Pediatric Pulmonology 47:1235–1241 (2012)
Effects of a Supervised, Outpatient Exercise and Physiotherapy Programme in Children With Cystic Fibrosis Donald Urquhart, MD, MRCPCH,1,2* Zoe Sell, MSc,1 Elaine Dhouieb, MSc,1 Gillian Bell, BSc,1 Sarah Oliver, BSc,1 Ryan Black, BSc,2 and Matthew Tallis, BSc2 Summary. Previous work suggests benefit from outpatient exercise and physiotherapy in children with cystic fibrosis (CF), namely improved exercise capacity and lung function measures, as well reduced intravenous (IV) antibiotic needs. Our study aim was to investigate the effect of a year-long supervised outpatient exercise and physiotherapy programme in children with CF. Subjects with CF aged 10 years who had received 4 courses of IV antibiotics in 2009 were enrolled and seen fortnightly for supervised exercise and physiotherapy throughout 2010. In addition, they were expected to exercise three times weekly, and if unwell complete additional physiotherapy sessions extra to usual chest physiotherapy. Assessments of exercise capacity using the Modified Shuttle Test (MST) and quality of life (QOL; CFQ-UK) were recorded at baseline and after 1 year. Regular spirometry was performed before and throughout the study. Data were collected on IV antibiotic days. 12 subjects (6 female) were enrolled with mean (95% CI) age of 13.3 (11.8–14.6) years at study entry. A significant reduction in IV antibiotic days from 60 (56–64) days in 2009 to 50 (44–56) in 2010 (P ¼ 0.02) was noted, along with improved MST distance (m) [735 (603–867) vs. 943 (725–1,161), P ¼ 0.04] and level attained [9.4 (8.4–10.5) vs. 11.1 (9.6–12.6), P ¼ 0.04]. Significant improvements in CFQ-UK scores for physical [59 (47–72) vs. 83 (74–92), P ¼ 0.001], emotional [63 (55–72) vs. 84 (74–93), P < 0.001], treatment [41 (30–51) vs. 61 (48–73), P ¼ 0.002], and respiratory [54 (42–66) vs. 76 (70–82), P ¼ 0.002] domains were noted. The mean (95% CI) rate of change of FEV1 was 4 (18, þ10)% in 2009, but was þ6 (2, þ13)% in 2010, although this did not reach statistical significance. Supervised, outpatient exercise and physiotherapy are associated with improvements in QOL and exercise tolerance, a reduction in IV antibiotic days, and a trend towards reducing lung function decline in children with CF. The cost of IV antibiotics was reduced by £66,384 ($104,000) in 2010 when compared with 2009. Such cost-benefit may have implications for workforce planning and service provision. Pediatr Pulmonol. 2012; 47:1235–1241. ß 2012 Wiley Periodicals, Inc. Key words: exercise; outpatient physiotherapy; cystic fibrosis. Funding source: none reported.
INTRODUCTION
A study undertaken in Brisbane, Australia suggested that an intensive outpatient physiotherapy programme in a group of children with cystic fibrosis (CF) had a beneficial effect on inpatient bed days, intravenous (IV) antibiotic requirements, exercise capacity and lung function over a 12-month period.1 A 48% reduction in IV antibiotic need was reported for the 12-month study period when compared to the preceding year. We sought to investigate the effects of such a programme, and hypothesized that application of a similar, supervised outpatient exercise and physiotherapy intervention would be cost-beneficial due to a reduction in IV antibiotic requirements. Exercise capacity is known to be correlated with survival in both adults,2,3 and children4 with CF. The ß 2012 Wiley Periodicals, Inc.
1 Department of Paediatric Respiratory Medicine, Royal Hospital for Sick Children, Edinburgh, UK. 2
Department of Paediatric Respiratory Medicine, Mater Children’s Hospital, Brisbane, Australia. Conflict of interest: None. Ethical approval: Approved by LREC; Guarantor: DSU. *Correspondence to: Donald Urquhart, MD, MRCPCH, Consultant in Paediatric Respiratory and Sleep Medicine, Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh EH9 1LF, UK. E-mail:
[email protected] Received 3 October 2011; Accepted 13 March 2012. DOI 10.1002/ppul.22587 Published online 2 May 2012 in Wiley Online Library (wileyonlinelibrary.com).
