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emotion’ they unfortunately provide a fairly one-sided evaluation of this treatment, based on an incomplete and largely outdated review of the available evidence1.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...
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emotion’ they unfortunately provide a fairly one-sided evaluation of this treatment, based on an incomplete and largely outdated review of the available evidence1.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
1. Polkey MI, Ambrosino N. Inspiratory muscle training in COPD: can data finally beat emotion? Thorax 2018 doi: 10.1136/thoraxjnl-2018-212070 [published Online First: 2018/06/28]
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]
3. Schultz K, Jelusic D, Wittmann M, et al. Inspiratory muscle training does not improve clinical outcomes in 3-week COPD rehabilitation: results from a randomised controlled trial. Eur Respir J 2018;51(1) doi: 10.1183/13993003.02000-2017 [published Online First: 2018/01/27]
4. Charususin N, Gosselink R, Decramer M, et al. Randomised controlled trial of adjunctive inspiratory muscle training for patients with COPD. Thorax 2018 doi: 10.1136/thoraxjnl-2017-211417 [published Online First: 2018/06/20]
5. Ambrosino N. The case for inspiratory muscle training in COPD. Eur Respir J 2011;37(2):233-35.
6. Beaumont M, Forget P, Couturaud F, et al. Effects of inspiratory muscle training in COPD patients: A systematic review and meta-analysis. Clin Respir J 2018 doi: 10.1111/crj.12905 [published Online First: 2018/04/18]
7. Sonetti DA, Wetter TJ, Pegelow DF, et al. Effects of respiratory muscle training versus placebo on endurance exercise performance. Respir Physiol 2001;127(2-3):185-99. [published Online First: 2001/08/16]
8. Illi SK, Held U, Frank I, et al. Effect of respiratory muscle training on exercise performance in healthy individuals: a systematic review and meta-analysis. Sports Med 2012;42(8):707-24. doi: 10.2165/11631670-000000000-00000 [published Online First: 2012/07/07]
9. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med 2013;188(8):e13-e64.
10. Camillo CA, Osadnik CR, van Remoortel H, et al. Effect of "add-on" interventions on exercise training in individuals with COPD: a systematic review. ERJ Open Res 2016;2(1) doi: 10.1183/23120541.00078-2015
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]
12. Leith DE, Bradley M. Ventilatory muscle strength and endurance training. J Appl Physiol 1976;41(4):508-16.
13. Morrissey MC, Harman EA, Johnson MJ. Resistance training modes: specificity and effectiveness. Med Sci Sports Exerc 1995;27(5):648-60. [published Online First: 1995/05/01]
14. Romer LM, McConnell AK. Specificity and reversibility of inspiratory muscle training. Med Sci Sports Exerc 2003;35(2):237-44. doi: 10.1249/01.MSS.0000048642.58419.1E [published Online First: 2003/02/06]
15. Gosselink R, De Vos J, van den Heuvel SP, et al. Impact of inspiratory muscle training in patients with COPD: what is the evidence? Eur Respir J 2011;37(2):416-25.
16. Gea J, Pascual S, Casadevall C, et al. Muscle dysfunction in chronic obstructive pulmonary disease: update on causes and biological findings. J Thorac Dis 2015;7(10):E418-38. doi: 10.3978/j.issn.2072-1439.2015.08.04 [published Online First: 2015/12/02]
17. Barreiro E, Bustamante V, Cejudo P, et al. Guidelines for the evaluation and treatment of muscle dysfunction in patients with chronic obstructive pulmonary disease. Arch Bronconeumol 2015;51(8):384-95. doi: 10.1016/j.arbres.2015.04.011 [published Online First: 2015/06/15]
18. Langer D, Ciavaglia C, Webb K, et al. Inspiratory muscle weakness in mildly- to moderately-hyperinflated patients with COPD. Eur Respir J 2014;44:Suppl 58:3344.
19. Martinez FJ, Couser JI, Celli BR. Factors influencing ventilatory muscle recruitment in patients with chronic airflow obstruction. Am Rev Respir Dis 1990;142(2):276-82. doi: 10.1164/ajrccm/142.2.276 [published Online First: 1990/08/01]
20. Nava S, Ambrosino N, Crotti P, et al. Recruitment of some respiratory muscles during three maximal inspiratory manoeuvres. Thorax 1993;48(7):702-7. [published Online First: 1993/07/01]
21. Hart N, Sylvester K, Ward S, et al. Evaluation of an inspiratory muscle trainer in healthy humans. Respir Med 2001;95(6):526-31.
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]
24. Segizbaeva MO, Donina Zh A, Timofeev NN, et al. EMG analysis of human inspiratory muscle resistance to fatigue during exercise. Adv Exp Med Biol 2013;788:197-205. doi: 10.1007/978-94-007-6627-3_29 [published Online First: 2013/07/10]
25. Dempsey JA, Romer L, Rodman J, et al. Consequences of exercise-induced respiratory muscle work. Respir Physiol Neurobiol 2006;151(2-3):242-50.
26. LeBlanc P, Summers E, Inman MD, et al. Inspiratory muscles during exercise: a problem of supply and demand. J Appl Physiol 1988;64(6):2482-89.
27. Luo YM, Hopkinson NS, Polkey MI. Tough at the top: must end-expiratory lung volume make way for end-inspiratory lung volume? Eur Respir J 2012;40(2):283-85.
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]
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....
