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Long‐term non‐invasive ventilation in cystic fibrosis: A bridge too far?

Domiciliary bilevel non-invasive ventilation (NIV) has evolved to treat hypoventilation in a variety of obstructive and restrictive lung diseases resulting in improved clinical outcomes. Although used widely in cystic fibrosis (CF), often as a bridge to transplantation, there is limited evidence for long-term clinical benefit in this population. In a recent publication in Respirology, the longest randomized trial of NIV in CF reports significant clinical benefits in a group of adults with nocturnal oxygen desaturation. Milross et al. randomized adult CF patients with nocturnal oxygen desaturation on polysomnography (defined as total sleep timeminimumaverage SpO2 < 90%) to nocturnal NIV or oxygen therapy over a 12-month period. Patients with an awake PaCO2 > 60 mm Hg on arterial blood gases were excluded. Participants had severe lung disease, but overall only borderline awake hypercapnia (mean PaCO2 45 mm Hg). NIV therapy resulted in an improved ‘event-free survival’ at 3 and 12 months, which was defined as no worsening hypercapnia (PaCO2 > 60 mm Hg, increase in PaCO2 > 10 mm Hg from baseline, increase in TcCO2 > 10 mmHg overnight), lung transplantation or death. However, lung function, arterial blood gases, hospitalization and quality of life were not affected. The strengths of the study include the prospective, randomized design, duration of treatment and use of overnight polysomnography to titrate NIV and oxygen therapy. The authors acknowledge the study was underpowered due to difficulty recruiting over a 12-year period (total of 29 participants) and adherence data for NIV and oxygen therapy were unreliable. Cystic fibrosis registry data indicate that NIV usage appears to be increasing. Whilst there is limited evidence that NIV may improve lung function, nocturnal hypoventilation and exercise capacity there is a lack of longer term or survival data. The current study is significant in this context and adds to the overall body of evidence supporting the use of NIV. However, it is interesting to note that nocturnal oxygen desaturation was used as the entry criteria and patients overall had only borderline hypercapnia. The purported mechanism of NIV is to improve alveolar hypoventilation and reduce hypercapnia, however this is less effective in treating hypoxia in the acute setting. So further consideration will be needed to understand the mechanism of this effect, and a re-appraisal of the indications for use of NIV in CF will be required if we adopt the PSG criteria suggested by Milross et al. Despite the finding of improved outcomes in this study, recent UK registry data are somewhat at odds, indicating that NIV in CF might improve spirometric values without showing benefit in survival. However, this comparison highlights the difficulties in comparing an intervention study with earlier-stage entry criteria to overall NIV usage in a large population. Registry subjects may well have been entered late, with established hypercapnia and limited options for treatment. Looking forward, the role of NIV is likely to be impacted by the new wave of modulator therapy that is altering the natural history of the disease. This may delay the need for initiation of NIV making it even more difficult to undertake large, randomized, controlled studies of sufficient duration to study longterm clinical outcomes. The current study by Milross helps to address some of these important questions but also opens up many more avenues for further investigation.