Long-term non-invasive ventilation in cystic fibrosis Experience over two decades

Journal of Cystic Fibrosis 11 (2012) 187 192 www.elsevier.com/locate/jcf Original Article Long-term non-invasive ventilation in cystic fibrosis Experience over two decades William G. Flight a, b,, Jonathan Shaw a, Susan Johnson a, A. Kevin Webb a,b, Andrew M. Jones a,b, Andrew M. Bentley b,c, Rowland J. Bright-Thomas a, b a Manchester Adult Cystic Fibrosis Centre, University Hospital of South Manchester, Southmoor Road, Manchester, M23 9LT, United Kingdom b Respiratory Research Group, University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom c Long-term Ventilation Service, University Hospital of South Manchester, Southmoor Road, Manchester, M23 9LT, United Kingdom Received 25 July 2011; received in revised form 21 November 2011; accepted 21 November 2011 Available online 16 December 2011 Abstract Background: Non-invasive ventilation (NIV) is accepted as a bridge to lung transplantation in cystic fibrosis (CF) but there is little evidence to support its use outside this setting. Methods: We reviewed the records of all patients with CF who received domiciliary NIV at our centre between 1991 and 2010. Results: Of 47 patients studied, 36% underwent lung transplantation, 28% died without transplantation and 30% remain alive on NIV. Median duration of NIV was 16 months (range 2 90). Mean FEV 1 fell by 212 ml over the year before NIV but increased by 18 ml in the following year (pb0.01). Individual response to NIV was associated with lower baseline and more rapid decline in FEV 1. From 1991 to 2000, 70% underwent lung transplantation; from 2001 to 2010 only 27% were transplanted. Conclusions: NIV may slow or reverse the decline in lung function in advanced CF. NIV is increasingly used beyond a bridge to transplantation at our centre. 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Non-invasive ventilation; Respiratory failure; Lung transplantation 1. Introduction Domiciliary non-invasive ventilation (NIV) is widely used in the treatment of hypercapnic respiratory failure due to neuromuscular disease and chest wall pathology [1 3]. In cystic fibrosis (CF), NIV has been used as an adjunct to airway clearance techniques [4] and has been shown in short-term studies to improve ventilation, blood gas tensions and sleep quality [5,6]. The role of long-term NIV in advanced CF, however, has still not been established some two decades after it became accepted as a bridge to lung transplantation [5,7]. The study data were previously presented in abstract form at the 34th European Cystic Fibrosis Conference, 8 11th June 2011 in Hamburg, Germany. Corresponding author at: Manchester Adult Cystic Fibrosis Centre, University Hospital of South Manchester, Southmoor Road, Manchester M23 9LT, United Kingdom. Tel.: +44 161 291 2016; fax: +44 161 291 4323. E-mail address: william.flight@uhsm.nhs.uk (W.G. Flight). A recent randomised crossover trial of nocturnal NIV, oxygen or supplemental air in eight patients with CF and hypercapnia showed improvements in dyspnoea and nocturnal hypoventilation, but not daytime hypercapnia, after 6 weeks of treatment with NIV [8]. Single-centre data from the UK published in 2002 suggested that the mean duration of long-term NIV usage was just 1 to 2 months [9]. The clearest data on outcomes including lung function following NIV comes from a retrospective review of 41 patients from the French CF registry [10]. This suggested that NIV slows the decline in FEV 1 over 12 months of follow-up, raising the possibility of a role for NIV as part of maintenance pulmonary therapy in advanced CF. To evaluate the impact of long-term NIV in advanced CF and assess whether the use of NIV has changed over the last two decades, we reviewed outcomes in all patients who have ever received domiciliary NIV at our centre. Data reported here have previously been presented in abstract form [11]. 1569-1993/$ -see front matter 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2011.11.006

