Non-invasive ventilation for cystic fibrosis

  • Review
  • Intervention

Authors

  • Fidelma Moran,

    Corresponding author
    1. University of Ulster, Institute of Nursing and Health Research and School of Health Sciences, Newtownabbey, Northern Ireland, UK
    • Fidelma Moran, Institute of Nursing and Health Research and School of Health Sciences, University of Ulster, Shore Road, Newtownabbey, Northern Ireland, BT37 0QB, UK. f.moran@ulster.ac.uk.

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  • Judy M Bradley,

    1. University of Ulster, Centre for Health and Rehabilitation Technologies (CHaRT), Institute of Nursing and Health Research, Newtownabbey, Northern Ireland, UK
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  • Amanda J Piper

    1. Royal Prince Alfred Hospital, Department of Respiratory and Sleep Medicine, Camperdown, NSW, Australia
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Abstract

Background

Non-invasive ventilation may be a means to temporarily reverse or slow the progression of respiratory failure in cystic fibrosis.

Objectives

To compare the effect of non-invasive ventilation versus no non-invasive ventilation in people with cystic fibrosis.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We searched the reference lists of each trial for additional publications possibly containing other trials.

Most recent search: 22 February 2013.

Selection criteria

Randomised controlled trials comparing a form of pressure preset or volume preset non-invasive ventilation to no non-invasive ventilation in people with acute or chronic respiratory failure in cystic fibrosis.

Data collection and analysis

Three reviewers independently assessed trials for inclusion criteria and methodological quality, and extracted data.

Main results

Fifteen trials were identified; seven trials met the inclusion criteria with a total of 106 participants. Six trials evaluated single treatment sessions and one evaluated a six-week intervention.

Four trials (79 participants) evaluated non-invasive ventilation for airway clearance compared with an alternative chest physiotherapy method and showed that airway clearance may be easier with non-invasive ventilation and people with cystic fibrosis may prefer it. We were unable to find any evidence that NIV increases sputum expectoration, but it did improve some lung function parameters.

Three trials (27 participants) evaluated non-invasive ventilation for overnight ventilatory support, measuring lung function, validated quality of life scores and nocturnal transcutaneous carbon dioxide. Due to the small numbers of participants and statistical issues, there were discrepancies in the results between the RevMan and the original trial analyses. No clear differences were found between non-invasive ventilation compared with oxygen or room air except for exercise performance, which significantly improved with non-invasive ventilation compared to room air over six weeks.

Authors' conclusions

Non-invasive ventilation may be a useful adjunct to other airway clearance techniques, particularly in people with cystic fibrosis who have difficulty expectorating sputum. Non-invasive ventilation, used in addition to oxygen, may improve gas exchange during sleep to a greater extent than oxygen therapy alone in moderate to severe disease. These benefits of non-invasive ventilation have largely been demonstrated in single treatment sessions with small numbers of participants. The impact of this therapy on pulmonary exacerbations and disease progression remain unclear. There is a need for long-term randomised controlled trials which are adequately powered to determine the clinical effects of non-invasive ventilation in cystic fibrosis airway clearance and exercise.

Plain language summary

Mechanical lung inflation and deflation via face mask to aid breathing and sputum clearance, reduce respiratory failure and improve exercise tolerance

As cystic fibrosis worsens, breathing can become difficult. This indicates the start of respiratory failure, where there is too much carbon dioxide and not enough oxygen in the blood. As respiratory failure progresses people may also have problems clearing sputum. Respiratory failure eventually results in death. This review includes seven trials. Six short-term trials showed that non-invasive ventilation can improve a range of breathing and gas exchange measures and ease sputum clearance. One longer-term trial showed that non-invasive ventilation is effective, safe and acceptable as overnight ventilation. When used with oxygen, non-invasive ventilation may improve gas exchange during sleep more than oxygen therapy alone. We found some evidence to support the use of non-invasive ventilation in addition to other airway clearance methods in people with cystic fibrosis. We were not able to find any evidence that non-invasive ventilation improves life expectancy. Further research needs to show whether non-invasive ventilation should be used in exercise training in severe disease.