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benefits of short-term supervised exercise programmes in CF on exercise capacity5,6 and quality of life (QOL)7 are reported, as are benefits of longer-term self-administered home exercise programmes8 including slowing of the rate of decline of lung function. In addition to the benefits on exercise capacity,9 lung function,8 and QOL,5,7 regular exercise promotes bone mineralization in CF,10 and in a non-CF population has been shown to improve airway clearance.11 Furthermore, longitudinal changes in nutritional status in CF correlate with exercise capacity.12 It is recommended that training programmes should incorporate both aerobic and anerobic exercise components,5,7 and also that training programmes should include varied activities for the acceptability of a single-exercise training programme decreases over time.13 Furthermore, aerobic exercise in CF should be undertaken in combination with resistance or strength training.5,14 A number of studies have considered the effects of chest physiotherapy and exercise in patients with CF. A Cochrane review has established short-term benefits of chest physiotherapy when compared with no physiotherapy,15 whilst it is reported that exercise when combined with chest physiotherapy is better than exercise alone,16 or physiotherapy alone,17 in terms of airway clearance. Aims
The aim of this present study was to evaluate the effects of a 1-year long supervised, outpatient exercise and physiotherapy programme on IV antibiotic need, lung function, exercise capacity, and QOL in children with CF. We hypothesized that such an intervention would be cost-beneficial due to a reduction in IV antibiotic requirements. In addition to this primary outcome, the effects of the intervention on secondary outcomes including lung function, exercise capacity, and QOL were studied. MATERIALS AND METHODS
Children with CF, aged >10 years who had received 4 or more IV antibiotic courses (each lasting 14 days or longer) in 2009 were eligible for participation. No microbiological exclusion criteria were set, and all those with baseline FEV1 >30% predicted were eligible to participate. Fifteen patients from the Royal Hospital for Sick Children (RHSC) Edinburgh CF cohort (n ¼ 138) met these entry criteria, and were invited to participate in the study which ran from January to December 2010. The study had ethical approval (NHS Lothian REC# 10/s1102/42). Signed consent was obtained from the parent or guardian of each subject. An individualized home exercise and airway clearance programme was derived with the help of the Pediatric Pulmonology
specialist physiotherapist and included airway clearance, nebulized mucolytic treatments, aerobic exercise, strength training, stretching and postural advice. Aerobic exercise was titrated to 60–80% of a subject’s peak heart rate (HR) as measured at baseline by Modified Shuttle Test (MST; described below), and advice on weights and number of repetitions completed was given by local gym instructors. Membership of local council gymnasia was procured for each child, where age permitted. Children were reviewed in the community every 2 weeks, or more frequently if unwell and a minimum of 30 min exercise three times per week was completed by each participant. Each child kept an exercise diary. School P.E. lessons were allowed to count for one of the exercise sessions per week. For each child, the lead physiotherapist visited the school, in order to validate the P.E. session for this purpose. The P.E. teacher was also aware of participation in the project, and the need to obtain an expected exercise level from the CF subject in question. If the child missed P.E. for whatever reason they were expected to make up that exercise session at another point in the week. Strength training in the gym was initially supervised on a one-to-one basis by the gym instructor and subsequently reviewed at regular intervals by gym instructor and lead physiotherapist alike. At times where children were deemed to be unwell, parents would contact the lead physiotherapist to instigate a review. This would involve a physiotherapy assessment at home or in outpatients, along with sampling of sputum for culture. A formal airway clearance session would be delivered and advice would be given on airway clearance and an interim physiotherapy and exercise programme given for the following week. Direct contact and a physiotherapist delivered session would be repeated within 