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)
The differentiation between an empyema and a peripheral lung abscess is really difficult. The authors have summarized most points on differentiation. We had of a similar case, which looked like an Abscess on Chest Xray and had Acute angulation with lungs on Chest Ct, but due to the smooth inner walls and enhancement of pleura, we treated the case like an Empyema. Interestingly the initial CT showed some volume loss with ribs appearing crowded and this feature was more pronounced in the subsequent CT done after 2 weeks. Thus, associated volume loss with rib crowding could also be an additional point in the differentiation favoring Empyema and this volume loss might appear fairly early as well.
The EPICC trial addresses the rarely investigated topic of rehabilitation in the critical care setting [1]. We note with interest that no improvement was found in outcomes in the rehabilitation group compared to the standard treatment group. Some of the reasons are clearly highlighted by Schaller et al. in their response to the paper including the time to starting intervention, therapy times and also sample size. Only 41% of the participants in the intervention group and 35% of the standard treatment group contributed data throughout the study period. In addition to this, only 8% of the intervention group managed over half the target therapy time and the EPICC trial showed that ‘an extra 10 minutes of physical therapy per day does not make a difference [2]’
This study triggered an audit within our own 16 bedded mixed surgical and medical intensive care department assessing the number of sessions carried out over a 2 week period compared to those attempted. We investigated the actual duration of sessions achieved as compared to a target of 45 minutes rehabilitation each day during the working week (Monday-Friday). On average, 23.3 (standard deviation 20.19 minutes) minutes of rehabilitation per day was achieved and only 35% of attempted physical therapy sessions were completed. These figures are similar to those cited within the EPICC trial and highlight some of the difficulties of achieving longer therapy times within a busy intensive care department. Some of the fac...
The EPICC trial addresses the rarely investigated topic of rehabilitation in the critical care setting [1]. We note with interest that no improvement was found in outcomes in the rehabilitation group compared to the standard treatment group. Some of the reasons are clearly highlighted by Schaller et al. in their response to the paper including the time to starting intervention, therapy times and also sample size. Only 41% of the participants in the intervention group and 35% of the standard treatment group contributed data throughout the study period. In addition to this, only 8% of the intervention group managed over half the target therapy time and the EPICC trial showed that ‘an extra 10 minutes of physical therapy per day does not make a difference [2]’
This study triggered an audit within our own 16 bedded mixed surgical and medical intensive care department assessing the number of sessions carried out over a 2 week period compared to those attempted. We investigated the actual duration of sessions achieved as compared to a target of 45 minutes rehabilitation each day during the working week (Monday-Friday). On average, 23.3 (standard deviation 20.19 minutes) minutes of rehabilitation per day was achieved and only 35% of attempted physical therapy sessions were completed. These figures are similar to those cited within the EPICC trial and highlight some of the difficulties of achieving longer therapy times within a busy intensive care department. Some of the factors cited by our physiotherapists include patient fatigue, limitations on staff availability and also clinical appropriateness of the patients for rehabilitation. Of interest, Schaller et al. have also suggested some solutions to the problems encountered in our own audit and also within the EPICC trial. We agree that the combined effort of the multi-disciplinary team is extremely important in order to maximise opportunities for rehabilitation sessions but also the ability to then consider multiple short sessions each day.
In summary, we applaud the attempts of Wright and colleagues for addressing this under-investigated area of rehabilitation. We have reservations about some of the conclusions of the paper due to limited differences between intervention and treatment and underpowering of the study. Our own unpublished data supports the finding that to consistently achieve 90 minutes of therapy per patient as stipulated for the intervention group in this study would be very difficult in the current framework but this is an area to improve with some solutions already suggested.
References:
1. Wright SE, Thomas K, Watson G, et al. Intensive versus standard physical rehabilitation therapy in the critically ill (EPICC): a multicentre, parallel-group, randomised controlled trial. Thorax 2017:thoraxjnl-2016-209858
2. Schaller SJ, Nydahl P, Blobner M, et al. What does the EPICC trial really tell us? Thorax 2018
In 2011, the National Lung Cancer Screening Trial (NLST) showed that annual low-dose computed tomography (LDCT) improved overall survival (1). More recently, longer interval between LDCT rounds was advocated to improve screening efficiency after baseline (2).
Schreuder et al reported a comprehensive model for optimization of LDCT by biennial rounds for subjects at lower 2-year risk of lung cancer (3). They built a promising polynomial model including both patient characteristics and nodule descriptors. The retrospective simulation on NLST data provided enough power to test Schreuder’s model (3) as well as other models for selection of subjects to be forwarded to biennial screening (2, 4). We appreciate this approach to parsimonious LDCT administration as we are strongly convinced that annual screening should be tailored to subjects with remarkably high risk of lung cancer. The authors refer that prospective randomized controlled trial with tailored screening intervals would be hardly feasible, however we would like to remind that some experience was already reported in the literature.
Since 2005, the Multicenter Italian Lung Detection (MILD) trial conducted a prospective comparison between annual (LDCT1 = 1,152 screenees) and biennial LDCT (LDCT2 = 1,151 screenees) (5). The LDCT2 screenees were shifted to annual screening in case of solid nodule > 60 mm^3 and/or subsolid nodules. In other words, the MILD trial prospectively tested a risk model for tailored s...
In 2011, the National Lung Cancer Screening Trial (NLST) showed that annual low-dose computed tomography (LDCT) improved overall survival (1). More recently, longer interval between LDCT rounds was advocated to improve screening efficiency after baseline (2).
Schreuder et al reported a comprehensive model for optimization of LDCT by biennial rounds for subjects at lower 2-year risk of lung cancer (3). They built a promising polynomial model including both patient characteristics and nodule descriptors. The retrospective simulation on NLST data provided enough power to test Schreuder’s model (3) as well as other models for selection of subjects to be forwarded to biennial screening (2, 4). We appreciate this approach to parsimonious LDCT administration as we are strongly convinced that annual screening should be tailored to subjects with remarkably high risk of lung cancer. The authors refer that prospective randomized controlled trial with tailored screening intervals would be hardly feasible, however we would like to remind that some experience was already reported in the literature.