Background

Description of the condition

Cystic fibrosis (CF) is the most common life-threatening autosomal recessively inherited disease in Caucasian populations, with a carrier rate of 1 in 25 and an incidence of 1 in 2,500 live births (CF Foundation 2006). Although this is a multisystem disease, the primary cause of death in CF is respiratory failure. Respiratory failure can be defined as the inability to maintain adequate gas exchange and is characterised by abnormalities of arterial blood gas tensions (BTS 2002).

In CF, severe airway obstruction and inflammatory bronchiectatic processes results in sputum retention, an increase in breathlessness, hyperinflation, ventilation perfusion mismatch, a decrease in respiratory muscle strength, and an inability to maintain arterial oxygenation within normal limits. When this occurs, reflex hypoxic vasoconstriction results in elevation of the blood pressure within the pulmonary circulation, right ventricular strain and, eventually, cor pulmonale.

Description of the intervention

With non-invasive mask ventilation, positive pressure ventilatory assistance can be delivered in the form of inspiratory pressure support (pressure pre-set) systems which deliver a variable volume according to a pre-set inspiratory pressure. Alternatively, a set tidal volume (volume pre-set) system may be used which delivers a fixed tidal volume irrespective of the airway pressure required to generate this volume. The earliest trials of non-invasive ventilation (NIV) employed volume pre-set equipment. However, later trials have used pressure pre-set devices, primarily due to simplicity and the comfort of the individual. The NIV machines entrain room air and additional oxygen may be entrained into the ventilatory tubing, or directly into the mask.

How the intervention might work

Non-invasive ventilation may be beneficial in acute respiratory failure in CF and could have a role to play in the management of chronic respiratory failure by acting as a bridge to transplantation as it may reverse or stabilise hypercapnia and hypoxaemia by improving alveolar ventilation, reducing respiratory muscle fatigue, or both (Hodson 1991; Piper 1992; Yankaskas 1999). The exact mechanisms by which NIV induces these changes may be different in acute and chronic disease and consequently different outcome measures may be necessary to reflect adequately the efficacy of NIV in acute and chronic respiratory failure in CF.

During sleep, decreases in respiratory neuromuscular output exaggerate these changes and lead to nocturnal hypoventilation before daytime respiratory failure becomes evident (Ballard 1996). While the addition of nocturnal oxygen improves hypoxaemia and may have favourable effects on cor pulmonale, it has not been shown to affect the progression of disease in CF (Zinman 1989). There is also some evidence that the use of oxygen therapy may be at the expense of worsening hypercapnia (Gozal 1997; Milross 2001). The use of NIV has been proposed as a means to temporarily reverse this process by assisting nocturnal ventilation, thereby slowing the progression of respiratory failure. The aim of NIV is to reduce hypoventilation and improve gas exchange by increasing minute ventilation and reducing the work of breathing without the associated complication of endotracheal intubation.

Clinically, NIV has also been used as an adjunct to airway clearance techniques in people with CF and moderate to severe disease. The exact mechanisms by which NIV may assist airway clearance are unclear but it is postulated that decreased respiratory muscle fatigue and prevention of airway closure during prolonged expirations may ultimately lead to an increase in effective alveolar ventilation, better compliance with airway clearance and increased sputum clearance (Holland 2003). Furthermore, recent guidelines state that NIV should be used for airway clearance in people with CF if there is respiratory muscle weakness or fatigue; where desaturation is present during airway clearance techniques; or when a patient has difficulty clearing secretions with other airway clearance techniques (Bott 2009).

There is a reasoned argument for using NIV during exercise to decrease dyspnoea and increase oxygenation resulting in an improvement in exercise tolerance; however there is no objective evidence to support this at present (Bott 2009).

Why it is important to do this review

It has been proposed that NIV may improve exercise tolerance and decrease exertional dyspnoea in CF. However there is no published evidence of randomised controlled trials to support this at present (Bye 2002). In order to establish an evidence base for the use of NIV, this review will aim to determine the effect of NIV in the management of acute and chronic respiratory failure in CF.

Objectives

The aim of this review is to compare the effect of pressure pre-set or volume pre-set NIV (that aims to increase minute ventilation) to no NIV in people with CF.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled clinical trials.

Types of participants

People with CF, of any age, diagnosed on the basis of clinical criteria and sweat testing or genotype analysis with any type of acute and chronic respiratory failure.

