Acute effects of combined exercise and oscillatory positive expiratory pressure therapy on sputum properties and lung diffusing capacity in cystic fibrosis: a randomized, controlled, crossover trial

Thomas Radtke, Lukas Böni, Peter Bohnacker, Marion Maggi-Beba, Peter Fischer, Susi Kriemler, Christian Benden, Holger Dressel, Thomas Radtke, Lukas Böni, Peter Bohnacker, Marion Maggi-Beba, Peter Fischer, Susi Kriemler, Christian Benden, Holger Dressel

Abstract

Background: Regular airway clearance by chest physiotherapy and/or exercise is critical to lung health in cystic fibrosis (CF). Combination of cycling exercise and chest physiotherapy using the Flutter® device on sputum properties has not yet been investigated.

Methods: This prospective, randomized crossover study compared a single bout of continuous cycling exercise at moderate intensity (experiment A, control condition) vs a combination of interval cycling exercise plus Flutter® (experiment B). Sputum properties (viscoelasticity, yield stress, solids content, spinnability, and ease of sputum expectoration), pulmonary diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO) were assessed at rest, directly and 45 min post-exercise (recovery) at 2 consecutive visits. Primary outcome was change in sputum viscoelasticity (G', storage modulus; G", loss modulus) over a broad frequency range (0.1-100 rad.s- 1).

Results: 15 adults with CF (FEV1range 24-94% predicted) completed all experiments. No consistent differences between experiments were observed for G' and G" and other sputum properties, except for ease of sputum expectoration during recovery favoring experiment A. DLNO, DLCO, alveolar volume (VA) and pulmonary capillary blood volume (Vcap) increased during experiment A, while DLCO and Vcap increased during experiment B (all P < 0.05). We found no differences in absolute changes in pulmonary diffusing capacity and its components between experiments, except a higher VA immediately post-exercise favoring experiment A (P = 0.032).

Conclusions: The additional use of the Flutter® to moderate intensity interval cycling exercise has no measurable effect on the viscoelastic properties of sputum compared to moderate intensity continuous cycling alone. Elevations in diffusing capacity represent an acute exercise-induced effect not sustained post-exercise.

Trial registration: ClinicalTrials.gov; No.: NCT02750722 ; URL: clinical.trials.gov; Registration date: April 25th, 2016.

Keywords: Airway clearance; Diffusing capacity for nitric oxide; Exercise; Lung disease; Mucus; Sputum viscoelasticity.

Conflict of interest statement

Ethics approval and consent to participate

Ethical approval was obtained from the Cantonal Ethics Committee of Zurich (2015–00153), Switzerland. All patients provided written informed consent.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Experimental study design. fR, respiratory frequency; HR, heart rate; SpO2, oxygen saturation; V’CO2, carbon dioxide production; V’E, minute ventilation; V’O2, oxygen consumption; VT, tidal volume. The grey shaded area represents the periods when the participants breathed through the mouthpiece for metabolic cart measurements
Fig. 2
Fig. 2
Rheology and spinnability of cystic fibrosis sputum. (a) Spinnability of sputum was assessed at the end of rheological measurements by lifting up the upper plate at a constant velocity of 3.6 mm s− 1. (b) Amplitude sweep (at 1 rad s− 1) showing a linear viscoelastic (LVE) regime up to about 1% deformation. The dashed violet lines show the graphical determination of the dynamic yield point / stress. (c, d) Frequency sweeps depicting G’ (storage modulus), G” (loss modulus) and η* (complex viscosity). The grey dashed lines represent the vertically shifted fitting curves (fitting between 0.1–10 rad s− 1). The blue dashed lines in (b, c) indicate the calculated instrument inertia limit