Since 2005, the Multicenter Italian Lung Detection (MILD) trial conducted a prospective comparison between annual (LDCT1 = 1,152 screenees) and biennial LDCT (LDCT2 = 1,151 screenees) (5). The LDCT2 screenees were shifted to annual screening in case of solid nodule > 60 mm^3 and/or subsolid nodules. In other words, the MILD trial prospectively tested a risk model for tailored screening intervals that was based on baseline LDCT findings. Given the small sample of this trial, we underline that the absence of outcome difference between LDCT1 and LDCT2 should be carefully interpreted (5).
In summary, baseline LDCT2 prospectively selected 147/1,151 (12.8%) screenees for annual screening, whilst 1,004/1,151 (87.2%) were forwarded to biennial round (6). The LDCT2 risk model allowed a sharp reduction by almost 90% LDCTs at the first incidence round. This is a considerable proportion compared to the retrospective analysis presented by Schreuder et al (simulations led to potential LDCT reduction ranging from 10.4% to 81.6%) (3). A similar figure was seen every other year throughout 7.3 years, with overall cuts of 32% LDCTs in LDCT2 compared with LDCT1 (6).
We would like to emphasize that the volumetric risk model allowed higher detection rate in LDCT2 screenees selected for annual screening (1.36% namely 2 lung cancers in 147 screenees) compared to LDCT1 screenees (0.45% namely 5 lung cancers in 1,111 screenees), at the first annual LDCT after baseline. Under this prospective condition, the number of scans needed to diagnose one lung cancer case (NND) was 74 in LDCT2, which is quite close to the 60 NND proposed by Schreuder by accepting a delay of diagnosis in 25% of screenees. On the other hand, NND was 222.2 in LDCT1, namely within the NND range reported in the literature (from 125 to 385) at the first annual LDCT by fixed annual screening algorithms (1, 7, 8). Hence, the LDCT2 algorithm prompted the lowest prospective NND reported in the literature. Through the median 7.3 years of LDCT screening in MILD, the cumulative NND during annual screenings was 63 for selected LDCT2 screenees and 250 for LDCT1 (p=0.003). Selective 3-year screening interval is now being tested in the bioMILD trial with higher volumetric threshold for solid nodules and including circulating biomarkers (ClinicalTrials.gov: NCT02247453; >4,000 baseline LDCTs acquired, results expected by 2020).
We hypothesize that the prospective application of Schreuder’s model might even improve the efficiency of MILD LDCT2. Furthermore, enrichment by clinical variables is encouraged, including circulating biomarkers. More models like Schreuder’s are fostered for optimization of radiologists’ workload for the seemingly approaching practice of population-based lung cancer screening by LDCT.
References
1. National Lung Screening Trial Research T, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. The New England journal of medicine. 2011;365(5):395-409.
2. Patz EF, Jr., Greco E, Gatsonis C, Pinsky P, Kramer BS, Aberle DR. Lung cancer incidence and mortality in National Lung Screening Trial participants who underwent low-dose CT prevalence screening: a retrospective cohort analysis of a randomised, multicentre, diagnostic screening trial. The Lancet Oncology. 2016;17(5):590-9.
3. Schreuder A, Schaefer-Prokop CM, Scholten ET, Jacobs C, Prokop M, van Ginneken B. Lung cancer risk to personalise annual and biennial follow-up computed tomography screening. Thorax. 2018.
4. White CS, Dharaiya E, Campbell E, Boroczky L. The Vancouver Lung Cancer Risk Prediction Model: Assessment by Using a Subset of the National Lung Screening Trial Cohort. Radiology. 2017;283(1):264-72.
5. Pastorino U, Rossi M, Rosato V, Marchiano A, Sverzellati N, Morosi C, et al. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation. 2012;21(3):308-15.
6. Sverzellati N, Silva M, Calareso G, Galeone C, Marchiano A, Sestini S, et al. Low-dose computed tomography for lung cancer screening: comparison of performance between annual and biennial screen. European radiology. 2016;26(11):3821-9.
7. Yousaf-Khan U, van der Aalst C, de Jong PA, Heuvelmans M, Scholten E, Walter J, et al. Risk stratification based on screening history: the NELSON lung cancer screening study. Thorax. 2017.
8. Tammemagi MC, Schmidt H, Martel S, McWilliams A, Goffin JR, Johnston MR, et al. Participant selection for lung cancer screening by risk modelling (the Pan-Canadian Early Detection of Lung Cancer [PanCan] study): a single-arm, prospective study. The Lancet Oncology. 2017.
We thank the authors of the letter in response to our paper for their interest and positive appraisal of our model. Likewise, we appreciate the design of the Multicenter Italian Lung Detection (MILD) trial which, despite its small sample size, demonstrates that annual intervals are unnecessary for the majority of screenees. Once more European data is available to perform cost-effectiveness analyses, we hypothesize that personalised screening intervals will prove to be the preferred design. Furthermore, it is estimated that most inclusion criteria used to select high-risk participants encompass only 70% of all lung cancer cases in the population; reassessing risk and tailoring interval groups after the baseline scan may enable the inclusion of persons of lower risk. As Silva et al mentioned, there is no reason to set the upper limit of follow-up intervals at 2-years. We also agree that volumetric nodule measurements are better suited for determining follow-up procedures than (perpendicular) diameter, and hope to be able to implement this into a future model. Moreover, risk scores may be calculated autonomously by computers in the future, with only a select few dubious cases requiring radiologist attention.