Types of interventions

Any type of prescribed pressure preset or volume preset method of NIV will be considered and compared to any other management strategy for acute and chronic respiratory failure.

Types of outcome measures

Primary outcomes
  1. Mortality

  2. Quality of life

  3. Symptoms of sleep disordered breathing

Secondary outcomes
  1. Lung function

  2. Gas exchange

  3. Respiratory symptom scores and sputum production

  4. Exercise tolerance

  5. Impact on health resources

  6. Nocturnal polysomnography

  7. Nutrition and weight

  8. Right-sided cardiac function

  9. Cost

  10. Adherence to treatment and preference

  11. Adverse events

Search methods for identification of studies

Electronic searches

Relevant trials were identified from the Group's Cystic Fibrosis Trials Register using the terms: oxygen OR physiotherapy AND (non-invasive positive pressure ventilation OR non-invasive mechanical ventilation OR pressure support ventilation OR inspiratory pressure support ventilation).

The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (Clinical Trials) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of EMBASE to 1995 and the prospective handsearching of two journals - Pediatric Pulmonology and theJournal of Cystic Fibrosis. Unpublished work is identified by searching through the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cystic Fibrosis and Genetic Disorders Group Module.

Date of the most recent search of the Group's CF Trials Register: 22 February 2013

Searching other resources

The bibliographic references of all retrieved trials were assessed for additional reports of trials.

Data collection and analysis

Selection of studies

Three authors (JB, AP, FM) independently selected the trials to be included in the review using a pro forma to capture the main inclusion criteria listed above. Disagreement did not arise on the suitability of a trial for inclusion in the review. However if this occurs for future updates of this review, the authors plan to reach a consensus by discussion.

Data extraction and management

Two authors independently extracted data using standard data acquisition forms: FM and JB: (Gozal 1997; Kofler 1998; Fauroux 1999; Milross 2001; Holland 2003; Young 2008); FM and AP (Placidi 2006). Disagreement did not arise on the quality of a trial included in the review. However, if this occurs for future updates of this review, the authors plan to reach a consensus by discussion.

In a post hoc change we have defined short-term trials as those with a duration less than three months. We decided to analyse single-night interventions separately from other short-term trials as we did not feel it appropriate to combine them with other longer trials. We planned to group outcome data from longer-term trials into those measured at three, six, twelve months and annually thereafter. If outcome data are recorded at other time periods, then consideration will be given to examining these as well.

Assessment of risk of bias in included studies

In order to assess the risk of bias in the included trials (yes, no or unclear), the authors as identified above, then assessed the methodological quality of each included trial based on a method described by Jüni (Jüni 2001). In particular, the authors examined details of the method of randomisation used, the method used to conceal allocation, whether the trial was blinded, whether assessors were independent or involved in the delivery of the interventions and if the number of participants lost to follow up or subsequently excluded from the trial were recorded. The authors assessed whether the primary investigators had made any statement regarding intention-to-treat analyses.

Measures of treatment effect

The authors combined data from all trials using the RevMan software (RevMan 2008). For continuous variables they calculated, as appropriate, the mean difference (MD) or a standardised mean difference (SMD) (if different effect measures were reported by the primary investigators e.g. for lung function) and their 95% confidence intervals (CI). For count data from cross-over trials conditional they used Poisson regression to analyse the data and they have presented the results as a relative rate. The authors carried out these analyses in Stata (Stata 2001) and present the results in RevMan (RevMan 2008).

There were no binary data in any of the trials included in this review. If the authors include binary data in future updates of this review, they will aim to calculate a pooled estimate of the treatment effect for each outcome across trials (the odds of an outcome among treatment allocated participants to the corresponding odds among controls).

Unit of analysis issues

All the trials included in this review were cross-over in design. When conducting a meta-analysis combining results from cross-over trials the authors would have liked to have used the methods recommended by Elbourne (Elbourne 2002) and also by Curtin (Curtin 2002). However, due to restrictions on the data that were available, the authors treated the cross-over trials as if they were parallel trials, except for the Milross trial as further individual patient data was provided by the authors (Milross 2001). Elbourne states that this approach will produce conservative results, as it does not take into account within-patient correlation (Elbourne 2002). Also each participant will appear in both the treatment and control group, so the two groups will not be independent. This may explain discrepancies found between original trial analyses and data presented in the review (Data and analyses). Where the authors have found discrepancies, both data from the original analyses and the statistical analysis for the review are detailed in the results. Another possible reason for discrepancies is that the methods used to analyse data were not always identical between the original trial report and the review. This will be noted in the text of the Effects of interventions section.

