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CYSTIC FIBROSIS |
1 Department of Allergy Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria, Australia
2 Department of Medicine, Monash University, Melbourne, Victoria, Australia
Correspondence to:
Dr A C Young, Department of Allergy Immunology and Respiratory Medicine, The Alfred Hospital, Commercial Rd, Prahran, Melbourne, VIC, 3181, Australia; alan.young{at}med.monash.edu.au
Received 11 April 2007
Accepted for publication 2 July 2007
 | ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Methods: In a randomised, placebo controlled, crossover study, eight subjects with CF, mean (SD) age 37 (8) years, body mass index 21.1 (2.6) kg/m2, forced expiratory volume in 1 s 35 (8)% predicted and PaCO2 52 (4) mm Hg received 6 weeks of nocturnal (1) air (placebo), (2) oxygen and (3) NIV. The primary outcome measures were CF specific QoL, daytime sleepiness and exertional dyspnoea. Secondary outcome measures were awake and asleep gas exchange, sleep architecture, lung function and peak exercise capacity.
Results: Compared with air, NIV improved the chest symptom score in the CF QoL Questionnaire (mean difference 10; 95% CI 5 to 16; p = 0.002) and the transitional dyspnoea index score (mean difference 3.1; 95% CI 1.2–5.0; p = 0.01). It reduced maximum nocturnal pressure of transcutaneous CO2 (PtcCO2 mean difference –17 mm Hg; 95% CI –7 to –28 mm Hg; p = 0.005) and increased exercise performance on the Modified Shuttle Test (mean difference 83 m; 95% CI 21 to 144 m; p = 0.02). NIV did not improve sleep architecture, lung function or awake PaCO2.
Conclusion: 6 weeks of nocturnal NIV improves chest symptoms, exertional dyspnoea, nocturnal hypoventilation and peak exercise capacity in adult patients with stable CF with awake hypercapnia. Further studies are required to determine whether or not NIV can improve survival.
Nocturnal non-invasive bi-level positive pressure ventilation (NIV) is beneficial for stable daytime hypercapnia due to kyphoscoliosis, neuromuscular disease and chronic obstructive pulmonary disease (COPD).6 Studies utilising NIV in CF have demonstrated improved gas exchange and reduced work of breathing during a single overnight session,3 4 and improved oxygenation during physiotherapy.5 7 Uncontrolled non-randomised studies suggest that NIV may bridge hypercapnic CF patients to lung transplantation.8–10 Potential complications of NIV include sleep fragmentation and drying of secretions with decreased sputum clearance. A recent Cochrane review highlighted the need for randomised controlled trials to assess the clinical effects of NIV in CF.11
We hypothesised that nocturnal NIV would improve QoL, functional and physiological outcomes in subjects with stable CF with impaired nocturnal gas exchange and daytime hypercapnia. Our aim was to perform a randomised placebo controlled trial of nocturnal NIV in these "at risk" subjects with CF to assess the effects on QoL, and functional and physiological outcomes. Some of the results of these studies have been reported previously in the form of an abstract.12
| METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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70% predicted, clinical stability (no hospitalisation or new antibiotics 2 weeks prior), positive screening overnight oximetry (SpO2 <90% for 
5% of the night), impaired gas exchange on polysomnography (SpO2 <90% for 5% of total sleep time and/or rise in pressure of transcutaneous CO2 (PtcCO2) 5 mm Hg non-rapid eye movement (NREM) to rapid eye movement (REM) sleep) and awake hypercapnia (PaCO2 >45 mm Hg). Exclusion criteria were: previous domiciliary oxygen (O2) or NIV, current sedative use, cardiac or neurological disease and obstructive sleep apnoea.
Study design
The trial design was randomised placebo controlled crossover. Each subject received 6 weeks of nocturnal (1) air (placebo), (2) O2 and (3) NIV in random order separated by a 2 week washout period. Data were collected at baseline and at the end of each treatment period (fig 1). Treatments were commenced, and post-treatment assessments were carried out during a period of clinical stability (defined as no current need for hospitalisation or intravenous antibiotics).
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5 mm Hg from NREM to REM sleep, expiratory positive airway pressure was increased in 1 cm H2O increments to eliminate any obstructive events, a backup rate was added if the patient failed to trigger the ventilator. Oxygen therapy was not added to NIV as the hypothesis being tested was that NIV alone would improve outcomes. The 6 weeks of O2 therapy was delivered from an O2 concentrator (Elite; AirSep, New York, USA) via nasal cannulae. At commencement, therapy was titrated using overnight oximetry. O2 was increased in 1 l/min increments to maintain SpO2 >90% for the entire night. The 6 weeks of air (placebo) was delivered through a disabled O2 concentrator and the flow rate was increased from 1 to 2 l/min during a sham "titration" session with overnight oximetry. Thus patients remained blinded as to whether they were receiving O2 or air. NIV and concentrator hours of usage for the entire treatment period were recorded.