We welcome the letter by Anna Humphreys and colleagues highlighting the secondary benefits of screening contacts of extra pulmonary tuberculosis for LTBI in areas where active cases are predominantly amongst the non-UK born (1).
We share the view that novel approaches are needed to identify and offer testing to those at risk of LTBI, and that contact tracing provides a unique opportunity to reach those who may be eligible.
Early results from the London Borough of Newham, the pilot site for the national latent TB screening programme highlight that uptake of LTBI screening amongst recent migrants is only 40 percent (2). Efforts are being made to improve awareness including animated health promotion tools (https://youtu.be/tKwAHJ7JeV0) and TB Alert’s Latent TB Handbook (https://www.tbalert.org/health-professionals/ltbi-toolkit/) and novel interventions to improve LTBI screening and treatment uptake are being implemented across the country. We are currently investigating the efficacy of managing LTBI entirely within primary care (https://clinicaltrials.gov/ct2/show/NCT03069807). Recent work has also identified that opportunistic LTBI screening in non-health settings is acceptable to recent migrants (3).
In areas where the majority of active cases are amongst those...
We welcome the letter by Anna Humphreys and colleagues highlighting the secondary benefits of screening contacts of extra pulmonary tuberculosis for LTBI in areas where active cases are predominantly amongst the non-UK born (1).
We share the view that novel approaches are needed to identify and offer testing to those at risk of LTBI, and that contact tracing provides a unique opportunity to reach those who may be eligible.
Early results from the London Borough of Newham, the pilot site for the national latent TB screening programme highlight that uptake of LTBI screening amongst recent migrants is only 40 percent (2). Efforts are being made to improve awareness including animated health promotion tools (https://youtu.be/tKwAHJ7JeV0) and TB Alert’s Latent TB Handbook (https://www.tbalert.org/health-professionals/ltbi-toolkit/) and novel interventions to improve LTBI screening and treatment uptake are being implemented across the country. We are currently investigating the efficacy of managing LTBI entirely within primary care (https://clinicaltrials.gov/ct2/show/NCT03069807). Recent work has also identified that opportunistic LTBI screening in non-health settings is acceptable to recent migrants (3).
In areas where the majority of active cases are amongst those born in high TB-burden countries, a reinterpretation of contact screening that encompasses the aims of identifying active TB cases, as well as recently and remotely acquired LTBI would allow TB programmes to reach many more people at risk.
The National guidelines were updated based on evidence that non-pulmonary TB is a lower risk for transmission (4). Screening contacts is justified given the public health risk of active disease in those recently exposed and a case can be made for screening contacts of extra pulmonary cases as they may have been infected by a previously unknown pulmonary index case.
However, should we decide to change our approach to screening contacts with the explicit aim of identifying LTBI due to remote infection then we must at least acknowledge this when we talk to patients about their recent contacts and ask them to share personal information. And, as a TB community, we must agree that this approach is ethical.
We would support this broader eligibility for screening contacts and believe it would strengthen an already vital tool in the fight to eliminate Tuberculosis in the UK.
1. Humphreys A, Abbara A, Williams S, John L, Corrah T, McGregor A, et al. Screening contacts of patients with extrapulmonary TB for latent TB infection. Thorax. 2018;73(3):277-8.
2. Loutet M. National Roll-out of Latent Tuberculosis Testing and Treatment for New Migrants in England: a retrospective evaluation in a high-incidence area. European Respiratory Journal. 2017:1-25.
3. Walker CL, Duffield K, Kaur H, Dedicoat M, Gajraj R. Acceptability of latent tuberculosis testing of migrants in a college environment in England. Public Health. 2018;158:55-60.
4. Hoppe LE, Kettle R, Eisenhut M, Abubakar I. Tuberculosis—diagnosis, management, prevention, and control: summary of updated NICE guidance. BMJ. 2016:h6747-9.
We are grateful to Dr. Duerden and Dr. Levy for their comments on our paper which highlight the difficulty of comparing doses of ICS steroids when there is no gold standard comparator. Our aim in compiling Table 1 was to point out that the NICE table does not allow for the greater potency of HFA FP compared to HFA BDP. We were concerned that this was a significant safety issue especially in children [1]. In our efforts to simplify this message, we had not fully explained or allowed for some of the other variables.
1. Dr. Levy is correct to point out that the original GINA table (used by NICE) of “Low, medium and high daily doses of inhaled corticosteroid for children 6-11 years” has a statement below indicating that the table is not a table of “dose equivalency”, the term we used in Table 1, but of “estimated clinical comparability”.
2. The GINA table (but not NICE) also has a footnote explaining the inclusion of beclometasone dipropionate CFC (BDP CFC) as a comparison with older literature. CFCs (chlorofluorocarbons), as propellants in metered dose inhalers, were phased out under the Montreal Protocol and were replaced by HFAs (hydrofluorolakanes). However, CFC BDP is still often used as the reference standard when comparing ICS in terms of their potency.
3. Most newer HFA ICSs have been formulated to be equipotent with the CFC ICS they were replacing. As one example, the BTS/SIGN table includes the proprietary HFA BPD, Clenil modulite, commonly us...
We are grateful to Dr. Duerden and Dr. Levy for their comments on our paper which highlight the difficulty of comparing doses of ICS steroids when there is no gold standard comparator. Our aim in compiling Table 1 was to point out that the NICE table does not allow for the greater potency of HFA FP compared to HFA BDP. We were concerned that this was a significant safety issue especially in children [1]. In our efforts to simplify this message, we had not fully explained or allowed for some of the other variables.
