Skip to main content

Main menu

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • COVID-19 submission information
    • Peer reviewer login
  • Alerts
  • Podcasts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • COVID-19 submission information
    • Peer reviewer login
  • Alerts
  • Podcasts
  • Subscriptions

Lessons from negative dyspnoea studies: arguments for the multidimensional evaluation of multidirectional therapeutic approaches

Thomas Similowski, Laure Serresse
European Respiratory Journal 2019 53: 1802471; DOI: 10.1183/13993003.02471-2018
Thomas Similowski
1Sorbonne Université, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France
2AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale du Département R3S, Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laure Serresse
3AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Unité Mobile d'Accompagnement et de Soins Palliatifs, Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • PDF
Loading

Abstract

Dyspnoea-targeted interventions should probably combine multiple approaches (multidirectional) and their evaluation should take the complex nature of dyspnoea into account (multidimensional) http://ow.ly/tLaM30ndprk

In this issue of the European Respiratory Journal, two articles are published that could at a glance appear to be only barely related [1, 2]. One of these articles [1] discusses patients with chronic respiratory diseases who suffer from chronic [3] or persistent [4] breathlessness, that is, who remain crippled by dyspnoea after they received the best known treatments for their underlying conditions. The other article [2] discusses patients with acute respiratory failure, either de novo or as complication of an underlying chronic cardiac or respiratory disorder, admitted to an intensive care unit (ICU) and who received noninvasive ventilation (NIV). The two studies yet have two things in common: they both aimed to relieve respiratory discomfort and were both deemed negative because their main outcome was not reached.

In the study by Currow et al. [1], 223 patients with chronic breathlessness were randomised at multiple sites to receive either sertraline or a placebo following a double blind, dose increment, parallel arm placebo-controlled adaptive design. Sertraline and placebo were administered to patients in addition to their treatments. The main outcome was defined as the proportion of patients reporting an improvement of breathlessness by more than 15% on a 100 mm visual analogue scale, relative to baseline. This target was not reached. Additionally, no subgroup demonstrated any response in any measure of breathlessness. There was no improvement of functional status, anxiety or depression. In the study by Messika et al. [2], 113 patients receiving NIV for acute respiratory failure were included at three medical centres to undergo either standard practice NIV (control), NIV with musical intervention, or NIV with sensory deprivation (acoustic and visual), with random assignment. The primary outcome was a change in respiratory comfort between NIV initiation and the 30th minute of the first NIV session. Again, this target was not reached, neither globally nor after various sensitivity analyses. Variations of respiratory discomfort were not significantly different between subsequent time-points nor in subsequent NIV sessions. These two studies can therefore be deemed negative without a doubt.

Interpreting randomised controlled trials that fail to demonstrate statistically significant differences in primary outcomes can be difficult, and one is often unduly tempted to focus on “trends” and secondary outcomes to “salvage” a study [5, 6]. Secondary outcomes can only be reasonably used to try and understand why the main outcome was not attained, or can be resorted to as “signals” to devise further research. In that vein, both the sertraline study and the musical intervention study published in this issue of the European Respiratory Journal [1, 2] hold interesting information. The sertraline study by Currow et al. [1] showed two things indeed. First, there was a weak signal favouring sertraline over placebo with regard to general quality of life scores. The proportion of patients who reported an improvement in breathlessness of more than 15% from baseline in the placebo group was not significantly different from the equivalent proportion of patients in the sertraline group, but this proportion was very high at 41%, hence the possibility of a floor effect. The musical intervention studies reported by Messika and co-workers showed that the peritraumatic distress inventory score at the time of ICU discharge was reduced by 50% (and significantly so) in patients subjected to musical intervention compared to patients having experienced sensory deprivation as well as control patients [2, 7]. A significant reduction in blood pressure was also noted in patients randomly affected to the music arm during the first NIV session. The study further showed that the numerical values of slopes of changes varied between groups, with respiratory discomfort decreasing faster in the musical intervention group than in the two other groups. Of note, NIV alone (control group) was efficient in reducing respiratory discomfort; this relieving effect could have been expected but is known to be inconstant [8]; it could have also led to a floor effect.

What lessons can we learn from the above “secondary signals” and how can they be useful for future research?

