Research therapist interactions during or after the encounter, and that References agencies did not clearly communicate their expectations to students early in the placement. Further research on this Andrich D, Lyne A, Sheridan B, Luo G (2003) RUMM2020. item and how it is being interpreted and scored by educators RUMM Laboratories Perth. is warranted. Australian Physiotherapy Council (2006) http://www. In the final field test no significant differential item physiocouncil.com.au/australian_standards_for_ functioning was demonstrated for the variables student physiotherapy/. [Accessed 16/08/2010]. age and experience, clinical educator age, gender, and experience as an educator, university, or field of practice. Bond TG, Fox MT (2007) Applying the Rasch Model. This indicates that APP item ratings were not systematically Fundamental measurement in the human sciences (2nd affected by any of these variables and supports nationwide edn). Mahwah, NJ: Erlbaum. use of this instrument across all clinical areas, facilities and universities. Cliff N, Keats JA (2003) Ordinal measurement in the behavioral sciences. Mahwah, NJ: Erlbaum. One of the primary advantages of Rasch analysis is that raw ordinal scores may be converted to interval level Rasch Coghlan D, Brannick T (2001) Doing action research in your scores. Given the almost perfect linear relationship between own organisation. Thousand Oaks, CA: Sage. Rasch logit scores and raw scores shown in Figure 4, the complexity associated with converting the raw score to a Dalton M, Keating J, Davidson M (2009) Development of the Rasch score does not appear warranted. Assessment of Physiotherapy Practice (APP): A standardised and valid approach to assessment of clinical competence in The APP was developed collaboratively, tested within physiotherapy. [Australian Learning and Teaching Council the constraints of a dynamic and unpredictable clinical (ALTC) Final report pp 6–28]. Brisbane: Griffith University. environment, and has been taken up almost universally Available online at: www.altc.edu.au as the assessment instrument in entry-level physiotherapy programs in Australia and New Zealand. The advantages of Lai J-S, Teresi J, Gershon R (2005) Procedures for the analysis a single, national instrument are the reduction of assessment of differential item functioning (DIF) for small sample sizes. burden on clinical educators dealing with students from Evaluation and the Health Professions 28: 283–294. multiple university programs, and the standardardisation of student assessment for entry-level practice ensuring Pallant JF, Tennant A (2007) An introduction to the Rasch that students are assessed against the same performance measurement model: an example using the Hospital Anxiety indicators, on the same rating scale, against explicit and Depression Scale (HADS). British Journal of Clinical standards for entry-level practice. Psychology 46: 1–18. The evidence of construct validity provided by Rasch Prescott-Clements L, van der Vleuten CP, Schuwirth LW, Hurst analysis supports the interpretation that a student’s score Y, Rennie JS (2008) Evidence for validity within workplace on the APP is an indication of their underlying level assessment: the Longitudinal Evaluation of Performance of professional competence as demonstrated during (LEP). Medical Education 42: 488–495. workplace-based placements. The reliability of judgements made with the APP will be published separately. Q Rasch G (1960) Probabilistic models for some intelligence and attainment tests. Chicago: University of Chicago Press. eAddenda: Figure 1 and Appendix 1 available at jop. physiotherapy.asn.au Rethans JJ, Norcini JJ, Baron-Maldonado M, Blackmore D, Jolly BC, LaDuca T et al (2002) The relationship between Ethics: Approval for the study was provided by the Human competence and performance: implications for assessing Ethics Committees of the nine participating universities. practice performance. Medical Education 36: 901–909. All participants gave written informed consent before data collection began. Rheault W, Coulson E (1991) Use of the Rasch model in the development of a clinical competence scale. Journal of Support: Funding from the Australian Learning and Physical Therapy Education 5: 10–13. Teaching Council (ALTC) enabled employment of a research assistant and travel to conduct focus groups and Southgate L, Hays RB, Norcini J, Mulholland H, Ayers B, training workshops. Woolliscroft J et al (2001) Setting performance standards for medical practice: a theoretical framework. Medical Education Acknowledgements: Thanks go to the clinical educators 35: 474–481. and students who participated, to the University Clinical Education MAnagers of Australia and New Zealand, and Streiner DL, Norman GR (2003) Health Measurement Scales. to the Council of Physiotherapy Deans, Australia and New A practical guide to their development and use (3rd edn). Zealand, who championed the development of a national New York: Oxford University Press. assessment instrument. Tennant A, Conaghan PG (2007) The Rasch measurement Correspondence: Dr Megan Dalton, Department of model in rheumatology: what is it and why use it? When Physiotherapy, School of Primary Health Care, Monash should it be applied, and what should one look for in a Rasch University, Australia. Email: [email protected] paper? Arthritis and Rheumatism 57: 1358–1362. Tennant A, Pallant JF (2006) Unidimensionality matters! (a tale of two Smiths). Rasch Measurement Transactions 20: 1048–1051. van der Vleuten C (2000) Validity of final examinations in undergraduate medical training. British Medical Journal 321: 1217–1219. Wilson M (2005) Constructing measures: an item response modeling approach. Mahwah, NJ: Erlbaum. Website Dalton MB (2011) Development of the Assessment of Physiotherapy Practice - A standardised and validated approach to assessment of professional competence in physiotherapy. Doctor of Philosophy Thesis, Monash University, Melbourne. URL: http://arrow.monash.edu.au/ hdl/1959.1/479140 246 Journal of Physiotherapy 2011 Vol. 57 – © Australian Physiotherapy Association 2011