188 W.G. Flight et al. / Journal of Cystic Fibrosis 11 (2012) 187 192 2. Methods Patients were identified from the database of the Long-term Ventilation Service of the University Hospital of South Manchester. Data was extracted from the clinical records of every patient who has been commenced on long-term domiciliary NIV since the opening of the Manchester Adult CF Centre (MACFC). Patients who received acute NIV during a hospital admission but were not discharged on home NIV were excluded. The study formed part of a service evaluation of the Long- Term Ventilation Service at our institution so formal ethics committee review was not considered necessary. Weight, body mass index (BMI), forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and arterialized blood gas measurements at the time of initiation of NIV were recorded. Values for these variables were also recorded at 12, 24 and 36 months before and after NIV set-up (i.e. year 3 through to year +3, with year 0 indicating the time of NIV initiation). Where these annual time points fell during a course of intravenous antibiotics, the values at the end of the treatment period were recorded. Patients were classified as responders to NIV if the FEV 1 improved after initiation of NIV or the rate of decline slowed. Non-responders were defined as those patients whose rate of decline of FEV 1 accelerated following NIV. The number of courses and total number of days on intravenous antibiotics were calculated for each year over the study period. The time to death, lung transplantation, withdrawal of NIV or 1st October 2010 was calculated for each patient. Transplant list status during the follow-up period was recorded for each patient. Ventilator dependence was defined as use of NIV for 24-h per day for more than 2 weeks with a subsequent inability to reduce the hours of NIV use. Statistical analysis was performed using Graphpad Prism v4.03. Paired t tests were used to compare mean values before and after NIV set-up for normally distributed data. The Mann Whitney test was used to compare non-parametric data. Categorical data were assessed using the chi-squared test. The conventional 0.05 level of significance was used. Numerical data are presented as mean (standard deviation) unless otherwise stated. 3. Results 48 patients were treated with long-term NIV at MACFC between 1991 and 2010. Records were available for 47 of these patients. Median age at set-up of NIV was 29 years (range 16 47) and 64% were male. Baseline characteristics are shown in Table 1. 17 patients (36.2%) underwent lung transplantation, 13 (27.6%) died without lung transplantation and 14 (29.8%) remain alive and continue to use NIV. 3 patients (6.4%) had NIV withdrawn: one due to bilateral pneumothoraces, one due to abdominal bloating and one due to substantial improvement in blood gas tensions. Median duration of NIV overall was 16 (range 2 90) months. Median time on NIV before transplantation, death or start of data collection was 16 Table 1 Baseline demographics at set-up of NIV. n=47 Mean (SD) unless stated Male n (%) 30 (64%) Age (years) a 29 (16 47) BMI (kg/m 2) 19.7 (3.3) FEV 1 % predicted 20.7 (6.1) ph 7.43 (0.04) po 2 (kpa) 7.63 (1.3) pco 2 (kpa) 6.72 (1.1) HCO 3 (mmol/l) 30.2 (2.4) IPAP (cm H 2 O) 22.5 (4.0) EPAP (cm H 2 O) 2.7 (0.9) Back-up Rate (breaths/min) 15.3 (3.6) Oxygen via NIV (l/min) 1.3 (1.6) Abbreviations: NIV: non-invasive ventilation. SD: standard deviation. BMI: body mass index. FEV 1 : forced expiratory volume in 1 s. po 2 : partial pressure of oxygen. pco 2 : partial pressure of carbon dioxide. HCO 3 : bicarbonate. IPAP: inspiratory positive airway pressure. EPAP: expiratory positive airway pressure. a Median (range). (2 44), 27 (3 90) and 14.5 (3 89) months respectively. Patients who underwent transplantation had a substantially lower FEV 1 % predicted at NIV set-up than those who died on NIV (17.1% vs 24.9%; p = 0.0015). No other statistically significant differences at baseline were seen between these groups. 