Firstly, the magnitude of the effect observed in the placebo arm of the sertraline study is of major interest [9, 10]. A similar finding has previously been resorted to as to explain the failure of nefopam (a non-opioid analgesic interfering with C-fibres) to alleviate experimental dyspnoea in healthy volunteers [11]. The mechanism at play can either be the placebo effect in the traditional sense (as proposed by Pattinson and Wanigasekera [9] in a letter also published in this issue of the journal) or the Hawthorne effect (as proposed by Currow et al. [10] in their response to said letter). The placebo effect could impact breathlessness by modifying anticipatory processes [12] that are increasingly recognised as determinants of the dyspnoea experience [13, 14]. The Hawthorne effect could influence breathlessness through patients realising that their dyspnoea is being observed and thus no longer ignored. Dyspnoea is indeed known to elicit at times unsatisfactory responses from caregivers, or even avoidance (“invisibility of dyspnoea” [15, 16]). This worsens the patients' negative experience through disempowerment [17]. It is therefore not surprising that participation in a dyspnoea-oriented clinical trial would suffice in generating clinical benefits. Offering reassurance and empathy should therefore be highly effective for persistent breathlessness, either chronic (as in the sertraline trial [10]) or acute (as in the music intervention trial [2]). This could and should be the subject of specific studies, with the aim to increase caregivers' sensibility to dyspnoea and improve their training to its management [18].

Secondly, the two studies were perhaps negative only because their primary outcomes were not properly chosen. In both cases, dyspnoea (or breathlessness, or respiratory comfort/discomfort) was assessed using one-dimensional tools evaluating “intensity”. Yet, dyspnoea is a complex experience [19]. Its multidimensional nature [20] can be captured clinically by specific tools such as the Multidimensional Dyspnea Profile or the Dyspnoea-12 [21, 22]. The very definition of dyspnoea implies that it features a sensory and an affective dimension that can vary independently of one another [23]. These dimensions correlate differently with different types of patient-related outcomes [24, 25]. For example, in patients suffering from chronic obstructive pulmonary disease (COPD) [24], correlations between the sensory dimension of dyspnoea were stronger with “activity” outcomes (such as the DIRECT disability questionnaire [26]) than with “quality of life” outcomes. Conversely, correlations were stronger between the affective dimension of dyspnoea and “psychological” outcomes (such as the Kessler psychological distress scale [27]). The same general pattern was also observed in patients with amyotrophic lateral sclerosis [25], where the affective dimension of dyspnoea proved to be the main driver of anxiety, according to the hospital anxiety and depression scale. Both sertraline and the musical intervention [1, 2] could have had a positive effect on the “affective dimension” of dyspnoea that was simply not picked up by the one-dimensional scales used to assess their effects. This hypothesis is consistent with some of the observations made in the two studies, such as the improvement in general quality of life in the sertraline arm of the sertraline study [1] and the reduction of acute stress (blood pressure) and peritraumatic stress at the time of ICU discharge in the musical intervention study [2]. Both are likely to relate to the affective dimension of dyspnoea.

Finally, one should remember that when neither the lung nor the brain are accessible to dyspnoea-relieving interventions, coping approaches can have a positive effect and “appease the mind” [28]: COPD patients have demonstrated significant and sustained benefits from mindfulness-based cognitive therapy, even in the absence of dyspnoea improvement [29]. In other words, an intervention that does not relieve dyspnoea can however be beneficial to the well-being of dyspnoeic patients.

The two studies that are the object of this editorial [1, 2] were both rigorously conducted by highly renowned teams and were completed in spite of demanding designs. They are worthy of publication in a high profile journal such as the European Respiratory Journal even though their negative nature will probably imply that they may not be widely cited in their respective fields. As in the case of negative studies in general, these publications are useful to spare other research groups futile efforts of a similar nature, and to avoid the unethical exposure of patients to procedures already known as ineffective. But beyond that the results of the two studies remind us that the outcomes of future dyspnoea-targeted studies should take into account the recent understanding of dyspnoea's complex nature: the use of multidimensional tools to evaluate dyspnoea-targeted interventions should thus probably be generalised. The two studies also suggest that gathering data describing the effects of mere human interactions on dyspnoea is necessary: it will allow investigators to better calibrate studies of more specific interventions, be they pharmacological or not. And in the end, these two studies raise the question of how single interventions (pharmacological or otherwise) are likely to be effective in patients with multiple needs in whom dyspnoea cannot be reduced to a symptom but represents a complex (and negative) life experience. Multidirectional approaches (such as the breathlessness support service concept [30, 31]) have proven to be effective, and should probably be favoured when addressing clinical dyspnoea.

One thing remains certain: “negative” dyspnoea studies should not tame our efforts to improve the identification and management of respiratory suffering, a major medical cause [32] that proceeds from no less than human rights issues [17, 33]. In this view, the authors of the two abovementioned studies must be commended not only for undertaking them, but also for not self-censoring themselves when submitting their work for publication.

Footnotes

  • Conflict of interest: T. Similowski reports personal fees and non-financial support from Novartis, and personal fees from AstraZeneca, Boerhinger Ingelheim France, GSK, Lungpacer Inc., TEVA, Chiesi, Pierre Fabre and Invacare, outside the submitted work; and in addition, has a patent about a “brain-ventilator interface to improve the detection of dyspnoea” licensed to Air Liquide Medical Systems and MyBrainTechnology.