Appraisal Clinimetrics The Neer sign and Hawkins-Kennedy test for shoulder impingement Description pathoanatomy of this clinical test involved driving the greater tuberosity under the coracoacromial ligament Two clinical diagnostic tests that take little time to undertake (Hawkins and Kennedy 1980). Hawkins and Kennedy and are commonly performed by primary practitioners (1980) noted that their impingement test was less reliable dealing with shoulder subacromial impingement are the than the Neer impingement sign. Neer sign (Neer 1983) and Hawkins-Kennedy test (Hawkins and Kennedy 1980). Diagnostic accuracy: The Hawkins-Kennedy test has derived negative likelihood ratios between 0.00 and 0.88 Requirements for testing: The Neer sign constitutes the first and positive likelihood ratios between 1.14 and 2.12 in seven part of the Neer injection impingement test where one hand evaluations across three studies (Hughes et al 2008). The stabilises the patient’s scapula while the other hand raises Neer sign has derived negative likelihood ratios between the arm into full flexion (Neer 1983). This was thought to 0.31 and 0.93 and positive likelihood ratios between 1.03 cause the greater tuberosity to impinge against the anterior and 2.31 in seven evaluations across three studies (Hughes acromion, damaging the rotator cuff tendons, long head et al 2008). of biceps, and the subacromial bursa, with a positive test indicated by pain (Neer 1983). The second part of the test Two studies investigated the combination of the Hawkins- involved a subsequent xylocaine injection to reduce the pain Kennedy test or the Neer sign for subacromial impingement and thereby differentiate impingement lesions from other (Hughes et al 2008). These studies derived negative causes of shoulder pain (Neer 1983). likelihood ratios to this combination of clinical tests between 0.16 to 0.95 and positive likelihood ratios between 1.04 and The Hawkins-Kennedy test involves flexing the shoulder 2.81. One study investigated the Hawkins-Kennedy test and to 90° then forcibly internally rotating it (Hawkins and the Neer sign in combination to derive negative likelihood Kennedy 1980), although gentle internal rotation has ratios between 0.12 and 0.75 and positive likelihood ratios also been suggested (Park et al 2005). A positive sign between 1.35 and 2.63 (Ardic et al 2006). involves reproducing the pain of impingement (Hawkins and Kennedy 1980). It was originally suggested that the A recent cadaver study has highlighted that the Hawkins- Kennedy test is less likely to involve the greater tuberosity Commentary and causes most compression anterior to the supraspinatus tendon at the rotator interval, while the Neer sign might Recent evidence suggests the pathaetiology of shoulder involve supraspinatus with internal rotation but might impingement involves a pre-existing dysfunctional rotator involve subscapularis with external rotation (Hughes et cuff causing superior humeral head migration in shoulder al 2011). This study suggested that the position that most elevation that causes damage to the subacromial structures compressed the supraspinatus tendon was internal rotation (Lewis 2010). in abduction. The higher the positive likelihood ratio the more probable These shoulder impingement tests take little time and are it is that a positive test will indicate the presence of the easy to perform; however, if they do not inform clinical condition. Positive likelihood ratios of 2–5 yield small reasoning, that is they are not useful in diagnosing increases in the post-test probability of condition, 5–10 impingement, then their continued use must be questioned. moderate increases, and above 10 large increases (Grimes Future research needs to seek a valid anatomical basis for and Shulz 2005). The smaller positive likelihood values impingement testing. indicate that positive tests results are less likely to indicate impingement. For negative likelihood values, a lower Phillip Hughes likelihood ratio indicates greater probability of a negative La Trobe University, Australia test excluding the condition and 0.2–0.5 is considered a small increase in the post-test probability of the condition, References 0.1–0.2 moderate, and below 0.1 a large increase (Grimes and Shulz 2005). The larger negative likelihood ratios Ardic F et al (2006) Am J Phys Med and Rehab 85: 53. indicated poor diagnostic accuracy. Calis M et al (2000) Ann Rheum Dis 59: 44. Poor reliability may be a factor for lack of diagnostic accuracy of clinical tests. Reliability studies for these tests Green R et al (2008) Phys Ther Rev 13: 17. have demonstrated around 70% agreement between testers (Michener et al 2009) and above 98% in another study Grimes D, Shulz K (2005) Lancet 365: 1500. (Calis et al 2000). This disparity is surprising given the test outcome is determined by the presence or absence of pain. Hawkins R, Kennedy J (1980) Am J Sports Med 8: 151. Studies investigating the diagnostic accuracy of Hughes P et al (2008) Aust J Physiother 54: 159. impingement tests may have returned poor results because of a lack of anatomical validity of the tests. A systematic Hughes P et al (2011) J Sci Med Sport Ze_0'&$'&',%`$ review of the anatomical basis of clinical tests for the jsams.2011.07.001 shoulder found that there was a lack of evidence supporting the anatomical validity of impingement testing (Green et Lewis J (2010) Br J Sports Med 44: 918. al 2008). Michener L (2009) Arch Phys Med Rehab 90: 1898. Neer C 1983 Clin Orthop Rel Res 173: 70. Park H et al (2005) J Bone Joint Surg (Am) 87: 1446. 260 Journal of Physiotherapy 2011 Vol. 57 – © Australian Physiotherapy Association 2011