3–7 days. Criteria for IV antibiotics included exacerbations defined by clinical symptoms or drops in lung function at the discretion of their treating physician. The majority of the children were on a programme of regular antibiotics; however, the frequency of these were affected by bed pressures at both the tertiary and shared-care centers. For example a child having regular 3-monthly antibiotics who was clinically well would have their antibiotics delayed, whereas an unwell child would have their antibiotics brought forward. The same criteria were applied in each of the 2-year studied. Exercise capacity was assessed at the beginning and end of the study using the 10 m MST,18,19 which provided information on distance achieved and level attained, as well as measures of HR, oxygen saturations (SpO2), and scores of both dyspnea and fatigue using the Borg scale.20 This differs from previously published methodology1 where a 20 m shuttle test was used.21 The space available in our physiotherapy gym allowed
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for a 10 m test only, however. Spirometry (Jaeger Masterscreen PFT pro) was undertaken on multiple occasions prior to and during the study. Data were expressed as z-score using the equations of Stanojevic et al.22 The CFQ-UK questionnaire, a valid, disease-specific tool for assessing QOL across several domains in children with CF23,24 was completed at the beginning and end of the intervention. The CFQ is a QOL assessment that was developed in France.23 It has since been adapted for use in a number of countries including the USA,25 Holland,26 and the UK.24 In each of these translations, both backward and forward translations were completed and re-validation of the questionnaire was carried out. A CD-ROM package that accompanies the questionnaire enables QOL dimensions to be assessed. The CFQ-14þ was used for children aged over 14 years, and is a self-assessed questionnaire that takes around 10 min to complete. The CFQ child P is a parent-proxy evaluation used for children aged 6–13 and was used for the younger children in our study. The CFQ-child P questionnaire assesses well being across eight different areas, namely physical, emotional, social, body, eating, treatment, respiratory, and digestion domains. The CFQ-14þ considers each of these domains and further scores well-being for role, vitality, health, and weight domains. In view of the small numbers in our study, only data from the eight CFQ domains that were common to each questionnaire were analyzed. Clinical data were also collected including anthropometric measures (which were converted to z-score), as well as data on hospital admissions and IV antibiotic days. All data were entered into a database (Microsoft Excel) and statistical analyses were undertaken using a statistical package (SPPS Statistics v17.0; SPSS Inc., Chicago, IL). Paired t-tests were used to compare data from the 12-month study period and the preceding year for our study population. An a priori power calculation established that 13 children were required to detect a difference of 21 days of IV antibiotics per year, with 80% power and at a significance level of P < 0.05. Costs of hospital admission for respiratory pediatrics were estimated as £657 per day (Finance Department, NHS Lothian, Personal communication). Home IV antibiotic course costs were estimated using the British National Formulary unit cost for the two most commonly used antimicrobial agents,27 namely ceftazidime (£53.70/day)27 and tobramycin which is administered three times daily in our center (£57.60).27 There are additional costs from pharmacy to make up these antibiotics (estimated at £20/day) as well as consumables in the form of a Gripper needle, needles, syringes, and saline/heparinized saline flushes (estimated at £10/day).
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Further hidden costs include an outpatient visit (£220/ visit estimated from 2008/09 national average for pediatric respiratory medicine)28 and lung function testing at beginning, middle and end (estimated at £35/visit) over the course of a home IV antibiotic course, which when averaged over a 2-week course add an extra £23.93/day to the cost. Thus a figure of £165.23 per day was estimated for the cost of home IV. RESULTS