6 patients (13%) became ventilator-dependent over the course of the study. Of the 47 patients studied, 24 (51.1%) were on the lung transplantation list whilst on NIV. Of those who died whilst on NIV, 9/13 (69.2%) were never on the transplant list. Three of these patients were declined transplantation on the basis of chronic infection with Burkholderia cepacia complex or Mycobacterium abscessus. The remainder were declined or not referred for transplant assessment due to other comorbidities. Of the 14 patients alive and continuing on NIV, 3 (21.4%) are on the transplant list; 6 are not considered as suitable candidates for transplantation; 4 have not yet been referred and 1 was removed from the transplant list due to a substantial improvement in lung function and clinical status following introduction of NIV. 10 patients commenced NIV between 1991 and 2000 compared with 37 patients starting NIV since 2001. The proportion going on to lung transplantation fell from 70% in the first decade to 27% in the second decade with only a further 8% currently on the transplant list. Clinical outcomes before and after initiation of NIV in the whole group are presented in Table 2. The overall trends in mean FEV 1 and FVC are depicted in Fig. 1. FEV 1 fell by a mean of 212 ml (95% CI 137 to 287 ml) over the year before NIV but rose by 18 ml (95% CI 60 to +96 ml) in the following year (p=0.0085). FVC fell by 443 ml (95% CI 265 to 621 ml) in the year before NIV but increased by 69 ml (95%

W.G. Flight et al. / Journal of Cystic Fibrosis 11 (2012) 187 192 189 Table 2 Clinical outcomes before and after initiation of NIV. 3 2 1 NIV set-up +1 +2 +3 P value # No. of patients 29 33 39 47 37 17 12 n/a BMI (kg/m 2 ) 20.1 (2.2) 19.9 (1.9) 19.5 (1.7) 19.7 (3.3) 19.9 (3.0) 20.4 (4.6) 20.5 (5.4) 0.44 FEV 1 (litres) 1.26 (0.5) 1.18 (0.4) 1.05 (0.4) 0.83 (0.3) 0.86 (0.4) 0.92 (0.4) 0.94 (0.5) 0.009 FVC (litres) 2.55 (1.0) 2.33 (0.9) 2.22 (0.9) 1.76 (0.7) 1.87 (0.8) 2.04 (0.8) 2.18 (1.0) 0.006 po 2 (kpa) 8.35 (1.0) 8.54 (1.3) 8.08 (1.3) 7.63 (1.3) 8.65 (1.7) 9.30 (2.3) 8.57 (1.9) 0.053 pco 2 (kpa) 5.23 (0.4) 5.33 (0.6) 5.63 (0.8) 6.72 (1.1) 6.13 (0.8) 6.03 (0.6) 6.62 (1.4) 0.0002 Abbreviations: NIV: non-invasive ventilation. BMI: body mass index. FEV 1 : forced expiratory volume in 1 s. FVC: forced vital capacity. po 2 : partial pressure of oxygen. pco 2 : partial pressure of carbon dioxide. Data presented as mean (standard deviation). # P values represent comparison of changes between year 1 to 0 versus year 0 to +1. P values b0.05 are highlighted in bold. CI 96 to +232 ml) in the subsequent year (p=0.0057). Over the three year period prior to NIV, FEV 1 and FVC fell by a mean of 398 and 658 ml but increased by 43 and 142 ml respectively in the 3 years after NIV (pb0.01 for both values). Blood gas analysis shows an improvement in mean pco 2 from 6.72 kpa to 6.13 kpa at one year post-niv (p=0.0002). There was no significant change in BMI across the study period. There was a non-significant trend towards increased intravenous antibiotic use in the first year after NIV as compared to the year before NIV (median 86 vs 65 days; p=0.102). It is possible that some of the differences in mean lung function data described above could have been due in part to patient drop out over the follow-up period. However, analysis of the 12 patients continuing on NIV for 3 years showed no significant differences in baseline age, lung function, BMI, or pco 2 when compared with those stopping NIV prematurely. Surprisingly, those using NIV for 3 years had a lower po 2 at set-up (6.9 vs 7.9 kpa; p=0.03). Fig. 1. Effect of long-term NIV on mean forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC). Error bars represent standard deviation. * pb0.01. Individual responses to NIV were assessed in the 33/47 patients who had data from both before and after NIV initiation. 