Bishop et al: Timing of dornase alpha and airway clearance in cystic fibrosis Timing of dornase alpha inhalation does not affect the efficacy of an airway clearance regimen in adults with cystic fibrosis: a randomised crossover trial Jennifer R Bishop, Odette J Erskine and Peter G Middleton Cystic Fibrosis Unit, Ludwig Engel Centre for Respiratory Research, Westmead Millenium Institute, University of Sydney at Westmead Question: Does the timing of inhalation of dornase alpha in relation to physical airway clearance techniques influence the effect of the entire airway clearance regimen? Design: A randomised crossover trial with concealed allocation, intention-to- treat analysis and blinding of patients, therapists, and assessors. Participants: Twenty adults with cystic fibrosis who were not taking dornase alpha were recruited, of whom 17 were randomised and completed the trial. Intervention: Participants performed an individually tailored session of physical airway clearance techniques for at least 15 minutes per day for 28 days. For 14 days, dornase alpha was inhaled before each session of airway clearance techniques and a placebo was inhaled after. For the other 14 days, placebo was inhaled before and dornase alpha after airway clearance techniques. The order of the two 14-day periods was randomised. Outcome measures: The primary outcome was the forced expiratory volume in 1 sec (FEV1). Secondary outcomes were forced vital capacity, 24-hour sputum production, sputum production during the airway clearance regimen, oxygen saturation, peak oxygen consumption during an incremental exercise test, oxygen desaturation during exercise, and quality of life. Results: Inhalation of dornase alpha after airway clearance techniques did not significantly affect the change in FEV1 compared with inhalation before airway clearance techniques, mean difference 0.04 L, 95% CI –0.14 to 0.23. None of the secondary outcomes differed significantly between the study arms. There was good correlation between the change in FEV1 and the change in quality of life scores. Conclusion: Timing of dornase alpha can be selected according to convenience, patient preference, or to accommodate the timing of other medications in the treatment regimen. Trial registration: ACTRN12611001041943 <#JTIPQ+3 &STLJOF0+ .JEEMFUPO1( 5JNJOHPGEPSOBTFBMQIBJOIBMBUJPO EPFTOPUBGGFDUUIFFGmDBDZPGBOBJSXBZDMFBSBODFSFHJNFOJOBEVMUTXJUIDZTUJDmCSPTJTBSBOEPNJTFEDSPTTPWFS USJBMJournal of Physiotherapyo> Key words: Cystic fibrosis, Dornase alpha, Airway clearance techniques, Lung function, Quality of life Introduction Fitzgerald and colleagues (2005) compared administration of dornase alpha 30 min before and 30 min after physical Treatment of sputum retention and the associated chronic airway clearance techniques in children and adolescents infection in the airways of people with cystic fibrosis with cystic fibrosis. They found that the two timing involves several therapeutic approaches. Antibiotics are regimens had similar effects on measures of lung function, administered to suppress infection (Southern et al 2004, quality of life, and peak exercise capacity. In a similar study, Ryan et al 2003, Smyth and Walters 2003), manual van der Giessen and colleagues (2007) also found that the physiotherapy techniques and other physical interventions regimens had non-significant differences in most measures are used to clear infected mucus from the airways (van der of lung function. However, as their primary outcome, they Schans et al 2000), and various mucoactive medications are included an additional measure: maximal expiratory flow at used to improve the properties of the mucus to facilitate 25% of the forced vital capacity (FVC). This outcome was its clearance (Jones and Wallis 2010, Wark and McDonald significantly better when dornase alpha was administered 2009). One of these mucoactive medications is recombinant before physical airway clearance techniques. Wilson and human deoxyribonuclease, or dornase alpha (Pulmozyme®). colleagues (2007) performed a similar study in adults It reduces the viscosity of sputum in people with cystic and children with cystic fibrosis and found no significant fibrosis by cleaving strands of the deoxyribonucleic acid differences for most outcomes. However, in those outcomes (DNA) released by neutrophils (Lieberman 1968). This that did differ (ie, forced expiratory flow rate between 25% makes the sputum flow more easily (Shak et al 1990). Regular use of dornase alpha improves lung function and What is already known on this topic: The timing of quality of life, and reduces the number and severity of dornase alpha in relation to physiotherapy techniques respiratory exacerbations (Hubbard et al 1992, Ramsey et may alter the effect of these two interventions on airway al 1993, Fuchs et al 1994). clearance. However, this has not been examined in adults with cystic fibrosis. Although dornase alpha has been used widely in the management of cystic fibrosis for more than 15 years, the What this study adds: The timing of dornase alpha optimal timing of administration with respect to physical does not strongly influence the efficacy of the airway airway clearance techniques is still unclear. During its clearance regimen in adults with cystic fibrosis. clinical development, trials allowed dornase alpha to be Therefore dornase alpha can be timed according to administered either before or after physical airway clearance convenience, patient preference or to accommodate techniques. Only recently have trials started to address this other medications in the treatment regimen. potentially important aspect of its administration. Journal of Physiotherapy 2011 Vol. 57 – © Australian Physiotherapy Association 2011 223