Primary outcome measures
Validated QoL measures assessed CF specific domains (CF QoL Questionnaire),13 sleepiness (Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index)14 15 and dyspnoea (Medical Research Council Dyspnoea Scale, Baseline and Transitional Dyspnoea Index).16 17 A priori, four domains of the CF QoL were selected (physical functioning, treatment issues, chest symptoms, emotional responses) based on our clinical experience of symptoms that might be expected to improve with nocturnal NIV. The CF Subjective Sleep Disturbance Questionnaire was developed inhouse and assessed six subjective symptoms of sleep disturbance. We have previously reported an association between higher/worse scores and nocturnal hypoxia in the form of an abstract.12 Subjects were asked "which treatment was most comfortable?" and "which treatment would you prefer to continue?" at study end.
Secondary outcome measures
PSG (Compumedics E-series, Abbottsford, Australia) was manually scored, blinded to the patient’s treatment, using standard criteria. Spirometry and lung volumes (Profiler and Elite Series, Medgraphics, Minnesota, USA) meeting American Thoracic Society criteria, awake supine arterial blood gases (model 865; Bayer HealthCare, New York, USA) and the validated Modified Shuttle Test18 were performed.
Neurocognitive testing was performed at the same time of day after abstinence from caffeine and alcohol. The Psychomotor Vigilance Task,19 Stroop Color and Word Test,20 Trail Making Test,21 Controlled Oral Word Association Test22 and Digit Span Test23 were undertaken (see online data supplement for further information regarding subjects, study design, interventions and outcome measures).
Statistics
Results are presented as mean (SD). Analysis was performed using SAS V.8.2 (SAS Institute Inc, North Carolina, USA). Data were analysed as difference from baseline. A repeated measures analysis of variance or Freidman two way analysis of variance assessed differences between treatments, with a two sided p value of 0.05 considered significant. Where a significant difference was identified, the paired t test or Wilcoxon signed rank test was used for post hoc analysis, with a p value of 0.017 considered significant to adjust for multiple comparisons. Assuming an SD of 15 points for the physical function domain of the CF QoL,24 a sample size of 18 subjects was needed to demonstrate a 10 point improvement (clinically important difference)1 in mean score with treatment, with a power of 0.8 and a two sided 
of 0.05.
| RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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The group (n = 8) mean age was 37 (8) years with a body mass index (BMI) of 21.1 (2.6) kg/m2 and FEV1 35 (8)% predicted. There was evidence of gas trapping (residual volume/total lung capacity ratio 59 (8)%), chronic hypercapnia (pH 7.39 (0.02), PaCO2 52 (4) mm Hg) and moderate hypoxaemia (arterial oxygen pressure (PaO2) 63 (5) mm Hg). Compared with patients who were randomised, the five patients declining participation had similar FEV1 (27 (9)% predicted), BMI (18.0 (2.9) kg/m2) and PaO2 (60 (5) mm Hg). However, they were younger (24 (5) years) with a milder degree of chronic hypercapnia (PaCO2 47 (4) mm Hg) (table 1).
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Quality of Life questionnaires
NIV significantly increased the chest symptom score in the CF QoL (mean difference 10; 95% CI 5 to 16; p = 0.002) and the Transition Dyspnoea Index (TDI) total score (mean difference 3.1; 95% CI 1.2–5.0; p = 0.01) compared with air. Six of seven patients who tolerated NIV increased their chest symptom score by 5 points (range 5–20) compared with air, and five patients increased their TDI by 2 points (range 2–9). There were no significant changes in these parameters with air or supplemental O2. There were no changes with any therapeutic manoeuvre in the other QOL measures (CF Subjective Sleep Disturbance Questionnaire, Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Medical Research Council Dyspnoea Scale) (table 2).
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Polysomnography, arterial blood gases, lung function, exercise testing
At baseline, sleep efficiency (86 (6)%), sleep latency (20 (23) min) and distribution of sleep stages were normal (table 3). However, there was significant nocturnal hypoxia (38 (43)% total sleep time with SpO2 <90%), hypercapnia (mean PtcCO2 58 (3) mm Hg, maximum PtcCO2 68 (12) mm Hg), tachypnoea (mean respiratory rate during slow wave sleep 23 (6) breaths/min) and tachycardia (mean heart rate 78 (15) beats/min) (table 4).
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tables 4, 5). Furthermore, NIV produced a significant increase in shuttle distance (mean difference 83 m; 95% CI 21 to 144 m; p = 0.016) compared with air (table 5). Six of seven patients who tolerated NIV increased their shuttle distance by 50 m (range 50–160) compared with air.
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Adverse effects
There were no significant side effects with air or O2 therapy. One patient developed a spontaneous pneumothorax while on air which was considered to be coincidental. Two patients complained of aerophagia with NIV which resolved with a reduction in IPAP by 2 cm H2O. There was no significant skin breakdown related to mask usage. No patients reported any worsening of mucus plugging or drying of secretions with NIV.
| DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Our findings are consistent with published NIV data in CF on several levels. Our NIV tolerance rate of 87.5% (seven out of eight patients) was similar to the 62–83% seen in medium term observational NIV studies 25 26 in CF. Our ventilator measured compliance was 4.3 h per night. Attenuation of the rise in PtcCO2 with NIV and worsening of PaCO2 with O2 therapy has been reported in single overnight sessions in CF.3 4 A meaningful improvement in dyspnoea score was reported in three of eight subjects during a 2 month trial with NIV.26 We demonstrated an increase in TDI of 3.1 units with NIV compared with placebo, which exceeds the minimally important clinical difference of 1 unit for this test.27 Five of seven subjects (71%) improved their TDI by a margin of 2 points demonstrating that the majority of subjects experienced a significant improvement.