1. Dr. Levy is correct to point out that the original GINA table (used by NICE) of “Low, medium and high daily doses of inhaled corticosteroid for children 6-11 years” has a statement below indicating that the table is not a table of “dose equivalency”, the term we used in Table 1, but of “estimated clinical comparability”.
2. The GINA table (but not NICE) also has a footnote explaining the inclusion of beclometasone dipropionate CFC (BDP CFC) as a comparison with older literature. CFCs (chlorofluorocarbons), as propellants in metered dose inhalers, were phased out under the Montreal Protocol and were replaced by HFAs (hydrofluorolakanes). However, CFC BDP is still often used as the reference standard when comparing ICS in terms of their potency.
3. Most newer HFA ICSs have been formulated to be equipotent with the CFC ICS they were replacing. As one example, the BTS/SIGN table includes the proprietary HFA BPD, Clenil modulite, commonly used in children. Clenil is clinically comparable to the legacy BDP CFC with a recommended starting dose of Clenil 50 2 puffs BD (100ug bd) in children (2). The BTS/SIGN table also includes the HFA BDP, Qvar, which is formulated as an extra-fine particle preparation and is usually considered as effective at half the dose. GINA and NICE give the doses for HFA BDP in children as half those of the BDP CFC but do not specify which preparations of HFA BDP they are referring to in their table.
4. HFA Fluticasone propionate (HFA FP) is as effective as other inhaled steroids at approximately half the microgram daily dose (3). So, for clinical comparability HFA FP should be used at half the dose of HFA BDP, as indicated in the BTS/SIGN table.
5. A further complication is that GINA provides doses as daily doses: BTS/SIGN provides puffs and frequency; NICE only specifies dose (though assumed to be daily dose as the table was taken from GINA). In preparing the table we should have made clear that the doses from the BTS/SIGN table were to be given twice a day.
The challenge was how to explain this simply in limited text and a small table and it was complicated by the other points discussed above. To clarify these issues, we suggest the table should be modified as follows:
More fundamentally, this discussion highlights the potential complexity for prescribers from the increasing number of corticosteroid molecules available in an ever-increasing number of devices. If a national guideline body and ‘experts’ who have spent some hours poring over these data struggle to achieve clarity what hope is there for the busy prescriber in clinical practice? Perhaps, this discussion should stimulate regulatory authorities to consider whether manufacturers of inhaled corticosteroids could be required to label their devices as providing doses equivalent to an agreed standard.
Finally, prescribers should always remember that the numbers in all these tables are only a guide. The correct dose of an inhaled steroid is the lowest dose that keeps the patient free of symptoms and that this dose should be adjusted dynamically in response to changes in status in accordance with an agreed action plan.
References
1. Paton J, Jardine E, McNeill E, et al. Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone. Arch Dis Child. 2006 Oct;91(10):808-13.
2. The electronic Medicines Compendium. https://www. medicines. org. uk/ emc/ medicine/30651 (accessed 14 Jan 2018).
3. The electronic Medicines Compendium. https://www. medicines. org. uk/ emc/ medicine/2913 (accessed 14 Jan 2018).
The article of Bhatt et al addresses an important topic (1). The authors assessed the relative contribution of intensity and duration of tobacco smoke exposure to the development of chronic obstructive pulmonary disease (COPD). They concluded that smoking duration alone provides stronger risk than the composite index of pack years. In other words, the effect of long and low intensity exposure has a stronger association with COPD than short exposures of high intensities. The article of Marks consents this finding, concluding that pack years are a suboptimal index of exposure (2).
A major limitation of the study of Bhatt, which surprisingly is not stated as such, is the use of a cross-sectional design that does not allow drawing causal conclusions. The conclusions drawn therefore might be flawed.
Selection bias due the healthy ‘survivor’ effect might have occurred. The duration of smoking could have been influenced by the deleterious effects a person experiences from the exposure to smoke. Those with a long smoke duration are more likely not to experience (or experience less) health issues due to smoking, and might therefore have less severe (or no) COPD than those with a short smoke duration. In line with this, selective ‘drop-out’ of the more diseased persons may have biased the results.
Furthermore, the authors use retrospective data, while this often leads to recall bias. Participants often do not precisely remember the numbers of cigarettes smoked...
The article of Bhatt et al addresses an important topic (1). The authors assessed the relative contribution of intensity and duration of tobacco smoke exposure to the development of chronic obstructive pulmonary disease (COPD). They concluded that smoking duration alone provides stronger risk than the composite index of pack years. In other words, the effect of long and low intensity exposure has a stronger association with COPD than short exposures of high intensities. The article of Marks consents this finding, concluding that pack years are a suboptimal index of exposure (2).
A major limitation of the study of Bhatt, which surprisingly is not stated as such, is the use of a cross-sectional design that does not allow drawing causal conclusions. The conclusions drawn therefore might be flawed.
Selection bias due the healthy ‘survivor’ effect might have occurred. The duration of smoking could have been influenced by the deleterious effects a person experiences from the exposure to smoke. Those with a long smoke duration are more likely not to experience (or experience less) health issues due to smoking, and might therefore have less severe (or no) COPD than those with a short smoke duration. In line with this, selective ‘drop-out’ of the more diseased persons may have biased the results.
Furthermore, the authors use retrospective data, while this often leads to recall bias. Participants often do not precisely remember the numbers of cigarettes smoked per day in a specific year or time period. Assuming that participants underestimate smoke intensity, it is likely that the association between smoke intensity and COPD is less strong than the association between smoke duration and COPD. This weaker association is then not due to the relative contribution of smoke intensity compared to that of duration, but to recall bias.