Although three trials evaluated NIV as a method of overnight ventilation involving overnight sleep trials in groups of participants which were similar in terms of age, lung function, body mass index and resting arterial blood gases, the results have not been pooled as the control group interventions were sufficiently different in the three trials (Gozal 1997; Milross 2001; Young 2008) and Young 2008 is a six-week trial.

Dealing with missing data

We contacted several of the original Investigators for further information (Fauroux 1999; Gozal 1997; Holland 2003; Kofler 1998; Milross 2001). Holland and Milross provided further data for analysis (Milross 2001; Holland 2003) and Young clarified the study design (Young 2008). We are currently contacting Placidi and any further information will be included in the next update (Placidi 2006).

Assessment of heterogeneity

The review authors tested for heterogeneity between trial results using the I2 statistic (Higgins 2003). This measure describes the percentage of total variation across trials that are due to heterogeneity rather than chance (Higgins 2003). The values of I2 lie between 0% and 100%, and a simplified categorization of heterogeneity that we used is of low (I2 value of 25%), moderate (I2 value of 50%), and high (I2 value of 75%) (Higgins 2003).

Assessment of reporting biases

We identified potential reporting bias by comparing the 'Methods' section with the 'Results' section in the published papers to see if all stated outcome measures are reported in the results of the full publication. Kofler is published in abstract format only, so for this study the comparison was not possible (Kofler 1998). In future updates, if sufficient trials are included, we plan to investigate potential publication bias using a funnel plot.

Data synthesis

We have analysed the data using a fixed-effect analysis. If in future, we establish there is heterogeneity between included trials, we will analyse the data using a random-effects analysis.

Subgroup analysis and investigation of heterogeneity

Althought we planned to do so, at present it is not possible to investigate heterogeneity by age or disease severity or mode of ventilation. Some trials include adults and children with mixed disease severities, with insufficient data in each subsection for analysis. There is also insufficient data to facilitate subgroup analysis by mode of ventilation.

Sensitivity analysis

We also planned to further investigate any heterogeneity by performing a sensitivity analysis based on the methodological quality of the included trials and will do so once there are sufficient trials to allow this.

Results

Description of studies

A full list of abbreviations can be found in the additional tables section (Table 1).

Table 1. List of abbreviations
AbbreviationDefinitionExplanation
ABGanalysis of blood gases 
CFcystic fibrosis 
COPDchronic obstructive pulmonary disease 
CPAPcontinuous positive airway pressurea system that maintains a positive pressure in the circuitry and airways throughout inspiration and expiration
CPTchest physiotherapy 
CSSChest symptom score

Validated CF Quality of Life Measurement.

Scale: 0 = worst; 100 = best.

ESSEpworth sleepiness scaleScale: 0 = best; 24 = worst.
FEF25-75flow rate between 25 and 75% of maximal expiration 
FEV1forced expiratory volume in 1 second 
FRCfunctional residual capacityresting volume of the lungs
FVCforced vital capacitytotal volume of air expired during a forced expiration following a full inspiration
Global PSQIGlobal score Pittsburgh sleep quality indexScale: 0 = best; 21 = worst.
MEF50maximal expiratory flow with 50% of vital capacity remaining in the lung 
mmHgmillimetres of mercury 
mSpO2mean oxygen saturation 
MSWTmodified shuttle walk testIncremental exercise tolerance test with minimum clinically important difference = 40m.
nadirSpO2the largest fall expressed in the absolute value of SpO2 
NIPPVnon-invasive positive pressure ventilation 
NIVnon-invasive ventilation 
NREMnon-rapid eye movementa phase during sleep
PaCO2partial pressure of carbon dioxide in arterial blood 
PaO2partial pressure of oxygen in arterial blood 
PEPpositive expiratory pressurean airway clearance technique
PSVpressure support ventilation 
QoLquality of life 
RDIrespiratory disturbance index 
REMrapid eye movementa phase during sleep
RRrespiratory rate 
SaO2saturation of haemoglobin with oxygen in arterial blood 
SDstandard deviation 
SpO2saturation of haemoglobin with oxygen using pulse oximetry 
*SpO2 maxthe largest fall expressed as the difference with the SpO2 just before the manoeuvre 
*SpO2 meanthe mean of *SpO2 max during the whole chest physiotherapy period 
TcCO2transcutaneous carbon dioxide 
TDItransitional dyspnoea index

CF QoL measurement.