We were unable to demonstrate a fall in awake hypercapnia with NIV, despite a sustained reduction in nocturnal CO2 levels. Uncontrolled studies of NIV in CF have shown a reduction in daytime PaCO2,25 but results have been conflicting.26 Our results may be due to a type II error, low levels of IPAP or a short treatment period with mild baseline hypercapnia. Patients underwent rigorous in-lab titration of IPAP and checking for mask leaks. Aerophagia was seen in two patients, indicating that higher pressures were not likely to be tolerated. Our protocol duration of 5 months was chosen to maximise recruitment, minimise dropouts as a result of lung transplantation and decrease baseline fluctuations which can weaken a crossover study.
This is the first study to demonstrate an improvement in exercise performance using nocturnal NIV in CF. Compared with placebo, NIV increased mean shuttle distance by 83 m, which exceeds the 40 m cut-off representative of a significant improvement in exercise performance.28 Six of seven subjects (86%) improved their shuttle distance by 50 m which is considerable given this is an incremental test. It is important to note that some of this difference was explained by a fall in exercise capacity while on placebo, as the absolute increase in mean shuttle distance from baseline with NIV was 25 m. A possible explanation is that NIV prevented the deterioration in exercise capacity seen with placebo. However, this hypothesis requires further study before any firm conclusions can be drawn.
Exercise performance with NIV has rarely undergone objective assessment in previous studies. Improvements in dyspnoea and exercise performance have been observed in COPD with the application of nocturnal, daytime and exercise NIV.29–31 In CF, improved muscle strength and oxygenation during chest physiotherapy has been achieved with the addition of inspiratory pressure support.7 The mechanism is likely to relate to improved gas exchange due to a reduction in the work of breathing. In CF patients with severe lung disease, NIV reduces diaphragmatic work while awake32 33 and improves alveolar ventilation while asleep.4 We postulate that unloading of the respiratory muscles overnight leads to the improved exercise capacity during the day. However, this concept requires further investigation. We found no improvement in lung function or nutritional status to account for these improvements. However, measurement of exercise flow volume loops and inspiratory capacity could further assess changes in lung mechanics. The importance of this finding cannot be underestimated as peak exercise capacity is an independent predictor of survival in both adults and children with CF.34 35
There was a strong trend towards a fall in mean nocturnal heart rate with NIV suggesting improved sympathovagal balance during sleep. A reduction in tachycardia is used clinically as a measure of success with NIV during acute exacerbations of COPD. Whether heart rate could be used as a marker of nocturnal work of breathing in CF remains untested.
The main strengths of this study were the inclusion of a placebo arm, random allocation of treatment order, the crossover design and objective assessment of treatment adherence. The crossover design increased the power of the study and matched baseline characteristics, which are major difficulties associated with clinical trials in CF. Nevertheless, the sample size limits further interpretation of our study and introduces the possibility of type II errors (ie, erroneously concluding no difference exists when one really does). In this context, our positive results are encouraging, given we corrected for multiple comparisons in statistical analysis to minimise type I errors (ie, erroneously concluding a difference when none exists). In addition, there was little more that could be done to increase recruitment. We are a large adult centre with 250 patients and we screened a significant proportion of our population. Most patients who declined participation cited time constraints and unwillingness to undergo multiple sleep studies and arterial blood gas measurements. This highlights the difficulty of powering studies with invasive and time consuming outcome measures in CF patients with advanced disease. Our study is of comparable size to published uncontrolled studies of NIV in CF.9 10 25 26
A potential weakness of the crossover design is a change in baseline characteristics over the study period due to deteriorating health, exacerbations or carry over effects from treatment. Ideally, reassessment (eg, QoL questionnaires, lung function testing) at the start of each treatment period could have been performed but, as alluded to previously, would have been extremely onerous for patients already undertaking multiple investigations. We attempted to address these issues by ensuring clinical stability at the start and end of each treatment period and incorporating a 2 week washout period in the study design. The absence of change in lung function with any treatment argues against pulmonary exacerbations being the explanation for the observed differences. However, we cannot be certain that some of the observed changes were not due to changes in underlying disease status or carry over effects from treatment.
In conclusion, we have shown that 6 weeks of nocturnal NIV can significantly improve nocturnal hypoventilation, chest symptoms, exertional dyspnoea and peak exercise capacity in CF subjects with daytime hypercapnia. However, there is a need for larger multicentre trials to further extend these findings, clarify which subgroups may benefit most and, in particular, determine whether NIV can improve survival.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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Published Online First 2 August 2007
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This article has been cited by other articles:
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  P. G Noone Non-invasive ventilation for the treatment of hypercapnic respiratory failure in cystic fibrosis Thorax, January 1, 2008; 63(1): 5 - 7. [Full Text] [PDF]
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