Research and 75% of the FVC and one measure of quality of life), measurement. Exclusion criteria were: FVC less than 40% administration of dornase alpha before physical airway of the predicted value, clinical instability (> 10% change in clearance techniques was less favourable. These somewhat forced expiratory volume in 1 sec (FEV1) over 14 days) or conflicting results make it difficult for clinicians to advise hospitalisation within the 14 days prior to randomisation, people – especially adults – with cystic fibrosis about how current use of dornase alpha, inability to perform to structure their treatment regimen for airway clearance. reproducible lung function tests, and poor adherence with therapy (defined as < 85% adherence based on self report This study was designed to compare the effectiveness of and vial counts). dornase alpha administered before versus after airway clearance techniques, in adults with cystic fibrosis. We Intervention were also interested in whether the response of some subgroups of participants might differ from others, defined The experimental intervention was to take dornase alpha by their baseline lung function, or by their baseline sputum after and the placebo before performing the airway clearance production. Therefore, the research questions for this study techniques once daily for 14 days. The control intervention were: was to take dornase alpha before and the placebo after the airway clearance techniques for 14 days. 1. Does the inhalation of dornase alpha before or after airway clearance techniques influence the effect on The active ampoules contained 2.5 mg of dornase alpha in lung function? 2.5 mL. The placebo ampoules contained 2.0 mL of 0.9% saline. To preserve blinding, all ampoules were stored 2. Does the inhalation of dornase alpha before or after under refrigeration – a requirement of dornase alpha. Each airway clearance techniques influence 24-hour participant was supplied with two jet nebulisersa to be sputum production, the percentage of daily sputum used for inhaling the trial solutions. The nebulisers were produced during the airway clearance regimen, colour-coded to match the trial solution packaging, but were oxygen saturation, peak oxygen consumption during otherwise identical. Separate nebulisers were necessary an incremental exercise test, oxygen desaturation because dornase alpha can be denatured by traces of other during exercise, and quality of life? compounds in the nebuliser chamber. At the start of the trial, all nebuliser pumps were tested to ensure that they 3. Do particular subgroups of participants differ in their produced adequate flow rates (6–8 L/min) with sufficient response to the two regimens? driving pressures (10–12 pounds per square inch, 69–83 kPa). Method All participants received usual medical and allied health Design management by the Cystic Fibrosis Unit if required during the trial period, and were encouraged to continue with their A randomised trial with concealed allocation and intention- other usual therapies. Participants who were already taking to-treat analysis and blinding of participants, therapists, bronchodilators were advised to inhale them before the and assessors was undertaken at the Cystic Fibrosis Unit inhalation of the first trial solution at each daily treatment at Westmead Hospital, Sydney. Participants were recruited session. Participants who were already taking inhaled from the outpatient clinic of the Cystic Fibrosis Unit. antibiotics were advised to inhale them after the inhalation Before entry into the study, each participant had their of the second trial solution at each daily treatment session. airway clearance techniques reviewed and optimised by one investigator (JRB). The range of techniques used Demographic and clinical data including age, gender, included conventional postural drainage and percussion, body mass index, bacterial colonisation of sputum, usual positive expiratory pressure via a mask interface, and active medication use, lung function, oxyhaemoglobin saturation, cycle of breathing techniques (Pryor and Prasad 2008). and quality of life were recorded at baseline (Day 0). All participants were then encouraged to perform at least 15 min of the techniques each day for the 28 days before On Day 1, participants received the blinded therapy under randomisation was scheduled, to ensure familiarity with clinical supervision. Lung function was measured before the techniques. Participants were assessed in the Cystic and after each nebulisation and both before and after the Fibrosis Unit 14 days prior to randomisation and on the day physical airway clearance techniques to assess any acute of randomisation (Day 0) to confirm clinical stability at changes during the intervention. Cumulative sputum the time of enrolment. Randomisation occurred within the weight was measured after each spirometry measurement. hospital pharmacy to maintain concealment of the random Subsequent doses were inhaled independently at home. On allocation list, which used a block size of four participants. the first day of the second treatment arm (Day 15) the same Dornase alpha and placebo in blinded