Score: -9 = worst; +9 = best.

MCID = 1 unit.

TLCtotal lung capacitytotal volume of air in lungs following a maximum inspiration
TSTtotal sleep time 
VIminute ventilation 
VTtidal volumevolume air inspired or expired during normal breathing
IPAPinspiratory positive airway pressure 
PIMaxinspiratory respiratory muscle strength 
PEMaxexpiratory respiratory muscle strength 

Results of the search

Fifteen trials were identified from the searches. Seven of these fulfilled the inclusion criteria and included a total of 106 participants (Fauroux 1999; Gozal 1997; Holland 2003; Kofler 1998; Milross 2001, Placidi 2006; Young 2008). A total of eleven trials were excluded (Elkins 2004; Falk 2006; Fauroux 2000; Fauroux 2001; Fauroux 2004; Greenough 2004; Piper 1992; Regnis 1994; Serra 2000; Serra 2002; Riethmueller 2006).

Included studies

Data from one of the included trials are reported in abstract form only (Kofler 1998). In one of the trials, NIV was compared to more than one intervention within the same trial (Placidi 2006). For this trial, independent analyses for NIV versus directed coughing and NIV versus positive expiratory pressure (PEP) are reported (Placidi 2006). Therefore, seven trials contributing eight randomised data sets have been included in this review.

All seven of the included trials were randomised and cross-over in design. Six compared a single session of NIV to a single session of another type of intervention (Fauroux 1999; Gozal 1997; Holland 2003; Kofler 1998; Milross 2001; Placidi 2006); and one reported a six-week intervention of nocturnal NIV compared to oxygen and air (Young 2008). Therefore the trials in this review were all short-term trials. The trials included people with mild, moderate and severe disease. Due to the way data have been reported in the original papers, we have chosen to ignore the cross-over design and treat the data from these trials as if it originated from parallel trials, except for the Milross trial for which individual patient data were obtained (see Data collection and analysis and the table Characteristics of included studies).

In trials comparing NIV to other methods of airway clearance techniques, the authors tested for heterogeneity between results for lung function using the I2 statistic but given the insufficient number of trials included in this review and the lack of meta-analysis the value of I2 is 0%.

The inclusion criteria for the trial were stated in five trials (Gozal 1997; Holland 2003; Milross 2001; Placidi 2006; Young 2008) and the exclusion criteria for the trial were explicitly stated in three trials (Holland 2003; Placidi 2006; Young 2008).

One trial included children only (Fauroux 1999); two trials included both adults and children (Gozal 1997; Kofler 1998); and four trials included adults only (Holland 2003; Milross 2001; Placidi 2006; Young 2008).

In six trials the participants were studied in a hospital setting (Fauroux 1999; Gozal 1997; Holland 2003; Kofler 1998; Milross 2001; Placidi 2006) and participants were at home in one trial (Young 2008). In four of the trials it is stated that participants were stable at the time of the trial (Fauroux 1999; Gozal 1997; Milross 2001; Young 2008); in two trials participants had an acute exacerbation (Holland 2003; Placidi 2006); and in one trial it is not clear (Kofler 1998). One trial recruited participants with mild (not defined) disease (Kofler 1998), while three trials recruited participants with moderate to severe (defined) disease (Holland 2003; Milross 2001; Young 2008). One trial had participants in all disease categories (Fauroux 1999). Participants in the remaining two trials had severe disease (Gozal 1997; Placidi 2006). For further details, please see the table Characteristics of included studies.

All machines used were positive pressure ventilators with a capacity for bilevel pressure ventilatory support (see Characteristics of included studies).