24 (73%) patients displayed either an improvement in FEV 1 or a reduction in the rate of decline in FEV 1 following introduction of NIV and were classified as responders. A comparison of baseline characteristics for responders versus non-responders is shown in Table 3 and individual trajectories of FEV 1 for Table 3 1 Baseline characteristics of patients according to response to NIV. Responders a Non-responders P Mean (95% CI) unless stated Mean (95% CI) unless stated value Number of patients 24 9 Age (years) b 28 (17 44) 27 (17 45) 0.7 Male (%) 75 33.3 0.03 NIV set-up post-2001 79 78 0.9 (%) Transplanted (%) 46 22 0.22 Dying on NIV (%) 16.7 66.7 0.005 BMI at NIV set-up 19.3 19.5 0.8 (kg/m 2 ) (18.6 to 20.1) (18.4 to 20.7) FEV 1 % pred. at NIV 19.6 24.7 0.04 set-up (17.1 to 22.1) (20.2 to 29.2) ΔFEV 1 before NIV 195 61 0.006 (ml/year) ( 246 to 146) ( 151 to +33) ΔFEV 1 after NIV +60 218 0.0004 (ml/year) ( 8 to +128) ( 395 to 43) po 2 at NIV set-up 7.50 8.13 0.23 (kpa) (6.99 to 8.02) (6.95 to 9.32) pco 2 at NIV set-up 6.67 6.44 0.5 (kpa) (6.27 to 7.07) (5.91 to 6.96) Abbreviations: NIV: non-invasive ventilation. BMI: body mass index. FEV 1 : forced expiratory volume in 1 s. po 2 : partial pressure of oxygen. pco 2 : partial pressure of carbon dioxide. a Responders defined as patients showing an improvement or reduction in the rate of decline of FEV 1 following initiation of NIV. b Median (range). P values b0.05 are highlighted in bold.

190 W.G. Flight et al. / Journal of Cystic Fibrosis 11 (2012) 187 192 Fig. 2. Trajectory of forced expiratory volume in 1 s (FEV 1 ) before and after NIV for a) responders to NIV (i.e. patients showing an improvement or reduction in decline of FEV 1 ) and b) non-responders to NIV (i.e. acceleration of decline in FEV 1 post-niv). these two groups are given in Fig. 2. Responders to NIV were more likely to be male and significantly fewer died whilst on NIV during the study period (16.7 vs 66.7%; p=0.005). Responders also had a significantly lower FEV 1 % predicted at NIV set-up than non-responders (19.6% vs 24.7%; p = 0.04) and had a steeper rate of FEV 1 decline prior to NIV set-up (195 ml/year vs 61 ml/year; p = 0.006). There was no significant difference in use of intravenous antibiotics in the year following NIV between responders and non-responders (median 88.5 vs 88 days; p=0.37). A variety of ventilators has been used in these patients. The Vivo40 (Breas, Mölnlycke, Sweden) was used in 32%, the NIPPY 1 (B&D Electromedical, Stratford-upon-Avon, UK) in 26% and the VPAP III (ResMed, San Diego, USA) in 19%. Pressure controlled mode was used in 46.8%, pressure support mode in 42.6% and a target volume mode in 10.6%. Mean inspiratory positive airway pressure (IPAP) at set-up was 22.5 (4.0) cm H 2 O. Mean expiratory positive airway pressure (EPAP) was 2.7 (0.9) cm H 2 O. A mean of 1.3 (1.6) l/min of oxygen was entrained through the NIV circuit. All patients used a nasal interface. 4. Discussion Despite widespread adoption of NIV in advanced CF, the evidence base to support its use remains scanty [12]. Patients with end-stage CF have usually exhausted standard medical interventions at the time of initiation of NIV. Placebo-controlled trials of nasal ventilation in established respiratory failure would have substantial ethical and practical difficulties. For this reason, the use of long-term NIV in CF has by necessity been guided by observational data of the kind reported here. Our findings suggest that NIV may slow or reverse the decline in lung function in adults with advanced CF attending our centre. The improvement in spirometry is most marked within the first year of treatment but appears to extend to 3 years of follow-up in those maintained on NIV to this point. Blood gas analysis shows a significant improvement in pco 2 following NIV suggesting an improvement in alveolar ventilation. This may have been achieved through the use of higher inspiratory pressures than those reported by other centres [6,8]. We have demonstrated that response to NIV in advanced CF is variable. No previous study has examined predictors of success with long-term NIV in CF. Amongst our cohort, the majority of patients showed improvements in FEV 1 following NIV although at least 23% experienced further falls in FEV 1 despite NIV. Those responding to NIV appeared to have more severe disease with lower baseline lung function which had been declining more rapidly. A marked gender difference was also seen with more males responding well