References

    1. Boucher RC. New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J. 2004;23:146–158. doi: 10.1183/09031936.03.00057003.
    1. Rowbotham NJ, Smith S, Leighton PA, Rayner OC, Gathercole K, Elliott ZC, Nash EF, Daniels T, Duff AJA, Collins S, Chandran S, Peaple U, Hurley MN, Brownlee K, Smyth AR. The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers. Thorax. 2018;73:388–390. doi: 10.1136/thoraxjnl-2017-210473.
    1. Morrison L, Innes S. Oscillating devices for airway clearance in people with cystic fibrosis. Cochrane Database Syst Rev. 2017;5:CD006842.
    1. McCarren B, Alison JA. Physiological effects of vibration in subjects with cystic fibrosis. Eur Respir J. 2006;27:1204–1209. doi: 10.1183/09031936.06.00083605.
    1. Konstan MW, Stern RC, Doershuk CF. Efficacy of the flutter device for airway mucus clearance in patients with cystic fibrosis. J Pediatr. 1994;124:689–693. doi: 10.1016/S0022-3476(05)81356-3.
    1. Dwyer TJ, Zainuldin R, Daviskas E, Bye PT, Alison JA. Effects of treadmill exercise versus flutter(R) on respiratory flow and sputum properties in adults with cystic fibrosis: a randomised, controlled, cross-over trial. BMC Pulm Med. 2017;17:14.
    1. App EM, Kieselmann R, Reinhardt D, Lindemann H, Dasgupta B, King M, Brand P. Sputum rheology changes in cystic fibrosis lung disease following two different types of physiotherapy: flutter vs autogenic drainage. Chest. 1998;114:171–177. doi: 10.1378/chest.114.1.171.
    1. Reix P, Aubert F, Werck-Gallois MC, Toutain A, Mazzocchi C, Moreux N, Bellon G, Rabilloud M, Kassai B. Exercise with incorporated expiratory manoeuvres was as effective as breathing techniques for airway clearance in children with cystic fibrosis: a randomised crossover trial. J Phys. 2012;58:241–247.
    1. Basser PJ, McMahon TA, Griffith P. The mechanism of mucus clearance in cough. J Biomech Eng. 1989;111:288–297. doi: 10.1115/1.3168381.
    1. Hebestreit A, Kersting U, Basler B, Jeschke R, Hebestreit H. Exercise inhibits epithelial sodium channels in patients with cystic fibrosis. Am J Respir Crit Care Med. 2001;164:443–446. doi: 10.1164/ajrccm.164.3.2007168.
    1. Dwyer TJ, Alison JA, McKeough ZJ, Daviskas E, Bye PT. Effects of exercise on respiratory flow and sputum properties in patients with cystic fibrosis. Chest. 2011;139:870–877. doi: 10.1378/chest.10-1158.
    1. Wheatley CM, Baker SE, Morgan MA, Martinez MG, Liu B, Rowe SM, Morgan WJ, Wong EC, Karpen SR, Snyder EM. Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis. Respir Med. 2015;109:1001–1011. doi: 10.1016/j.rmed.2015.05.018.
    1. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, Rosenstein BJ, Smith AL, Wohl ME. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group N Engl J Med. 1994;331:637–642. doi: 10.1056/NEJM199409083311003.
    1. Cinkotai FF, Thomson ML. Diurnal variation in pulmonary diffusing capacity for carbon monoxide. J Appl Physiol. 1966;21:539–542. doi: 10.1152/jappl.1966.21.2.539.
    1. Ewoldt RH, Johnston MT, Caretta LM. Experimental challenges of shear rheology: how to avoid bad data. Biol Med Phys Biomed. 2015:207–41.
    1. Burnett J, Glover FA, Blair GW. Field measurements of the "spinability" of bovine cervical mucus. Biorheology. 1967;4:41–45. doi: 10.3233/BIR-1967-4202.
    1. Critchfield AS, Yao G, Jaishankar A, Friedlander RS, Lieleg O, Doyle PS, McKinley G, House M, Ribbeck K. Cervical mucus properties stratify risk for preterm birth. PLoS One. 2013;8:e69528. doi: 10.1371/journal.pone.0069528.
    1. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J. Standardisation of spirometry. Eur Respir J 2005;26:319–338.
    1. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson JL, Ip MS, Zheng J, Stocks J. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40:1324–1343. doi: 10.1183/09031936.00080312.
    1. Radtke T, Benden C, Maggi-Beba M, Kriemler S, van der Lee I, Dressel H. Intra-session and inter-session variability of nitric oxide pulmonary diffusing capacity in adults with cystic fibrosis. Respir Physiol Neurobiol. 2017;246:33–38. doi: 10.1016/j.resp.2017.08.002.