Fifteen subjects met inclusion criteria for the study of whom one lived in the Scottish Borders—some distance from Edinburgh and where free gym facilities were unavailable. Of the 14 subjects approached, 1 did not wish to take part in the study. Thirteen children were recruited to the study, although one subject dropped out before the start of the study as they felt unable to commit to the study. A total of 12 (6 female) completed the study with a mean (95% CI) age at study entry of 13.3 (11.8–14.6) years. 58% (7/12) were homozygous for the F508del mutation, with the remainder being compound F508del heterozygotes. Baseline demographic data are displayed in Table 1. Subjects undertook significantly more exercise in the year of the intervention. At baseline in 2009, subjects reported that they undertook a mean (95% CI) of 50 (28–72) minutes of exercise sessions per week, whereas in 2010 an average of 181 (152–209) minutes per week were recorded in subject diaries as spent exercising (P < 0.001). All but one child were able to secure gym membership. This young man undertook aerobic exercise including running, cycling, and circuit training as well as attending Sea Cadets where organized aerobic activity was undertaken once to twice weekly. He also undertook dynamic strengthening exercises including press-ups and squats (among others) along with isometric exercises such as the plank to improve core stability. A significant reduction in IV antibiotic days (the primary study outcome) from a mean (95% CI) of 60 (56– 64) in 2009 to 50 (44–56) in 2010 (P ¼ 0.02) was noted (Table 2). This represents a 17% reduction in IV antibiotic requirements (Fig. 1). No subject recorded an increase in IV antibiotic days. In total, 122 less IV antibiotic days were recorded in 2010 versus 2009 for the study population. Three hundred eighteen hospital IV days and 406 home IV days were recorded in 2009, compared with 224 and 378 days respectively in 2010. This represents a cost reduction of £66,384 ($103,785) for 2010 versus 2009. These data are shown in Table 3. Furthermore, significant improvements in exercise capacity with regard to both distance covered and level attained on MST were observed following this 1-year intervention. Exercise parameters are displayed in Pediatric Pulmonology
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TABLE 1— Baseline Demographics of Study Population
Sex Age CFTR genotype Microbiological status Chronic Pseudomonas aeruginosa Chronic Staphylococcus aureus Chronic Burkholderia cepacia History of APBA History of NTM FEV1 z-score FVC z-score Height z-score Weight z-score BMI z-score
Number
Range
Mean (95% CI)
6 Male 6 Female — f508del/f508del (n ¼ 7) f508del/other (n ¼ 5)
— — 10.6 to 16.8 —
— 13.2 (11.8, 14.6) —
6 (50%) 6 (50%) 1 (8%) 1 (8%) 2 (17%) — — — — —
— — — — — 4.87 to þ0.05 3.72 to þ0.96 1.8 to þ3.3 0.9 to þ1.9 1.1 to þ1.6
— — — — — 2.70 (3.77, 1.63) 1.54 (2.49, 0.6) 0.34 (0.61, 1.30) 0.61 (0.01, 1.20) 0.64 (0.17, 1.12)
TABLE 2— Mean (95% CI) of Clinical Data Before and After 1 Year of Supervised, Intensive Outpatient Exercise/ Physiotherapy
Exercise (min/week) IV antibiotic days FEV1 (L) FVC (L) FEV1 z-score FVC z-score Rate of change of FEV1 (%predicted) Rate of change of FVC (%predicted) Body mass index (BMI) z-score
Start
Finish
P-value
50 (28, 72) 60 (56, 64) 1.87 (1.26, 2.48) 2.54 (1.81, 3.28) 2.70 (3.77, 1.63) 1.54 (2.49, 0.6) 3.9 (17.5, þ9.7) 6.3 (18, þ5.5) 0.64 (0.17, 1.12)
181 (152, 209) 50 (44, 56) 2.06 (1.37, 2.75) 2.82 (2.07, 3.56) 2.46 (3.59, 1.33) 1.58 (2.45, 0.7) þ5.7 (1.6, þ13.1) þ9 (þ0.6, þ17.4) 0.67 (0.21, 1.14)
<0.001 0.02 0.008 0.01 0.35 0.74 0.24 0.10 0.82
Paired t-test.
Table 4. Absolute FEV1 increased significantly, but when corrected to % predicted values, no significant differences in lung function were noted between the beginning and the end of the study. It is very interesting to note however that the trend for rate of change of FEV1 whilst declining across the group in 2009, showed a mean increase for 2010. These data are all summarized in Table 2. Finally, statistically significant improvements in QOL for CFQ-UK physical, emotional, social, body, treatment, and respiratory domains were observed following a year of intensive supervised, outpatient exercise and physiotherapy (Table 5). DISCUSSION
Demonstrable improvements in exercise capacity and QOL were shown, along with a reduction in IV antibiotic requirements following a 1-year supervised, outpatient physiotherapy and exercise programme in Pediatric Pulmonology
Fig. 1. Boxplot of mean (95% CI) of IV antibiotic days before (2009) and during (2010) a one-year supervised out-patient exercise and physiotherapy programme.
