Initial reports of noninvasive ventilation (NIV) use in cystic fibrosis (CF) patients were as a short-term bridge to transplantation in patients with end-stage lung disease . NIV has since become an established intervention for the management of symptomatic chronic ventilatory failure in such patients [2,3]. Its role outside transplant-listed patients is not yet fully established, although clinical experience in some centres supports its use in those not suitable for transplantation with patients remaining stable on NIV for many years . In other lung diseases, both knowledge and experience of NIV has evolved and created a climate of innovation with respect to technical features of ventilators and interfaces, which in turn may influence future treatment options within CF . This review will focus on studies using NIV in CF patients, NIV modalities, interfaces and recent technical advances. NIV use with nebulization, with exercise and as a physiotherapy adjunct, is outside the scope of this review.
DEFINITION AND TERMINOLOGY
In CF, NIV is used most frequently to deliver respiratory support to correct ventilatory failure. It augments minute ventilation, reduces the work of breathing and rests the respiratory muscles. A nose or face mask allows flexible ventilation; individuals can use it just at night, for part of the day in addition, or for 24 h as indicated by clinical status. Normal mechanisms for airway clearance, nutrition and communication are maintained. It can be provided at the bedside within a normal ward and therefore has many advantages over invasive ventilation.
NIV can be delivered using either a pressure or a volume preset ventilator. Pressure preset systems use an inspiratory positive airway pressure (IPAP) to augment inspiratory effort enhancing tidal volume and decreasing inspiratory muscle load. The majority of machines can also deliver an expiratory positive airway pressure (EPAP). Depending on the exhalation system, EPAP may be required to flush exhaled carbon dioxide (CO2) through the exhalation port to prevent rebreathing. It may also stabilize the upper airway during sleep, recruit alveoli and decrease microatelectasis. It is synonymous with the term positive end-expiratory pressure (PEEP).
There are two fundamental modes of pressure-preset ventilation. In pressure support mode, breaths are triggered and cycled by the patient with a backup rate set if the patient fails to trigger the machine for a predetermined time. In pressure control mode, each breath once triggered is delivered for a preset time, regardless of patient effort with backup rate as for pressure support. As ventilator technology has developed, many additional refinements have been introduced, often individual to manufacturers.
Volume preset ventilators deliver a set tidal volume and were employed in most of the early studies of NIV. These machines deliver a constant tidal volume in the face of changing airways resistance and lung compliance. In recent years, the use of pressure preset machines delivering a set airway pressure (but variable volume) has taken over as they offer better leak compensation and maximal IPAP can be set protecting the airways from high peak pressures . Some modern machines can now deliver either preset volume or pressure.
Terminology of NIV can be confusing, and for the purpose of this review, we will use term NIV rather than noninvasive positive pressure ventilation or names of individual ventilators, such as BiPAP (Respironics Inc., Murrysville, Pennsylvania, USA) or Nippy (B&D ElectroMedical, Stratford-upon-Avon, Warwickshire, UK).
CYSTIC FIBROSIS NONINVASIVE VENTILATION DATA
Over the past 2 decades, a number of studies have demonstrated benefits of NIV therapy in CF patients. However, all the reported data of NIV use in CF patients involve only small patient numbers.
Decreased respiratory neuromuscular output during sleep is thought to predispose CF patients to nocturnal hypoventilation before daytime respiratory failure becomes evident . It has been postulated in CF that as forced expiratory volume in 1 second (FEV1) falls, there is increased respiratory muscle load and work of breathing. The increase in load is predominated by a decrease in lung compliance rather than an increase in total pulmonary resistance or intrinsic PEEP. As a result, patients develop a compensatory mechanism of rapid shallow breathing pattern in an attempt to reduce the increased load. Although this breathing strategy may result in oxygenation being maintained, the partial pressure of carbon dioxide (PCO2) rises, providing a physiological rationale as to why CF patients may be ideal candidates for NIV . NIV will increase tidal volume, reduce respiratory rate and reduce muscle load.
