.2522/ptj.20140245 [doi]
  36. Beaumont M, Mialon P, Couturaud F. Breathlessness measurement should be standardised for the level of exertion. Eur Respir J 2018;51(5) doi: 10.1183/13993003.00820-2018 [published Online First: 2018/06/01]

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  Conflict of Interest:
  None declared.

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