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TABLE 3— Cost-Benefit Analyses of Hospital and Home IV Before and After 1 Year of Supervised, Intensive Outpatient Exercise/Physiotherapy
Hospital IV days (£657/day) Home IV days (£165.23/day) Total cost of IV
2009
2010
Difference
318 (£208,926) 406 (£67,083) £276,009
224 (£147,168) 378 (£62,457) £209,625
94 (£61,758) 28 (£4,626) £66,384 ($103,785)
children with CF. A trend towards a reduction in lung function decline was also suggested. Previous studies have shown evidence of improved QOL with supervised exercise programmes.5,7,29 Our study has further assessed various QOL domains following a 1-year long exercise programme, demonstrating significant improvements in areas relating to physical health, namely CFQ-UK physical, treatment, health, and respiratory domains. Furthermore, key domains that are pertinent to emotional well-being including emotional and social domains also showed marked improvement. The observed improvement across multiple health-related QOL domains suggests that exercise promotion may be a useful adjunct to psychology services in improving QOL in children with CF. This study verified the findings of Black et al.1 of a reduced need for IV antibiotics (a finding also reported in an Adelaide-based study of outpatient physiotherapy in CF)30 when undertaking a programme of supervised exercise and physiotherapy, as well as modest improvements in exercise capacity. In our study, a mean of 10 fewer IV antibiotic days per subject were noted in the year of the study intervention. This led to an estimated reduction of £66,384 ($103,785) in IV antibiotic costs which would suggest that such an intervention programme is likely to be cost beneficial, and might have implications for workforce planning. Such cost savings more than cover the direct cost of the physiotherapists’ salary and given the benefits observed on exercise capacity and QOL, the true cost savings may be greater than can be readily quantified. Those devising models
of care for children with CF may wish to evaluate home-delivered programmes such as this one for their cost-effectiveness, clinical benefit, and acceptability to patients and families alike. The study failed to demonstrate any change in BMI, which may suggest that one of the limitations of the study was a lack of dietetic input. Subjects were being expected to undertake more frequent and more intensive levels of exercise during this 1-year study, and we acknowledge that closer attention should have been paid to matching calorie utilization with increased calorie provision. We would plan to address this in future studies by providing regular nutritional review in conjunction with the exercise programme. The study has some recognized limitations. The study had no control group with whom to compare, although it may be argued that they acted as their own controls for the comparison of a year with (2010) and without (2009) this intervention. The study had no blinding, and subjects knew that the physiotherapist was administering a therapy and exercise programme for them. One could question whether the regular healthcare contact alone resulted in improvements in well-being. Future studies should consider a randomized trial of outpatient physiotherapy and exercise compared to a physiotherapist simply visiting families on a 2-weekly basis but offering no intervention. The measurement of exercise capacity using the MST as opposed to precise measurement of VO2max on a cardiopulmonary exercise test may be considered to be a further limitation of the study. The distance covered and level of attainment on an MST may increase
TABLE 4— Mean (95% CI) of Exercise Parameters Before and After 1 Year of Supervised, Intensive Outpatient Exercise and Physiotherapy
Exercise (min/week) MST distance (m) MST level Maximum heart rate (HR) on MST DHR from start to finish of MST Lowest SpO2 on MST DSpO2 from start to finish of MST
Start
Finish
P-value
50 (28, 72) 735 (603, 867) 9.4 (8.4, 10.5) 142 (127, 156) 45 (29, 61) 93 (91, 95) 3.8 (5.5, 2)
181 (152, 209) 943 (725, 1,161) 11.1 (9.6, 12.6) 160 (149, 170) 64 (45, 83) 93 (92, 95) 3.3 (2.4, 4.2)
<0.001 0.04 0.04 0.08 0.44 0.72 0.17
Paired t-test.
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TABLE 5— Mean (95% CI) of CFQ Domain Scores Before and After 1 Year of Supervised, Intensive Outpatient Exercise/ Physiotherapy
CFQ Physical CFQ Emotional CFQ Social CFQ Body CFQ Eating CFQ Treatment CFQ Respiratory CFQ Digestion
Start
Finish
P-value
59 (47–72) 63 (55–72) 60 (52–68) 64 (46–82) 87 (77–96) 41 (30–51) 54 (42–66) 80 (71–89)
83 (74–92) 84 (74–93) 80 (73–87) 86 (71–100) 97 (94–100) 61 (48–73) 76 (70–82) 81 (67–95)
0.001 <0.001 <0.001 <0.001 0.05 0.002 0.002 0.67
Paired t-test.