  • Conflict of interest: L. Serresse has nothing to disclose.

  • Received December 31, 2018.
  • Accepted January 2, 2019.
  • Copyright ©ERS 2019

References

  1. ↵
    1. Currow DC,
    2. Ekström M,
    3. Louw S, et al.
    Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial. Eur Respir J 2019; 53: 1801270.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Messika J,
    2. Martin Y,
    3. Maquigneau N, et al.
    A musical intervention for respiratory comfort during noninvasive ventilation in the ICU. Eur Respir J 2019; 53: 1801873.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Johnson MJ,
    2. Yorke J,
    3. Hansen-Flaschen J, et al.
    Towards an expert consensus to delineate a clinical syndrome of chronic breathlessness. Eur Respir J 2017; 49: 1602277.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Morelot-Panzini C,
    2. Adler D,
    3. Aguilaniu B, et al.
    Breathlessness despite optimal pathophysiological treatment: on the relevance of being chronic. Eur Respir J 2017; 50: 1701159.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Arunachalam L,
    2. Hunter IA,
    3. Killeen S
    . Reporting of randomized controlled trials with statistically nonsignificant primary outcomes published in high-impact surgical journals. Ann Surg 2017; 265: 1141–1145.
    OpenUrl
  6. ↵
    1. Boutron I,
    2. Dutton S,
    3. Ravaud P, et al.
    Reporting and interpretation of randomized controlled trials with statistically nonsignificant results for primary outcomes. JAMA 2010; 303: 2058–2064.
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Messika J,
    2. Hajage D,
    3. Panneckoucke N, et al.
    Effect of a musical intervention on tolerance and efficacy of non-invasive ventilation in the ICU: study protocol for a randomized controlled trial (MUSique pour l'Insuffisance Respiratoire Aigue - Mus-IRA). Trials 2016; 17: 450.
    OpenUrl
  8. ↵
    1. Dangers L,
    2. Montlahuc C,
    3. Kouatchet A, et al.
    Dyspnoea in patients receiving noninvasive ventilation for acute respiratory failure: prevalence, risk factors and prognostic impact: a prospective observational study. Eur Respir J 2018; 52: 1702637.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Pattinson K,
    2. Wanigasekera V
    . Sertraline or placebo in chronic breathlessness? Lessons from placebo network. Eur Respir J 2019; 53: 1802225.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Currow DC,
    2. Agar M,
    3. Ekström M
    . Sertraline or placebo in chronic breathlessness? Lessons from placebo network. Eur Respir J 2019; 53: 1802316.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Dangers L,
    2. Laviolette L,
    3. Charbit B, et al.
    Nefopam, a non-opioid analgesic, does not alleviate experimental work/effort dyspnoea in healthy humans: a randomised controlled trial. Pulm Pharmacol Ther 2016; 39: 74–80.
    OpenUrl
  12. ↵
    1. Ongaro G,
    2. Kaptchuk TJ
    . Symptom perception, placebo effects, and the Bayesian brain. Pain 2019; 160: 1–4.
    OpenUrl
  13. ↵
    1. Esser RW,
    2. Stoeckel MC,
    3. Kirsten A, et al.
    Brain activation during perception and anticipation of dyspnea in chronic obstructive pulmonary disease. Front Physiol 2017; 8: 617.
    OpenUrl
  14. ↵
    1. Faull OK,
    2. Pattinson KT
    . The cortical connectivity of the periaqueductal gray and the conditioned response to the threat of breathlessness. Elife 2017; 6: e21749.
    OpenUrl
  15. ↵
    1. Carel H,
    2. Macnaughton J,
    3. Dodd J
    . Invisible suffering: breathlessness in and beyond the clinic. Lancet Respir Med 2015; 3: 278–279.
    OpenUrl
  16. ↵
    1. Gysels M,
    2. Higginson IJ
    . Access to services for patients with chronic obstructive pulmonary disease: the invisibility of breathlessness. J Pain Symptom Manage 2008; 36: 451–460.
    OpenUrlCrossRefPubMedWeb of Science
  17. ↵
    1. Başoğlu M
    . Effective management of breathlessness: a review of potential human rights issues. Eur Respir J 2017; 49: 1602099.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Birkholz L,
    2. Haney T
    . Using a dyspnea assessment tool to improve care at the end of life. J Hosp Palliat Nurs 2018; 20: 219–227.
    OpenUrl
  19. ↵
    1. Hayen A,
    2. Herigstad M,
    3. Pattinson KT
    . Understanding dyspnea as a complex individual experience. Maturitas 2013; 76: 45–50.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Lansing RW,
    2. Gracely RH,
    3. Banzett RB
    . The multiple dimensions of dyspnea: review and hypotheses. Respir Physiol Neurobiol 2009; 167: 53–60.
    OpenUrlCrossRefPubMedWeb of Science
  21. ↵
    1. Banzett RB,