Three trials did not make any comments on negative or adverse effects (Fauroux 1999; Gozal 1997; Placidi 2006). One trial reported that there were no untoward effects in any participant (Kofler 1998).Three trials provided information about negative effects (Holland 2003; Milross 2001; Young 2008): Milross reported consequential deviations in treatment in one participant who was unable to tolerate increases in IPAP (Milross 2001); Holland reported that one participant withdrew at the beginning of the trial because of pain on respiratory muscle testing (Holland 2003); Young reported that four participants withdrew in total: one participant withdrew from the NIV arm of the trial as they did not tolerate NIV due to mask discomfort; one participant withdrew following consent due to developing a pneumothorax whilst on air; and two participants experienced aerophagia which resolved when the IPAP was reduced by 2 cmH20. (Young 2008). No adverse effects were described in any trial.

The role of NIV as a method of airway clearance

Four trials, with a total of 79 participants, evaluated NIV as a method of airway clearance (Fauroux 1999; Holland 2003; Kofler 1998; Placidi 2006). The results of these four trials will be detailed in the Effects of interventions section under the heading of 'The role of NIV as a method of airway clearance'. These four trials compared the outcome of a single treatment session of NIV and another airway clearance technique: PEP (Kofler 1998; Placidi 2006) or chest physiotherapy (Fauroux 1999; Holland 2003; Placidi 2006). Only one trial compared NIV to more than one active intervention (Placidi 2006). The outcome measures in these four trials focused on lung function, gas exchange, sputum weight, ease of expectoration, breathlessness, fatigue, participant and physiotherapist preference. A sensitivity analysis was performed entering the Placidi data separately so that participants were not counted twice i.e. either chest physiotherapy including directed cough or chest physiotherapy including PEP and both data were reported.

The role of NIV in overnight ventilation

Three trials, with a total of 27 participants, evaluated NIV as a method of overnight ventilation (Gozal 1997; Milross 2001; Young 2008). The results of these three trials will be detailed in the Effects of interventions section under the heading of 'The role of NIV in overnight ventilation' with the single-night trials and the six-week trial being discussed separately. In one single-night trial, participants received room air on the first trial night (Gozal 1997). If they exhibited significant hypoxaemia or hypercapnia or both on the room air night, the results were compared to a single overnight session of NIV and oxygen and to a single overnight session of oxygen (Gozal 1997). In another single-night trial an overnight session of NIV (with or without oxygen) was compared to an overnight session of low level continuous positive airway pressure (CPAP) and oxygen and a single overnight session of low level CPAP and room air (Milross 2001). In a domiciliary six-week trial, CF participants with daytime hypercapnia received six weeks of room air or oxygen or NIV (Young 2008).

Excluded studies

Two trials were excluded because they were not randomised controlled trials (Piper 1992; Regnis 1994;) and six were excluded as they did not compare NIV with other management for acute or chronic respiratory failure (Elkins 2004; Fauroux 2000; Fauroux 2001; Fauroux 2004; Serra 2000; Serra 2002). Three trials were excluded as they did not include NIV (Falk 2006 ; Greenough 2004; Riethmueller 2006 ) .

Risk of bias in included studies

The quality of all the included trials was assessed based on the criteria described by Jüni (Jüni 2001). However, one of the included trials has only been published in abstract form (Kofler 1998) and there is limited information in the abstract to assess quality using the quality assessment criteria we have employed.

Assessment of trials describing NIV as a method of airway clearance

Four trials reported on NIV as a method of airway clearance (Fauroux 1999; Holland 2003; Kofler 1998; Placidi 2006).

Allocation

The methods of randomisation of treatment order was only reported in one trial therefore there is a low risk of bias for this trial (Placidi 2006), but an unclear risk of bias for the other three trials which were described as randomised but no further details supplied (Fauroux 1999; Holland 2003; Kofler 1998).

Details of allocation concealment were not reported in any of the trials and therefore the overall risk of bias is unclear (Fauroux 1999; Holland 2003; Kofler 1998; Placidi 2006).

Blinding

When assessing the quality of the included trials, it should be noted that it is difficult to blind these types of trials. In fact it would not have been possible to blind either the participants or the clinicians administering treatment to the intervention. It would only have been possible to blind the outcome assessors.