To conclude, the statements made in the paper seem to be very convincing, but are based on research with methodological limitations. Prospective studies assessing the relative contribution of smoke intensity and smoke duration are thus urgently needed.
1. Bhatt SP, Kim YI, Harrington KF, Hokanson JE, Lutz SM, Cho MH, et al. Smoking duration alone provides stronger risk estimates of chronic obstructive pulmonary disease than pack-years. Thorax. 2018.
2. Marks GB. Guiding policy to reduce the burden of COPD: the role of epidemiological research. Thorax. 2018.
We have read with great interest the multi-centred EPICC trial that randomized over 300 patients [1]. While the delivery of a complex physical rehabilitation intervention in clinical trials is difficult, we believe that several aspects of the trial may have resulted in the inability to detect a difference between the control and intervention groups. These factors include the delayed time to start the intervention, inadequate delivery of the intervention and the large loss to follow-up for the primary outcome measure. In our opinion, these three factors limit the interpretation of the results of the study. While the authors have mentioned some of these concerns in their discussion, and Connolly et al. raised some of these points already [2], we hope to learn some important lessons from the authors to better understand these limitations and how they can be minimized in future studies.
The number of randomized controlled trials evaluating early physical rehabilitation in ICUs is increasing [3]. Positive effects on primary outcomes were only found in studies in which physical rehabilitation was started within 72 hours of ICU admission [4-6]. Studies, which did not meet this criterion of early onset of physical rehabilitation, did not demonstrate benefit of the intervention [7]. Therefore, this time frame has been defined in rehabilitation guidelines [8]. Based on this evidence, we are not surprised that the authors of the EPICC trial were unable to demonstrate beneficial...
We have read with great interest the multi-centred EPICC trial that randomized over 300 patients [1]. While the delivery of a complex physical rehabilitation intervention in clinical trials is difficult, we believe that several aspects of the trial may have resulted in the inability to detect a difference between the control and intervention groups. These factors include the delayed time to start the intervention, inadequate delivery of the intervention and the large loss to follow-up for the primary outcome measure. In our opinion, these three factors limit the interpretation of the results of the study. While the authors have mentioned some of these concerns in their discussion, and Connolly et al. raised some of these points already [2], we hope to learn some important lessons from the authors to better understand these limitations and how they can be minimized in future studies.
The number of randomized controlled trials evaluating early physical rehabilitation in ICUs is increasing [3]. Positive effects on primary outcomes were only found in studies in which physical rehabilitation was started within 72 hours of ICU admission [4-6]. Studies, which did not meet this criterion of early onset of physical rehabilitation, did not demonstrate benefit of the intervention [7]. Therefore, this time frame has been defined in rehabilitation guidelines [8]. Based on this evidence, we are not surprised that the authors of the EPICC trial were unable to demonstrate beneficial effects of their intervention, since it approximately started on day 8 (the median (IQR) duration of ventilation at randomisation was 4 (3–7) days with a further 3 (1–6) days until the first physical rehabilitation was received), which may be too late to confer benefit.
The EPICC protocol aimed to compare 30 min vs. 90 min of physical rehabilitation, which was not achieved in either group. The authors report that the daily physical therapy was applied for 23 min in the intervention group (26% of the planned intervention) and for 13 min in standard of care group (43% of the planned standard care), respectively. Not only this amount of physical rehabilitation is hardly conceivable as an effective therapeutic strategy, but in terms of testing the hypothesis, it did not achieve the planned separation between the groups. In other words, the EPICC trial teaches us that an additional 10 minutes of physical rehabilitation per day does not make a difference.
The authors describe two main reasons for not achieving their planned intervention: (a) sedation and (b) patient fatigue. We have difficulties understanding why these two factors could not be controlled. The authors do not report the sedation regime during the study. If there was no standardized sedation protocol with daily awakening trials, this is a further shortcoming of the protocol as well as another reason for inability to improve the patients’ outcome in the intervention group. Deep sedation not only inhibits effective physical rehabilitation but is associated with increased mortality and length of stay [8]. To better appreciate the study results, it would be important that the authors report the sedation protocols/regimes of the participating centres.
Furthermore, how was the treatment plan of the intervention in “difficult” patients with low physical reserve or pre-existing frailty implemented? From our own experience patients with impaired functional reserves or frailty might only be trained for a short period of time. However, to achieve an intervention time of 90 minutes per day, such patients must be trained several times a day (e.g. for 15 minutes every hour). If 23 minutes are achieved in the intervention group, there might have been an additional “resource” limitations which is not presented, e.g. that a physical therapist would not be able to do more than a session every 4 hours or than four times a day. Would it be possible to elaborate on the available staff resources to deliver the intervention? If we assume that the lack of staff resources were an additional limitation not mentioned by the authors, it supports our belief that a successful early rehabilitation program has to be interprofessional, including both physical therapists and nursing staff to maximize physical rehabilitation opportunities throughout the day [5, 10].
Finally, the authors chose a primary outcome (Physical Component Summary Score of the SF-36 version 2) that does take into account mortality. Approximately one third of patients enrolled died before the functional outcome could be assessed. This functional outcome “truncated due to death” creates challenges in the definition and statistical evaluation of the treatment effect, and deserves careful planning of statistical analyses [11].
An additional 25% of enrolled patients were lost to follow-up. Therefore 57% of the enrolled patients did not contribute to the primary outcome measure, making the overall results of the study difficult to interpret.