to NIV. Of particular note is the substantially increased proportion of patients amongst non-responders whose final outcome was death, a difference which was highly statistically significant. The mechanism behind these important differences in response to NIV remains unclear and represents an area for future research. The use of NIV at our centre has undoubtedly increased over the last 20 years. The explanation for this is likely to reflect a combination of increased life expectancy of CF patients, increasing size of the unit (patient numbers have increased from 120 patients in 1990 to 370 in 2010), increased acceptance of NIV by patients due to improvements in mask and interface technology as well as a greater willingness to recommend NIV amongst staff at the unit. It is also apparent from this evaluation of our practice that NIV is being used beyond the traditional scope of a bridge to transplantation. Approximately half of the patients we have treated with long-term NIV were not on the lung transplant waiting list. This group had a median duration of NIV of 16 months with some patients being maintained on nocturnal NIV for over 7 years. Such prolonged survival is at odds with the extreme severity of lung disease in this group: mean FEV 1 %-predicted at set-up of NIV was 23.1% amongst those not on the transplant list. In a clear change in practice, the proportion of patients successfully being transplanted has fallen dramatically over the last 10 years. Specific information on the indication for NIV and symptoms of hypercapnia for individual patients was not available for this cohort. The unit policy for initiation of NIV has been

W.G. Flight et al. / Journal of Cystic Fibrosis 11 (2012) 187 192 191 consistent over the study period, namely: persistent daytime hypercapnia and/or inability to maintain safe oxygenation with controlled oxygen therapy. We define safe oxygenation as achievement of po 2 8 kpa with a rise in pco 2 b1 kpa on administration of supplemental oxygen. Our standard assessment of patients prior to NIV set-up involves overnight oximetry (with the addition of transcutaneous CO 2 monitoring since 2004) followed by early-morning blood gas analysis. We do not perform polysomnography as standard. Prior to 2004, ventilator settings were adjusted in response to repeat overnight oximetry and early-morning blood gases. Our current practice also incorporates titration of NIV pressures in real time in response to transcutaneous CO 2 levels during set-up. The low overall mean EPAP level of 2.7 cm H 2 O in our cohort is partly explained by the 26% of patients treated with the NIPPY1 ventilator which did not allow the application of any EPAP. Other ventilators and masks require a minimum EPAP level to be set which varies according to the device. There is a theoretical risk of rebreathing exhaled CO 2 from the mask if very low EPAP levels are administered but all our patients used nasal interfaces with very little dead space which minimises this risk. Close monitoring of pco 2 levels is advised if full face masks are used. Our use of relatively low levels of EPAP allows us to maximise pressure support whilst keeping inspiratory pressures within the limits of patient tolerability. Patients with end-stage CF lung disease receiving NIV undoubtedly have a high treatment burden and, given the retrospective design of this study, we are unable to provide quality of life data. However, on average patients were able to spend over 75% of the year after starting NIV free from intravenous antibiotics. As suggested by Madden et al. previously [9], NIV does not seem to be merely prolonging the terminal phase of CF lung disease but does appear to be increasing longevity in our patients. In this regard, prospective quality of life data in future studies of long-term NIV would be enlightening. NIV appears to be well tolerated in this group with a very low withdrawal rate of just 2/47 patients due to adverse effects. The high rate of continued NIV use was observed despite the use of relatively high inspiratory pressures. Our cohort overall has been treated