Data collection was described in three trials though reporting was not consistent; therefore the overall risk of bias is unclear (Fauroux 1999; Holland 2003; Placidi 2006). In one trial, participants' subjective impressions were evaluated by individuals who were not involved in the trial and were unaware of the treatment regimen; but it was not reported who was responsible for collecting and weighing secretions or performing lung function testing (Fauroux 1999). In a second trial, an independent data collector who was blinded to the treatment order obtained all measurements (Holland 2003). These two trials had a lower risk of bias than the other trials. The third trial did not report who was responsible for weighing sputum or collating subjective impressions induced by the treatment (Placidi 2006). Data collection was not described in the fourth trial, so we judged this trial to also have an unclear risk of bias (Kofler 1998).

Incomplete outcome data

One trial provided information on drop outs: there was one drop out at the start of testing (Holland 2003) and all participants were accounted for in the remaining trials (Fauroux 1999; Kofler 1998; Placidi 2006). We judge there to be a low risk of bias for all trials.

Selective reporting

When the 'Methods' section of each trial published in full was compared to the 'Results' sections, we were not able to identify any selective outcome reporting. Therefore there is a low risk of bias for these three trials (Fauroux 1999; Holland 2003; Placidi 2006). As Kofler is published in abstract form only, it is unclear whether all outcome measures have been reported and the risk of bias is unclear (Kofler 1998).

Other potential sources of bias

The methods of statistical analysis were described in three trials therefore there is a low risk of bias for these (Fauroux 1999; Holland 2003; Placidi 2006); but analysis methods were not described in the Kofler trial leading to an unclear risk of bias (Kofler 1998).

Quality assessment of trials describing NIV as a method of overnight ventilation

Three trials reported on NIV as a method of overnight ventilation (Gozal 1997; Milross 2001; Young 2008).

Allocation

The method of randomisation of treatment order was not described and there were no details of allocation concealment given in two trials regarding overnight ventilation; therefore there is an unclear risk of bias (Gozal 1997; Milross 2001). Treatment order was randomly assigned using a computer-generated Latin square design in one trial and the order of randomisation was sealed in sequentially numbered opaque envelopes by a person not involved in the trial and opened as each participant was enrolled; therefore there is a low risk of bias for both randomisation and concealment of allocation in this trial (Young 2008).

Blinding

As has already been stated, it is difficult to blind these type of trials. The Gozal trial stated that participants were obviously aware of the intervention being administered; however, all were reportedly unaware of the purpose of the trial with participants and sleep technicians blinded to the results until completion of the third night (Gozal 1997). We therefore judge there to be an unclear risk of bias for this trial. There was no evidence of blinding of assessors, investigators or participants in the published report of one trial, which we therefore judge to have a high risk of bias (Milross 2001). There is evidence of blinding in the Young trial only for participants receiving either oxygen or room air, so we judge the risk of bias for this to be unclear (Young 2008). Overall risk of bias is therefore unclear.

Incomplete outcome data

In one trial we judged there to be a low risk of bias since there were no dropouts (Milross 2001). In the Young trial, one participant dropped out following consent due to a pneumothorax on air and there was a drop out in the NIV group as the participant could not tolerate the mask (Young 2008). We judge there to be a low risk of bias in this trial. In the Gozal trial two participants dropped out due to non-tolerance of NIV; it was not explicitly stated that intention-to-treat was not used, but results are based on the remaining six participants who completed the trial (Gozal 1997). We judge this trial to have an unclear risk of bias.

Selective reporting

We were not able to identify any selective outcome reporting after comparing trial 'Methods' sections to final sections on 'Results' for three trials (Gozal 1997; Milross 2001; Young 2008). Consequently, the risk of bias is low as all outcome measures we expected to be reported have been (Gozal 1997; Milross 2001; Young 2008).

Other potential sources of bias

The methods of statistical analysis were described in all three trials, therefore there is a low risk of bias (Gozal 1997; Milross 2001; Young 2008).

Effects of interventions

Due to variations in the type and duration of trials, times at which outcomes were measured, different methods of reporting outcomes, omission of data relating to either mean change from baseline for each group and the standard deviation or standard error it was not possible to pool data for many of the outcomes.