In 1989, Zinman et al. were unable to demonstrate any benefit from the addition of nocturnal oxygen (O2) therapy in 28 hypoxic, but stable, CF patients in any of the variables studied including mortality over 3 years. Reports of NIV use in CF clinical practice began in 1991 when Hodson et al. reported six CF adult patients in whom NIV was used as a bridge to transplantation with a trend for survival to transplant. Piper et al. subsequently described four CF patients maintained on domiciliary NIV for up to 18 months and reported improved blood gases, sleep quality, daily activities and possibly respiratory muscle strength. Three subsequent randomized controlled trials have demonstrated the potential benefits of NIV in CF. Gozal  compared nocturnal O2 with NIV (randomized to one night of each) in six CF patients who had significant nocturnal desaturation. O2 therapy was associated with significant increases in transcutaneous CO2 tension, whereas NIV prevented sleep-induced hypoxia without modification of sleep quality and efficiency and improved alveolar ventilation during all sleep states . Milross et al. compared sleep on air, low flow O2 and NIV in 13 CF patients and identified hypoventilation in rapid eye movement (REM) sleep with both air and O2 groups which was attenuated by NIV. The authors concluded that overcoming REM hypoventilation with NIV over a long period may be important in delaying onset of awake hypoxaemia and hypercapnia, both of which are poor prognostic markers for survival in CF . A subsequent longer term randomized crossover trial of nocturnal NIV, O2 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 .
To date, no study has examined survival benefits of NIV in CF. Retrospective examination of data on 47 adult CF patients receiving NIV between 1991 and 2010 at our centre demonstrated a median duration of NIV use of 16 months (range 2–90), with NIV being used in a domiciliary setting. Half of the patients studied were not on the transplant list, and NIV appeared to slow the rate of decline in lung function . The treatment burden is, however, high and no study has examined quality of life of patients on long-term NIV.
MACHINES AND INTERFACES
For NIV to be successful, optimal ventilator settings and patient selection are essential.
Choosing the optimal ventilator in clinical practice is extremely difficult. In-depth understanding of the properties of each ventilator and careful clinical bedside assessment are required. Bench studies evaluating and comparing performance provide some insight into the potential differences between ventilator models, but variable experimental settings prevent firm conclusions . The different variables which need to be considered include the following.
Face masks, nasal masks and mouthpieces are all available to use. Nasal interfaces are the most appropriate for CF patients. They interfere less with speech and oral intake, allow cough and expectoration and are less likely to cause gastric distension . A randomized controlled trial has demonstrated that nasal pillows can be as effective as face masks in reducing PCO2. In addition to the advantages described above, they are quick and easy to fit and remove, they provide no nasal bridge pressure and leave the field of vision free. Mouthpiece ventilation has not been studied in CF patients.
Most commonly, O2 is entrained into the NIV circuit. This provides a variable oxygen concentration, depending on the oxygen injection site, varying inspiratory and expiratory pressures and the type of exhale valve or leak [18▪]. Some NIV machines now provide air-oxygen blenders for precise oxygen concentration regulation, irrespective of these variables. Further investigation into the clinical impact of this development is required, but it is an important option which could prove most useful on an individual patient basis, particularly when maintenance of stable oxygenation proves to be difficult.
NIV delivers air of relatively low humidity which can be increased by heated humidification . In CF heated humidification is always required to prevent the adverse effects of cool dry gases on the airways epithelium .
Changing lung compliance and inspiratory muscle effort have been shown in bench tests to affect intraventilator and interventilator performance in intensive-care ventilators. Such information suggests that one ventilator may not suit all patients, nor may one ventilator provide optimal ventilation in individual patients as their clinical status changes and underlines the importance of regular clinical evaluation .