    2. O'Donnell CR,
    3. Guilfoyle TE, et al.
    Multidimensional Dyspnea Profile: an instrument for clinical and laboratory research. Eur Respir J 2015; 45: 1681–1691.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Yorke J,
    2. Swigris J,
    3. Russell AM, et al.
    Dyspnea-12 is a valid and reliable measure of breathlessness in patients with interstitial lung disease. Chest 2011; 139: 159–164.
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    1. Parshall MB,
    2. Schwartzstein RM,
    3. Adams L, et al.
    An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 2012; 185: 435–452.
    OpenUrlCrossRefPubMedWeb of Science
  24. ↵
    1. Morelot-Panzini C,
    2. Gilet H,
    3. Aguilaniu B, et al.
    Real-life assessment of the multidimensional nature of dyspnoea in COPD outpatients. Eur Respir J 2016; 47: 1668–1679.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Morelot-Panzini C,
    2. Perez T,
    3. Sedkaoui K, et al.
    The multidimensional nature of dyspnoea in amyotrophic lateral sclerosis patients with chronic respiratory failure: Air hunger, anxiety and fear. Respir Med 2018; 145: 1–7.
    OpenUrl
  26. ↵
    1. Aguilaniu B,
    2. Gonzalez-Bermejo J,
    3. Regnault A, et al.
    Disability related to COPD tool (DIRECT): towards an assessment of COPD-related disability in routine practice. Int J Chron Obstruct Pulmon Dis 2011; 6: 387–398.
    OpenUrlPubMed
  27. ↵
    1. Kessler RC,
    2. Andrews G,
    3. Colpe LJ, et al.
    Short screening scales to monitor population prevalences and trends in non-specific psychological distress. Psychol Med 2002; 32: 959–976.
    OpenUrlCrossRefPubMedWeb of Science
  28. ↵
    1. Similowski T
    . Treat the lungs, fool the brain and appease the mind: towards holistic care of patients who suffer from chronic respiratory diseases. Eur Respir J 2018; 51: 1800316.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Farver-Vestergaard I,
    2. O'Toole MS,
    3. O'Connor M, et al.
    Mindfulness-based cognitive therapy in COPD: a cluster-randomised controlled trial. Eur Respir J 2018; 51: 1702082.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Gysels M,
    2. Reilly CC,
    3. Jolley CJ, et al.
    How does a new breathlessness support service affect patients? Eur Respir J 2015; 46: 1515–1518.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Higginson IJ,
    2. Bausewein C,
    3. Reilly CC, et al.
    An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: a randomised controlled trial. Lancet Respir Med 2014; 2: 979–987.
    OpenUrl
  32. ↵
    1. Demoule A,
    2. Similowski T
    . Respiratory suffering in the intensive care unit: time for our next great cause. Am J Respir Crit Care Med 2018; in press [https://doi.org/10.1164/rccm.201812-2248ED].
  33. ↵
    1. Currow DC,
    2. Abernethy AP,
    3. Ko DN
    . The active identification and management of chronic refractory breathlessness is a human right. Thorax 2014; 69: 393–394.
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top
View this article with LENS
Vol 53 Issue 1 Table of Contents
European Respiratory Journal: 53 (1)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Lessons from negative dyspnoea studies: arguments for the multidimensional evaluation of multidirectional therapeutic approaches
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Lessons from negative dyspnoea studies: arguments for the multidimensional evaluation of multidirectional therapeutic approaches
Thomas Similowski, Laure Serresse
European Respiratory Journal Jan 2019, 53 (1) 1802471; DOI: 10.1183/13993003.02471-2018

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Lessons from negative dyspnoea studies: arguments for the multidimensional evaluation of multidirectional therapeutic approaches
Thomas Similowski, Laure Serresse
European Respiratory Journal Jan 2019, 53 (1) 1802471; DOI: 10.1183/13993003.02471-2018
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Footnotes
    • References
  • Info & Metrics
  • PDF
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

  • CFTR: a missing link between smoking and chronic airway diseases?
  • Update March 2022: ERS guidelines for management of hospitalised COVID-19 patients
  • Improving IGRA interpretation: are IP-10 and MIG the solution?
Show more Editorials

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERJ

  • Journal information
  • Editorial board
  • Reviewers
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • Podcasts
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN:  0903-1936
Online ISSN: 1399-3003

Copyright © 2022 by the European Respiratory Society