In summary, we think that the conclusion and key message do not entirely reflect the study results. Physical therapy interventions of 90 min vs. 30 minutes were not achieved in the study. Additionally, less than half of enrolled patients contributed data to the primary outcome measure and excluding patients who did not survive limits the interpretation of this complex intervention.
References
1. Wright, S.E., et al., Intensive versus standard physical rehabilitation therapy in the critically ill (EPICC): a multicentre, parallel-group, randomised controlled trial. Thorax, 2017.
2. Connolly B and Denehy L Hindsight and moving the needle forwards on rehabilitation trial design. Thorax. 2018 Mar;73(3):203-205. doi: 10.1136/thoraxjnl-2017-210588. Epub 2017 Nov 14. http://thorax.bmj.com/content/73/3/203
3. Fuest, K. and S.J. Schaller, Recent evidence on early mobilization in critical-Ill patients. Curr Opin Anaesthesiol, 2018.
4. Schweickert, W.D., et al., Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet, 2009. 373(9678): p. 1874-82.
5. Schaller, S.J., et al., Early, goal-directed mobilisation in the surgical intensive care unit: a randomised controlled trial. Lancet, 2016. 388(10052): p. 1377-1388.
6. Investigators, T.S., et al., Early mobilization and recovery in mechanically ventilated patients in the ICU: a bi-national, multi-centre, prospective cohort study. Crit Care, 2015. 19: p. 81.
7. Moss, M., et al., A Randomized Trial of an Intensive Physical Therapy Program for Patients with Acute Respiratory Failure. Am J Respir Crit Care Med, 2016. 193(10): p. 1101-10.
8. Bein, T., et al., S2e guideline: positioning and early mobilisation in prophylaxis or therapy of pulmonary disorders : Revision 2015: S2e guideline of the German Society of Anaesthesiology and Intensive Care Medicine (DGAI). Anaesthesist, 2015. 64 Suppl 1: p. 1-26.
9. Stephens, R.J., et al., Practice Patterns and Outcomes Associated With Early Sedation Depth in Mechanically Ventilated Patients: A Systematic Review and Meta-Analysis. Crit Care Med, 2018. 46(3): p. 471-479.
10. McWilliams, D., et al., Earlier and enhanced rehabilitation of mechanically ventilated patients in critical care: A feasibility randomised controlled trial. J Crit Care, 2018. 44: p. 407-412.
11. Colantuoni, E., et al., Statistical methods to compare functional outcomes in randomized controlled trials with high mortality. BMJ, 2018. 360: p. j5748.
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.
Show MoreComplexity 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...
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.
Show MoreWhilst 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....
The differentiation between an empyema and a peripheral lung abscess is really difficult. The authors have summarized most points on differentiation. We had of a similar case, which looked like an Abscess on Chest Xray and had Acute angulation with lungs on Chest Ct, but due to the smooth inner walls and enhancement of pleura, we treated the case like an Empyema. Interestingly the initial CT showed some volume loss with ribs appearing crowded and this feature was more pronounced in the subsequent CT done after 2 weeks. Thus, associated volume loss with rib crowding could also be an additional point in the differentiation favoring Empyema and this volume loss might appear fairly early as well.
****can provide CT films of the same****
The EPICC trial addresses the rarely investigated topic of rehabilitation in the critical care setting [1]. We note with interest that no improvement was found in outcomes in the rehabilitation group compared to the standard treatment group. Some of the reasons are clearly highlighted by Schaller et al. in their response to the paper including the time to starting intervention, therapy times and also sample size. Only 41% of the participants in the intervention group and 35% of the standard treatment group contributed data throughout the study period. In addition to this, only 8% of the intervention group managed over half the target therapy time and the EPICC trial showed that ‘an extra 10 minutes of physical therapy per day does not make a difference [2]’
Show MoreThis study triggered an audit within our own 16 bedded mixed surgical and medical intensive care department assessing the number of sessions carried out over a 2 week period compared to those attempted. We investigated the actual duration of sessions achieved as compared to a target of 45 minutes rehabilitation each day during the working week (Monday-Friday). On average, 23.3 (standard deviation 20.19 minutes) minutes of rehabilitation per day was achieved and only 35% of attempted physical therapy sessions were completed. These figures are similar to those cited within the EPICC trial and highlight some of the difficulties of achieving longer therapy times within a busy intensive care department. Some of the fac...
In 2011, the National Lung Cancer Screening Trial (NLST) showed that annual low-dose computed tomography (LDCT) improved overall survival (1). More recently, longer interval between LDCT rounds was advocated to improve screening efficiency after baseline (2).
Show MoreSchreuder et al reported a comprehensive model for optimization of LDCT by biennial rounds for subjects at lower 2-year risk of lung cancer (3). They built a promising polynomial model including both patient characteristics and nodule descriptors. The retrospective simulation on NLST data provided enough power to test Schreuder’s model (3) as well as other models for selection of subjects to be forwarded to biennial screening (2, 4). We appreciate this approach to parsimonious LDCT administration as we are strongly convinced that annual screening should be tailored to subjects with remarkably high risk of lung cancer. The authors refer that prospective randomized controlled trial with tailored screening intervals would be hardly feasible, however we would like to remind that some experience was already reported in the literature.
Since 2005, the Multicenter Italian Lung Detection (MILD) trial conducted a prospective comparison between annual (LDCT1 = 1,152 screenees) and biennial LDCT (LDCT2 = 1,151 screenees) (5). The LDCT2 screenees were shifted to annual screening in case of solid nodule > 60 mm^3 and/or subsolid nodules. In other words, the MILD trial prospectively tested a risk model for tailored s...