    1. Zavorsky GS, Hsia CC, Hughes JM, Borland CD, Guenard H, van der Lee I, Steenbruggen I, Naeije R, Cao J, Dinh-Xuan AT. Standardisation and application of the single-breath determination of nitric oxide uptake in the lung. Eur Respir J. 2017;49
    1. Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, Gustafsson P, Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pedersen OF, Pellegrino R, Wanger J. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005;26:720–735.
    1. Godfrey S, Mearns M. Pulmonary function and response to exercise in cystic fibrosis. Arch Dis Child. 1971;46:144–151. doi: 10.1136/adc.46.246.144.
    1. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14:377-81.
    1. Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman D, Franklin B, Guazzi M, Gulati M, Keteyian SJ, Lavie CJ, Macko R, Mancini D, Milani RV. Clinician's guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation. 2010;122:191–225. doi: 10.1161/CIR.0b013e3181e52e69.
    1. EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990;16:199–208. doi: 10.1016/0168-8510(90)90421-9.
    1. International Physiotherapy Group for Cystic Fibrosis. Physiotherapy for people with cystic fibrosis: from infant to adult. 4th edition. 2009. Available online: accessed at April 27th 2018.
    1. Homnick DN, Anderson K, Marks JH. Comparison of the flutter device to standard chest physiotherapy in hospitalized patients with cystic fibrosis - a pilot study. Chest. 1998;114:993–997. doi: 10.1378/chest.114.4.993.
    1. Volsko TA, DiFiore J, Chatburn RL. Performance comparison of two oscillating positive expiratory pressure devices: acapella versus flutter. Respir Care. 2003;48:124–130.
    1. Serisier DJ, Carroll MP, Shute JK, Young SA. Macrorheology of cystic fibrosis, chronic obstructive pulmonary disease & normal sputum. Respir Res. 2009;10:63. doi: 10.1186/1465-9921-10-63.
    1. Tomaiuolo G, Rusciano G, Caserta S, Carciati A, Carnovale V, Abete P, Sasso A, Guido S. A new method to improve the clinical evaluation of cystic fibrosis patients by mucus viscoelastic properties. PLoS One. 2014;9:e82297. doi: 10.1371/journal.pone.0082297.
    1. Hill DB, Vasquez PA, Mellnik J, McKinley SA, Vose A, Mu F, Henderson AG, Donaldson SH, Alexis NE, Boucher RC, Forest MG. A biophysical basis for mucus solids concentration as a candidate biomarker for airways disease. PLoS One. 2014;9
    1. Radtke T, Böni L, Bohnacker P, Fischer P, Benden C, Dressel H. The many ways sputum flows - dealing with high within-subject variability in cystic fibrosis sputum rheology. Respir Physiol Neurobiol. 2018;254:36–39. doi: 10.1016/j.resp.2018.04.006.
    1. King M, Macklem PT. Rheological properties of microliter quantities of normal mucus. J Appl Physiol Respir Environ Exerc Physiol. 1977;42:797–802.
    1. King M. Relationship between mucus viscoelasticity and ciliary transport in Guaran gel-frog palate model system. Biorheology. 1980;17:249–254.
    1. King M. The role of mucus viscoelasticity in cough clearance. Biorheology. 1987;24:589–597. doi: 10.3233/BIR-1987-24611.
    1. Daviskas E, Anderson SD, Gomes K, Briffa P, Cochrane B, Chan HK, Young IH, Rubin BK. Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum. Respirology. 2005;10:46–56. doi: 10.1111/j.1440-1843.2005.00659.x.
    1. Daviskas E, Anderson SD, Jaques A, Charlton B. Inhaled mannitol improves the hydration and surface properties of sputum in patients with cystic fibrosis. Chest. 2010;137:861–868. doi: 10.1378/chest.09-2017.
    1. Schnurr B, Gittes F, MacKintosh FC, Schmidt CF. Determining microscopic viscoelasticity in flexible and semiflexible polymer networks from thermal fluctuations. Macromolecules. 1997;30:7781–7792. doi: 10.1021/ma970555n.
    1. Hsia CC. Recruitment of lung diffusing capacity: update of concept and application. Chest. 2002;122:1774–83.

Source: PubMed

3
Tilaa