with age and leg length, although the greater HR levels achieved on the 2010 test when compared with 2009, suggest that a greater effort (and a true increase in exercise capacity) was demonstrated post-intervention for our study population. The study was underpowered for the level of difference in primary outcome that was detected. Nonetheless, the study findings coupled with similar results from Brisbane,1 and Adelaide,30 are strongly suggestive of benefit. In conclusion, benefits to the individual patient with CF, namely reduced antibiotic requirements, as well improved exercise capacity and QOL are suggested by the results of our small, supervised outpatient physiotherapy study. Service improvement, in the form of cost-benefit is also suggested. There remain some unanswered questions, including the sustainability of such an intervention and whether physiological and psychological improvements would be maintained over periods longer than 1 year. Further larger-scale and longer-term studies are needed to verify these findings. ACKNOWLEDGMENTS
Thanks are due to Dr. Andy Fall, Dr. Tom Marshall, and Dr. Steve Cunningham, as well as Ms. Emily Taylor, Mrs. Aileen Mallinson, Mrs. Amanda McGrath, Mrs. Ingrid Boyd, and Mr. David Fynn for their help in the undertaking of this project. REFERENCES 1. Black R, Tallis M, Urquhart DS, Harris M, Cooper D, Dakin C. Intensive out-patient physiotherapy—an approach to optimising lung health in childhood cystic fibrosis. Pediatr Pulmonol 2009; 44:391–392. 2. Nixon PA, Orenstein DM, Kelsey SF, Doershuk CF. The prognostic value of exercise testing in patients with cystic fibrosis. N Engl J Med 1992;327:1785–1788. 3. Moorcroft AJ, Dodd ME, Webb AK. Exercise testing and prognosis in adult cystic fibrosis. Thorax 1997;52:291–293. 4. Pianosi P, Leblanc J, Almudevar A. Peak oxygen uptake and mortality in children with cystic fibrosis. Thorax 2005;60: 50–54.
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Supervised, O/P Exercise and Physiotherapy in CF-R1 19. Bradley J, Howard J, Wallace E, Elborn S. Validity of a modified shuttle test in adult cystic fibrosis. Thorax 1999;54:437– 439. 20. Wilson RC, Jones PW. A comparison of the visual analogue scale and modified Borg scale for the measurement of dyspnoea during exercise. Clin Sci 1989;76:277–282. 21. Selavadurai HC, Cooper PJ, Meyer N, Blimkie CJ, Smith L, Mellis CM, van Asperen PP. Validation of shuttle tests in children with cystic fibrosis. Pediatr Pulmonol 2003;35:133–138. 22. Stanojevic S, Wade A, Cole TJ, Lum S, Custovic A, Silverman M, Hall GL, Welsh L, Kirkby J, Nystad W, et al. Spirometry centile charts for young Caucasian children: The Asthma UK Collaborative Initiative. Am J Respir Crit Care Med 2009;180: 547–552. 23. Henry B, Grosskopf C, Aussage P, Goehers J-M, Launois R, French CFQoL Study Group. Construction of a disease-specific quality of life questionnaire for cystic fibrosis. Pediatr Pulmonol 1997;22:337–338. 24. Bryon M, Buu A, Davis MA, Watrous M, Quittner AL. CFQUK: Cystic Fibrosis Questionnaire, a health-related quality of life measure (English UK, Version 1). Bexley: Forest Laboratories UK Ltd; 2009.
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25. Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of the cystic fibrosis questionnaire in the United States: a health-related quality of life measure for cystic fibrosis. Chest 2005;128:2347–2354. 26. Klijn PH, van Stel HF, Quittner AL, van der Net J, Doeleman W, van der Schans CP, van der Ent CK. Validation of the Dutch cystic fibrosis questionnaire (CFQ) in adolescents and adults. J Cystic Fibros 2004;3:29–36. 27. British National Formulary for Children 2011–12. Available: at http://www.bnfc.org (accessed on 22 September 2011). 28. National Schedule of Reference Costs Year: ‘2008–09’—NHS Trusts Consultant Led: Follow up Attendance Non-Admitted Face to Face. Available at: http://www.dh.gov.uk/prod_consum_dh/ groups/dh_digitalassets/@dh/@en/@ps/documents/digitalasset/dh_ 118322.xls#Start8 (accessed on 23 September 2011). 29. Hebestreit H, Keiser S, Junge S, Ballmann M, Hebestreit A, Schindler C, Schenk T, Posselt HG, Kriemler S. Long-term effects of a partially supervised conditioning programme in cystic fibrosis. Eur Respir J 2010;35:578–583. 30. Kong W, Potter A. Ambulatory physiotherapy: improving outcomes for children with declining health. Pediatr Pulmonol 46:355–356.
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