packaging were measurements were performed. dispensed through the hospital pharmacy to maintain blinding. Participants inhaled dornase alpha before and Outcome measures placebo after performing their airway clearance techniques for 14 days, and placebo before and dornase alpha after the All outcome measures were recorded at the start and techniques for the other 14 days. The order of the two 14- end of the first 14-day period (Days 1 and 14) and at the day periods was randomised. Participants were assessed at start and end of the second 14-day period (Days 15 and the beginning and end of each 14-day period, as presented 28), as presented in Figure 1. All measurements were in Figure 1. performed by an investigator who was blinded to whether the participant was in the experimental or control arm of Participants the study. Participants were also blinded throughout the study, including when they completed the quality of life Outpatients attending the Cystic Fibrosis Unit were eligible questionnaires. to participate if they were aged 18 years or more and had a diagnosis of cystic fibrosis confirmed by a clinical history, a positive sweat test and/or nasal potential difference 224 Journal of Physiotherapy 2011 Vol. 57 – © Australian Physiotherapy Association 2011
Bishop et al: Timing of dornase alpha and airway clearance in cystic fibrosis Day –14 Patients screened for participation (n = 30) Excluded (n = 10) Already taking dornase alpha (n = 7) Declined to participate (n = 3) Review of physical airway clearance techniques and assessment of clinical status (n = 20) Withdrew (n = 3) Time constraints (n = 3) Day 0 Randomised (n = 17) (n = 9) (n = 8) Day 1 Measured lung function, sputum weight, oxygenation, exercise capacity and quality of life (n = 9) (n = 8) Lost to follow-up (n = 0) Experimental arm Control arm Lost to follow-up (n = 0) usual care usual care dornase alpha after dornase alpha before airway clearance airway clearance techniques techniques Day 14 Measured lung function, sputum weight, oxygenation, exercise capacity, and quality of life (n = 9) (n = 8) Day 15 Measured lung function, sputum weight, oxygenation, exercise capacity, and quality of life (n = 9) (n = 8) Lost to follow-up (n = 0) Control arm Experimental arm Lost to follow-up (n = 0) usual care usual care dornase alpha dornase alpha before airway after airway clearance clearance techniques techniques Day 28 Measured lung function, sputum weight, oxygenation, exercise capacity, and quality of life (n = 9) (n = 8) 'JHVSF Design and flow of participants through the trial. Journal of Physiotherapy 2011 Vol. 57 – © Australian Physiotherapy Association 2011 225
Research 5BCMFCharacteristics of participants. Characteristic All Exp first Con first (n = 17) (n = 9) (n = 8) Age (yr), mean (SD) 25 (11) 27 (15) 23 (4) Gender, n males (%) 9 (53) 5 (56) 4 (50) BMI (kg/m2), mean (SD) 20.6 (3.3) 20.9 (4.1) 20.3 (2.2) Bacterial colonisation of sputum, n (%) 16 (94) 8 (89) 8 (100) Pseudomonas aeruginosa 5 (29) 1 (11) 4 (50) Staphylococcus aureus 1 (6) 0 (0) 1 (13) MRSA 1 (6) 1 (11) 0 (0) Burkholderia cepacia Regular therapies, n (%) 8 (47) 5 (56) 4 (50) exercise 10 (59) 5 (56) 5 (63) bronchodilator 7 (41) 3 (33) 4 (50) antiinflammatory 0 (0) 0 (0) oral steroids 0 (0) 4 (44) 5 (63) antibiotics 10 (59) 7 (78) 4 (50) Dornase alpha naïve, n (%) 11 (65) Exp = experimental condition (dornase alpha after physical airway clearance techniques), Con = control condition (dornase alpha before physical airway clearance techniques), BMI = body mass index, MRSA = Methicillin-resistant Staphylococcus aureus. Lung function was measured using a standard spirometerb significant. We recruited 20 participants to allow for loss to according to American Thoracic Society guidelines follow-up. (American Thoracic Society 1995). The spirometric measures recorded were FEV1 in litres and as a percentage Continuous data were summarised as means and standard of the predicted value, and FVC as a percentage of the deviations and categorical data were summarised as predicted value. Predicted values were calculated using the frequencies and percentages. The normality of the equations of Knudson and colleagues (1976). distribution of the data was examined with the Kolmogorov- Smirnov test. Although some of the raw data were not The sputum expectorated within a 24-hr period was normally distributed, the within-subject differences were collected in a plastic flask by the participants and weighed normally distributed. Therefore the data were analysed on an electronic scale. The amount of sputum expectorated using parametric statistics. Between-group differences in during a session of airway clearance techniques was change from baseline were analysed using paired t-tests. collected independently in a separate flask, so that it could Mean differences (95% CI) between groups are presented. be calculated as a proportion of the 24-hour sputum weight. Data were analysed by intention-to-treat. The effect of the timing regimen on FEV1 was correlated against Oxygenation was measured using a standard pulse oximeter baseline FEV1 and against baseline sputum production, with a finger probe. Stable readings were required for 10 and the strength of the relationship was reported using the sec before recording the data. Oxygenation was also coefficient of determination (r2). continuously monitored during the exercise test (described below) to determine the greatest reduction during the Results exercise test. Flow of participants, therapists and centres Exercise capacity was measured using the original 10-m through the trial shuttle test (Singh et al 1994) or the Multi Stage Fitness Test (Léger and Lambert 1989). Oxygen uptake at peak exercise Thirty adults from the Cystic Fibrosis Unit were screened was estimated from the exercise testing using standard for eligibility. Twenty met the initial eligibility criteria, but equations (Singh et al 1994, Léger and Lambert 1989). three withdrew during the 14-day period of regular use of airway clearance techniques, citing time constraints. Participants completed the adult Australian Cystic Fibrosis The remaining 17 participants were randomised: 9 to the Quality of Life (CFQOL) questionnairec independently. experimental arm (dornase alfa after airway clearance This questionnaire results in an overall score between 0 techniques) first (post-pre group), and 8 to the control arm (worst) and 100 (best). (dornase alfa before airway clearance techniques) first (pre- post group). The flow of participants through the trial is Data analysis illustrated in Figure 1. The characteristics of the participants were similar at the start of each arm of the study (Table 1 A change in FEV1 of 10% is used as a threshold for Australian and the first two columns of Table 2). Twelve participants government reimbursement of the cost of dornase alpha. We were using positive expiratory pressure as their physical therefore nominated 10% as the between-group difference airway clearance technique. Seven participants were using we sought to identify. Assuming a within-patient SD of 10%, active cycle of breathing techniques, of whom 4 were using 18 participants would provide 80% power, at the 2-sided percussion as well. One participant used positive expiratory 5% significance level, to detect a 10% difference in FEV1 pressure once daily and percussion once daily. between the experimental and control arms as statistically 226 Journal of Physiotherapy 2011 Vol. 57 – © Australian Physiotherapy Association 2011
Bishop et al: Timing of dornase alpha and airway clearance in cystic fibrosis 5BCMF Mean (SD) for outcomes for each group, mean (SD) difference within groups, and mean (95% CI) differences between groups. Groups Difference within Difference between groups groups Start End End minus Start End minus Start Exp Con Exp Con Exp Con Exp minus Con (n = 17) (n = 17) (n = 17) (n = 17) FEV1 2.29 2.35 2.31 2.32 0.01 –0.03 0.04 (L) (0.81) (0.95) (0.83) (0.85) (0.21) (0.28) (–0.14 to 0.23) FEV1 67 68 68 68 1 0 1 (% predicted) (22) (25) (23) (24) (6) (7) (–4 to 6) 83 81 81 –2 3 FVC (22) (23) (23) 84 (6) (7) –6 (% predicted) 97 96 97 (20) 0 0 (–11 to 0) (2) (5) (2) (1) (2) SpO2 27 27 26 96 0 1 0 (%) (8) (8) (7) (4) (2) (3) (–1 to 1) Estimated VO2 –4.8 –4.7 –5.2 28 –0.4 0.2 –1 peak (4.0) (3.3) (4.1) (10) (1.2) (1.6) (–3 to 2) (mL/kg/min) 73 71 73 –4.6 0 3 –0.8 SpO2 change (9) (13) (12) (3.7) (10) (10) (–1.8 to 0.3) with exercise (n = 16) (absolute %) –3 74 (–9 to 3) Quality of life (10) (0 to 100) Shaded row = primary outcome, Exp = experimental condition (dornase alpha after physical airway clearance techniques), Con = control condition (dornase alpha before physical airway clearance techniques), FEV1 = forced expiratory volume in 1 sec, SpO2% = percentage saturation of oxyhaemoglobin estimated by pulse oximetry, VO2 peak = oxygenation consumption at peak exercise 5BCMF Mean (SD) for outcomes for each group at the end of the intervention period, and mean (95% CI) difference between groups. Groups Difference between groups Exp Con Exp minus Con (n = 17) (n = 17) 24-hour sputum weight (g) 21 24 –3 (23) (36) (–12 to 7) Proportion of 24-hr sputum obtained during airway clearance regimen (%) 17 23 –5 (15) (25) (–15 to 4) Exp = experimental condition (dornase alpha after physical airway clearance techniques), Con = control condition (dornase alpha before physical airway clearance techniques) The airway clearance regimen, including tailoring of clearance techniques). This was considered unlikely to be the physical techniques and confirming the appropriate related to treatment and resolved spontaneously despite nebulisation procedures, was determined by the Cystic continuation of the allocated treatment regimen. Fibrosis Unit physiotherapist, who had 6 years of clinical experience, including 4 years in the cystic fibrosis area. Effect of intervention The Cystic Fibrosis Unit of Westmead Hospital in Sydney was the only centre to recruit and test patients in the trial. Group data for all outcomes for the experimental and The Cystic Fibrosis Unit managed approximately 60 adult control interventions are presented in Tables 2 and 3, while patients during the time of the study. individual data are presented in Table 4 (see eAddenda for Table 4). Compliance with trial method The timing of the inhalation of dornase alpha did not have All randomised participants completed both arms of the trial. statistically significant effects on lung function. The best According to diary card entries and vial counts, compliance estimate of the average effect of changing from inhaling with the allocated therapies was > 85%. No participants dornase alpha before to after the physical techniques was in either arm had adverse clinical changes during the to increase FEV1 by only 40 mL (95% CI –140 to 230 intervention that required cessation of the intervention. mL). When the FEV1 data were considered in terms of a One participant with a history of recurrent haemoptysis had percentage of the predicted value, the best estimate of the a single episode after the first 14-day intervention period effect and the limits of the confidence interval all indicated (during which he was taking dornase alpha before airway that any effect was too small to be clinically worthwhile. Journal of Physiotherapy 2011 Vol. 57 – © Australian Physiotherapy Association 2011 227