A wide variation in ventilator performance in different leak scenarios has been demonstrated during both NIV and invasive ventilation. Ventilators may perform better in situations of decreasing rather than increasing leak and with lower rather than higher levels of EPAP [22▪▪].
Asynchrony between patient and ventilator has been shown to contribute to fatigue, dyspnoea and discomfort in ventilated patients. It is a common problem in NIV, but whether the frequency of asynchrony is a reflection of illness severity or is a contributing factor to illness severity requires future investigation. Increased leak and levels of pressure support are factors associated with a greater degree of asynchrony .
Common types of asynchrony and their potential causes have been identified including the following.
Missed trigger: related to leak, inappropriate sensitivity setting, respiratory muscle weakness, diminished drive, dynamic hyperinflation or a combination.
Auto triggering (breaths delivered in the absence of patient effort): secondary to leaks or inappropriate sensitivity setting.
Premature cycling: related to inspiratory time mismatch.
Late cycling: possibly related to a rise time which is too slow.
Some ventilators have technology capable of automatically adjusting the triggering and cycling mechanisms during pressure support ventilation. In clinical practice, this may have an important influence on the numbers of asynchronous events and/or patient comfort .
INITIATION OF NONINVASIVE VENTILATION
Initiation of NIV should take place during the day as follows:
- pre and post earlobe blood gas measurement
- real-time transcutaneous CO2 and oxygen saturation (SpO2) measurement
- respiratory rate
- tidal volume, minute ventilation and leak
- work of breathing and patient comfort
- how to switch ventilator on/off
- mask choice; usually nasal interface, application and removal
- how to speak, cough and expectorate, attend to activities of daily living
- oxygen requirement when not on NIV
- ongoing assessment:
- overnight oximetry and/or transcutaneous CO2
- early morning blood gases (sleeping)
- realistic daily ventilation plans agreed and supported
- regular re-evaluation
- review parameters, for example, pressure support vs. pressure control mode, inspiratory time, rise time, backup rate.
From a practical perspective, it is important that NIV is initiated in a controlled ward environment, usually supported by staff familiar to the patient. Successful ventilation requires skilled introduction, careful physiological monitoring, education of the patient and ward nursing staff, time and support. As clinical status changes, re-evaluation is needed. It should be remembered that optimal ventilation may not be achieved by one ventilator brand throughout the disease course, and so ventilator and interface options should be available. Prior to initiation and on subsequent re-evaluation, there should be clear individualized goals of treatment, for example, normalization of nocturnal CO2, or adequate oxygenation without concomitant elevation of nocturnal CO2. This approach should ensure that adequate levels of pressure support are used to optimize ventilation and potentially influence clinical stability . Longer-term considerations include systems for support, servicing and maintenance 365 days a year; number of ventilators required with a backup machine needed if regular NIV use approaches 16 h per day, and if dependence increasing requirement for battery backup during transport or in the case of power failure.
Data suggest that individuals who are normocapnic in the day, but hypercapnic at night, without hypoxia during an acute exacerbation have a worse 3-year outcome in terms of survival or requirement for transplantation . Whether this could be influenced by use of NIV is unknown and warrants further investigation, but may represent an earlier indication for NIV with important clinical benefit.
There is little understanding of what it is like to experience NIV from the perspective of people living with CF in whom treatment burden is already high and mean daily treatment time is 108 (standard deviation 58) min . It is important to be able to contrast the efficacy of new indications for NIV with its burden on the patient before any change to routine practice can be recommended.
There are currently no studies exploring the role of short-term NIV use in CF patients with acute respiratory exacerbations.
NIV is now an established treatment for CF patients in respiratory failure. Although CF data combined with recent technical advances may theoretically support its extended use, multicentre prospective studies using modern equipment are needed to determine the optimum timing of initiation and long-term effects of NIV and the burden of this treatment also needs to be considered. Understanding the causes of inadequate ventilation and having a range of ventilators available with different properties may improve clinical outcomes and facilitate future CF NIV practice.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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