We thank the authors of the letter in response to our paper for their interest and positive appraisal of our model. Likewise, we appreciate the design of the Multicenter Italian Lung Detection (MILD) trial which, despite its small sample size, demonstrates that annual intervals are unnecessary for the majority of screenees. Once more European data is available to perform cost-effectiveness analyses, we hypothesize that personalised screening intervals will prove to be the preferred design. Furthermore, it is estimated that most inclusion criteria used to select high-risk participants encompass only 70% of all lung cancer cases in the population; reassessing risk and tailoring interval groups after the baseline scan may enable the inclusion of persons of lower risk. As Silva et al mentioned, there is no reason to set the upper limit of follow-up intervals at 2-years. We also agree that volumetric nodule measurements are better suited for determining follow-up procedures than (perpendicular) diameter, and hope to be able to implement this into a future model. Moreover, risk scores may be calculated autonomously by computers in the future, with only a select few dubious cases requiring radiologist attention.
We welcome the letter by Anna Humphreys and colleagues highlighting the secondary benefits of screening contacts of extra pulmonary tuberculosis for LTBI in areas where active cases are predominantly amongst the non-UK born (1).
We share the view that novel approaches are needed to identify and offer testing to those at risk of LTBI, and that contact tracing provides a unique opportunity to reach those who may be eligible.
Early results from the London Borough of Newham, the pilot site for the national latent TB screening programme highlight that uptake of LTBI screening amongst recent migrants is only 40 percent (2). Efforts are being made to improve awareness including animated health promotion tools (https://youtu.be/tKwAHJ7JeV0) and TB Alert’s Latent TB Handbook (https://www.tbalert.org/health-professionals/ltbi-toolkit/) and novel interventions to improve LTBI screening and treatment uptake are being implemented across the country. We are currently investigating the efficacy of managing LTBI entirely within primary care (https://clinicaltrials.gov/ct2/show/NCT03069807). Recent work has also identified that opportunistic LTBI screening in non-health settings is acceptable to recent migrants (3).
Show MoreIn areas where the majority of active cases are amongst those...
We are grateful to Dr. Duerden and Dr. Levy for their comments on our paper which highlight the difficulty of comparing doses of ICS steroids when there is no gold standard comparator. Our aim in compiling Table 1 was to point out that the NICE table does not allow for the greater potency of HFA FP compared to HFA BDP. We were concerned that this was a significant safety issue especially in children [1]. In our efforts to simplify this message, we had not fully explained or allowed for some of the other variables.
1. Dr. Levy is correct to point out that the original GINA table (used by NICE) of “Low, medium and high daily doses of inhaled corticosteroid for children 6-11 years” has a statement below indicating that the table is not a table of “dose equivalency”, the term we used in Table 1, but of “estimated clinical comparability”.
2. The GINA table (but not NICE) also has a footnote explaining the inclusion of beclometasone dipropionate CFC (BDP CFC) as a comparison with older literature. CFCs (chlorofluorocarbons), as propellants in metered dose inhalers, were phased out under the Montreal Protocol and were replaced by HFAs (hydrofluorolakanes). However, CFC BDP is still often used as the reference standard when comparing ICS in terms of their potency.
3. Most newer HFA ICSs have been formulated to be equipotent with the CFC ICS they were replacing. As one example, the BTS/SIGN table includes the proprietary HFA BPD, Clenil modulite, commonly us...
Show MoreThe article of Bhatt et al addresses an important topic (1). The authors assessed the relative contribution of intensity and duration of tobacco smoke exposure to the development of chronic obstructive pulmonary disease (COPD). They concluded that smoking duration alone provides stronger risk than the composite index of pack years. In other words, the effect of long and low intensity exposure has a stronger association with COPD than short exposures of high intensities. The article of Marks consents this finding, concluding that pack years are a suboptimal index of exposure (2).
A major limitation of the study of Bhatt, which surprisingly is not stated as such, is the use of a cross-sectional design that does not allow drawing causal conclusions. The conclusions drawn therefore might be flawed.
Selection bias due the healthy ‘survivor’ effect might have occurred. The duration of smoking could have been influenced by the deleterious effects a person experiences from the exposure to smoke. Those with a long smoke duration are more likely not to experience (or experience less) health issues due to smoking, and might therefore have less severe (or no) COPD than those with a short smoke duration. In line with this, selective ‘drop-out’ of the more diseased persons may have biased the results.
Furthermore, the authors use retrospective data, while this often leads to recall bias. Participants often do not precisely remember the numbers of cigarettes smoked...
Show MoreWe have read with great interest the multi-centred EPICC trial that randomized over 300 patients [1]. While the delivery of a complex physical rehabilitation intervention in clinical trials is difficult, we believe that several aspects of the trial may have resulted in the inability to detect a difference between the control and intervention groups. These factors include the delayed time to start the intervention, inadequate delivery of the intervention and the large loss to follow-up for the primary outcome measure. In our opinion, these three factors limit the interpretation of the results of the study. While the authors have mentioned some of these concerns in their discussion, and Connolly et al. raised some of these points already [2], we hope to learn some important lessons from the authors to better understand these limitations and how they can be minimized in future studies.
Show MoreThe number of randomized controlled trials evaluating early physical rehabilitation in ICUs is increasing [3]. Positive effects on primary outcomes were only found in studies in which physical rehabilitation was started within 72 hours of ICU admission [4-6]. Studies, which did not meet this criterion of early onset of physical rehabilitation, did not demonstrate benefit of the intervention [7]. Therefore, this time frame has been defined in rehabilitation guidelines [8]. Based on this evidence, we are not surprised that the authors of the EPICC trial were unable to demonstrate beneficial...
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