with NIV for a median duration of 16 months, substantially longer than mean durations of 1.5 5.1 months reported in previous observational studies [6,9]. Given a median waiting time for lung transplantation of 519 days in the UK [13], the long-term efficacy and acceptability of NIV is clearly of crucial importance for those patients under consideration for transplantation. Our study is limited in several regards. Firstly, the retrospective nature of the study, small numbers and lack of a control group restrict our ability to demonstrate conclusively a benefit from NIV alone. Similarly, our findings cannot be generalised to the wider CF population. It is difficult to completely exclude premature drop-out of patients as a cause of change in mean lung function across the study period but the similarities in baseline lung function, BMI and hypercapnia of patients continuing to 3 years compared with premature drop-outs argue against this explanation. These results suggest that the observed improvements in lung function and blood gases are not due to bias from the sickest patients dying or being transplanted early in the follow-up period. It must be acknowledged that there was a trend to slightly higher use of intravenous antibiotics in the year after NIV but this was not statistically significant and is insufficient to explain the changes in lung function observed. The patients in our study all received intensive therapy for their respiratory failure including physiotherapy, antibiotics, nebulised medication, treatment of concomitant diabetes and nutritional support. These standard aspects of CF care were pursued throughout the study period, suggesting that the improvements in lung function we have seen are indeed related to the use of NIV. A further weakness of our study is the variable record of acid base data for individual patients. Blood gases were taken at different times of day and on a mixture of air, supplemental oxygen and NIV which makes interpretation of the data challenging. Furthermore, it is hard to ascertain to what degree metabolic alkalosis, a recognised phenomenon in CF [14], contributes to hypercapnia in these patients. The mean ph of 7.43 and bicarbonate of 30.2 mmol/l at set-up argue against a predominant role for metabolic alkalosis in our cohort. It is due to these uncertainties over the blood gas data that we have focused on changes in FEV 1, rather than pco 2, in this study as we feel that the spirometry data is much more robust. However, NIV does appear to lead to a small but genuine improvement in control of hypercapnia at 12 months of follow-up. Finally, we have a limited record of adherence to NIV in terms of hours of use per 24-hour period. The cohort includes both patients who were 24-hour dependent on NIV and others who just used their NIV overnight. It has been the policy of the unit to remove ventilators from those patients who persistently do not use the therapy and this has occurred in just one case over 20 years. Allowing for these limitations, long-term NIV appears to slow the decline in lung-function in patients with advanced CF attending our centre. The prolonged survival and improvement in lung function in those not suitable for lung transplantation suggests that NIV has a role in maintaining lung health in advanced CF. The use of long-term NIV at our centre has moved beyond a mere bridge to transplantation. Large, multicentre prospective studies are now required to clarify the effects of NIV in CF and to determine the optimum timing of initiation of NIV in relation to oxygen and other pulmonary therapies. We share our experiences in the hope of re-opening a debate within the CF community as to the future role of positive pressure ventilation in advanced CF. Conflicts of interest and funding The authors have no conflicts of interest relevant to this study to declare. No external funding was received for this study. Acknowledgements The authors would like to thank the staff of the Manchester Adult CF Centre and the Long-term Ventilation Service at the

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