Research FVC tended to favour the inhalation of dornase alpha before studies in children with cystic fibrosis. Fitzgerald and airway clearance techniques, but the result was only of colleagues (2005) examined the effect of timing of dornase borderline statistical significance. alpha in children with less severe cystic fibrosis lung disease than our cohort. This trial also did not identify an effect of Daily sputum production did not appear to be influenced timing on any outcome. Interestingly, post-hoc analysis of by the timing regimen, and nor did the amount of sputum their cohort identified that inhalation of dornase alpha after obtained during the airway clearance regimen as a physical airway clearance techniques was more beneficial proportion of the daily amount. for FEV1 in those participants who were colonised with Pseudomonas aeruginosa. Although virtually all the There was little change in resting oxygen saturation levels participants in our study were colonised with Pseudomonas in all participants throughout both arms of the study. aeruginosa, it did not demonstrate a clear advantage of The timing of inhalation of dornase alpha did not have a inhaling dornase alpha after physical airway clearance significant effect on this outcome. Exercise capacity was techniques. In a different study, dornase alpha inhaled 30 also quite stable among all participants, with no significant min before physical airway clearance techniques improved effect due to the timing of dornase alpha. On average, expiratory flow at 25% of the forced vital capacity (van participants showed a fall in oxygenation of about 5% der Giessen et al 2007). However, FEV1, FVC, and visual (absolute) during the exercise test at the start and end of analogue scores of sputum and cough were not affected both arms of the study. differently by the two timing regimens in that study. The quality of life data showed that most patients’ quality Although the other studies in this area reported the amount of life scores improved during the study regardless of the of sputum expectorated, ours was the only study to report timing of dornase alpha. Change in quality of life score the amount of sputum obtained during the airway clearance showed a good correlation with change in FEV1 (r2 = 0.4, regimen as a proportion of daily sputum production. We p < 0.001). The effect of the timing regimen on FEV1 was believe this is an important measure because it reflects not significantly correlated with baseline FEV1 (r2 = 0.11). It the immediate efficacy of airway clearance interventions was also not significantly correlated with baseline sputum and the extent to which the person with cystic fibrosis will production (r2 = 0.02). be productive of sputum throughout the remainder of the day when they may be undertaking work, study or social Discussion activities. On average, about one-fifth of daily sputum production occurred during the airway clearance regimen. This is the first study to consider the effect of the timing of dornase alpha in relation to airway clearance techniques The correlational analyses we conducted confirmed that our in adults with cystic fibrosis. The main finding is that the overall result – the timing of dornase alpha inhalation had timing of dornase alpha does not have a substantial impact little effect on lung function – can be considered applicable on clinical outcomes over a 14-day period. This finding is to all people with cystic fibrosis who meet the eligibility likely to be accurate because many aspects of the study criteria for this study. That is, the lack of an effect on lung design eliminated sources of potential bias. For example, function in this study was not due to a real effect in some the groups were similar on their baseline measures and are participants being diluted or masked by a weak or adverse likely to have been similar on unmeasured characteristics effect in participants with different characteristics such as as well, due to the use of randomisation and concealment of baseline lung function or baseline sputum production. allocation, which circumvents some potential confounders of the randomisation process. Potential sources of bias were The knowledge that the timing of dornase alpha in relation also eliminated from the outcome data through blinding to physical airway clearance techniques does not affect of participants, the assessors, and the physiotherapist who clinical outcomes is useful for patients and clinicians, explained the intervention to the participants and who because the regimen of dornase alpha can be prescribed taught them how to administer the trial solutions. The according to other priorities. For most patients, the timing of study was adequately powered, with no loss to follow- dornase alpha in relation to airway clearance can be tailored up after randomisation, resulting in a confidence interval to patient preferences or timing in relation to other inhaled around the primary outcome that excluded the possibility therapies. The correlation between change of quality of life that the timing of dornase alpha has clinically important scores and change in FEV1 suggests that the majority of effects. Previous large multi-centre studies have shown that patients can assess a true improvement subjectively. N-of- the maximum effect of dornase alpha on FEV1 is achieved 1 trials may therefore be useful in determining a suitable within the first 7 to 14 days (Fuchs et al 1994), so presumably timing regimen for an individual patient. the duration of the study arms was sufficient to identify the effect on lung function. In summary, the timing of dornase alpha inhalation does not appear to have a strong influence on the efficacy In addition to the strengths of the study design, we of the overall airway clearance regimen in adults with acknowledge that there were some limitations in the cystic fibrosis. The inhalation of dornase alpha can be methods. Peak oxygen consumption was not measured prescribed according to convenience, patient preference, directly and one of two exercise tests was used to estimate or to accommodate the timing of other medications in the it. Also, there was a minimal washout period between the treatment regimen. Q two study arms. However, there was minimal difference between the groups at the end of the first treatment period, Footnotes: aSidestream, Medic-Aid, Pagham, UK, suggesting that the lack of a long washout period was not a bVitalograph, Vitalograph Ltd, Buckinghamshire, UK, substantial confounder. cRoche Products Pty Limited, Dee Why, Australia The results of the study were also consistent with similar 228 Journal of Physiotherapy 2011 Vol. 57 – © Australian Physiotherapy Association 2011
Bishop et al: Timing of dornase alpha and airway clearance in cystic fibrosis eAddenda: Table 4 available at jop.physiotherapy.asn.au Physiology and Occupational Physiology 49: 1–12. Ethics: The Western Sydney Area Health Service Human Lieberman J (1968) Dornase aerosol effect on sputum viscosity Research Ethics Committee approved this study, HREC in cases of cystic fibrosis. JAMA 205: 312–313. 98/9/4.8 (695). All participants gave written informed consent before data collection began. Pryor JA, Prasad SA (2008) Physiotherapy techniques (Ch 5) In, Pryor JA, Prasad SA (Eds) Physiotherapy for Respiratory Competing interests: Nil. and Cardiac Problems 4th ed. London: Churchill Livingstone. Support: This study was partially supported by Roche Ramsey BW, Astley SJ, Aitken ML, Burke W, Colin AA, Dorkin Products Pty Ltd. HL et al (1993) Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in Acknowledgements: The authors are grateful to the patients with cystic fibrosis. American Review of Respiratory participants for their involvement and to Dr Mark Elkins Disease 148: 145–151. for his valuable assistance in preparation of the manuscript. Ryan G, Mukhopadhyay S, Singh M (2003) Nebulised anti- Correspondence: Peter Middleton, Ludwig Engel Centre pseudomonal antibiotics for cystic fibrosis. Cochrane for Respiratory Research, Westmead Millenium Institute, Database of Systematic Reviews Issue 3. Art. No.: CD001021. University of Sydney at Westmead, Westmead NSW 2145, :E?0'&$'&&(%'*,+'.+.$9:&&'&('$ Australia. Email: [email protected] Shak S, Capon DJ, Hellmiss R, Marsters SA (1990) References Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proceedings of the National Academy of American Thoracic Society (1995) Standardization of Sciences USA 87: 9188–9192. spirometry: 1994 update. American Journal of Respiratory and Critical Care Medicine 152: 1107–1136. Singh SJ, Morgan MD, Hardman AE, Rowe C, Bardsley PA (1994) Comparison of oxygen uptake during a conventional Fitzgerald DA, Hilton J, Jepson B, Smith L (2005) A crossover, treadmill test and the shuttle walking test in chronic airflow randomized, controlled trial of dornase alfa before versus limitation. European Respiratory Journal 7: 2016–2020. after physiotherapy in cystic fibrosis. Pediatrics 116: 549– 554. Smyth AR, Walters S (2003) Prophylactic anti-staphylococcal antibiotics for cystic fibrosis. Cochrane Database of Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Systematic Reviews Issue 3. Art. No.: CD001912. DOI: Ramsey BW et al (1994) Effect of aerosolized recombinant '&$'&&(%'*,+'.+.$9:&&'/'($ human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. Southern KW, Barker PM, Solis-Moya A (2004) Macrolide New England Journal of Medicine 331: 637–642. antibiotics for cystic fibrosis. Cochrane Database of Systematic Reviews Issue 2. Art. No.: CD002203. DOI: Hubbard RC, McElvaney NG, Birrer P, Shak S, Robinson '&$'&&(%'*,+'.+.$9:&&((&)$fkX($ WW, Jolley C et al (1992) A preliminary study of aerosolized recombinant human deoxyribonuclease I in the treatment of van der Giessen LJ, de Jongste JC, Gosselink R, Hop WCJ, cystic fibrosis. New England Journal of Medicine 326: 812– Tiddens HAWM (2007) RhDNase before airway clearance 815. therapy improves airway patency in children with CF. Pediatric Pulmonology 42: 624–630. Knudson RJ, Slatin RC, Lebowitz MD, Burrows B (1976) The maximal expiratory flow-volume curve. Normal standards, van der Schans CP, Prasad A, Main E (2000) Chest variability, and effects of age. American Review of Respiratory physiotherapy compared to no chest physiotherapy for cystic Disease 113: 587–600. fibrosis. Cochrane Database of Systematic Reviews Issue 2. 7hj$De$09:&&'*&'$:E?0'&$'&&(%'*,+'.+.$9:&&'*&'$ Jones AP, Wallis C (2010) Dornase alfa for cystic fibrosis. Cochrane Database of Systematic Reviews Issue 3. Art. No.: Wark P, McDonald VM (2009) Nebulised hypertonic saline for 9:&&''(-$:E?0'&$'&&(%'*,+'.+.$9:&&''(-$fkX($ cystic fibrosis. Cochrane Database of Systematic Reviews ?iik[ ($ 7hj$ De0 9:&&'+&,$ :E?0 '&$'&&(%'*,+'.+.$ Léger LA, Lambert J (1989) A maximal multistage 20-m shuttle CD001506.pub3. run test to predict VO2 max. European Journal of Applied Wilson CJ, Robbins LJ, Murphy JM, Chang AB (2007) Is a longer time interval between recombinant human deoxyribonuclease (dornase alfa) and chest physiotherapy better?: a multi-center, randomized crossover trial. Pediatric Pulmonology 42: 1110–1116. Journal of Physiotherapy 2011 Vol. 57 – © Australian Physiotherapy Association 2011 229
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