There are discrepancies in some of the results reported between the original trial analyses and the analyses in the Data and analyses section. These discrepancies may be due to some or all of the following reasons. As mentioned in the Unit of analysis issues section, due to restrictions on the data that were available, the method that we used for some of the analysis was to treat the cross-over trials as if they were parallel trials. Furthermore, as the trials included within this review are very small it is unlikely that the results are normally distributed, (which is an assumption made within RevMan 5 when calculating the MD). Therefore, non-parametric tests were used to analyse the original data in two of the trials (Gozal 1997; Milross 2001). This may lead to differences between the results obtained in Data and analyses and in the primary analysis. We have been unable to confirm which statistical method was used in one trial (Kofler 1998). Where discrepancies have been found, the results from both the original analysis and Data and analyses are detailed in the text. Some trials reported statistical or non-statistical differences between groups, but did not provide adequate data (means and standard deviations (SD) that could be presented in the RevMan software (RevMan 2008). When this has occurred the information from the original trial has been included in the text.

See table of Data and analyses for data available from trials and calculations of MD and SMD.

A full list of abbreviations can be found in the additional tables section (Table 1).

The role of NIV as a method of airway clearance

There are four trials included under this intervention (Fauroux 1999; Holland 2003; Kofler 1998; Placidi 2006).

Primary outcomes
1. Mortality

No trials looked at mortality.

2. Quality of life

Fatigue was reported in two trials. In the Fauroux trial, 15 out of 16 participants felt less tired after the NIV session compared to the chest physiotherapy session (Fauroux 1999). In the Placidi trial participants reported feeling less tired after NIV than after PEP (Placidi 2006).

3. Symptoms of sleep disordered breathing

No trials looked at symptoms of sleep disordered breathing.

Secondary outcomes
1. Lung function

Forced expiratory volume at one second (FEV1), forced vital capacity (FVC) and forced mid-expiratory flow rate (FEF25-75) were reported in four trials (Fauroux 1999; Holland 2003; Kofler 1998; Placidi 2006).There were no primary data available for one trial (Kofler 1998). This trial reported that there was no significant difference in post-intervention lung function between the groups (Kofler 1998). In the other three trials comparing chest physiotherapy including directed cough with NIV there was no statistical difference in post treatment between groups FEV1, SMD -0.05 (95% CI -0.41 to 0.31) (Fauroux 1999; Holland 2003; Placidi 2006). There was no statistical difference reported for FVC, SMD 0.02 (95% CI -0.35 to 0.38) (Fauroux 1999; Holland 2003; Placidi 2006) or for FEF25-75 -0.03 (95% CI -0.39 to 0.33) (Fauroux 1999; Holland 2003; Placidi 2006).

Comparing chest physiotherapy including PEP with NIV there was again no statistical difference in post treatment between groups for FEV1, FVC or FEF 25-75: FEV1, SMD -0.06 (95% CI -0.43 to 0.30); FVC, SMD -0.01 (95% CI -0.37 to 0.35); FEF25-75 SMD 0.00 (95% CI -0.36 to 0.36) (Fauroux 1999; Holland 2003; Placidi 2006).

Maximal inspiratory mouth pressure (PImax) and maximal expiratory mouth pressure (PEmax) was reported in two trials (Fauroux 1999; Holland 2003). In the original paper, Holland reported that there was a significant reduction in PImax following standard treatment (P = 0.04). PImax was maintained following NIV treatment resulting in a significant difference compared with standard treatment PImax, WMD 9.04 cmH2O (95% CI 4.25 to 13.83) (Holland 2003). PEmax did not change significantly following standard treatment but increased following NIV, MD 8.04 cm H2O (95% CI 0.61 to 15.46) (Holland 2003). Fauroux reported PImax and PEmax decreased significantly after the chest physiotherapy session. After the NIV session both PImax and PEmax increased but the difference was significant only for PImax. Post-treatment values for both PImax and PEmax were significantly greater after NIV than chest physiotherapy, PImax MD 23.00 cmH2O (95% CI 18.01 to 27.99); PEmax MD 10.50 cmH2O (95% CI 6.18 to 14.82) (Fauroux 1999).

Tidal volume was reported in one trial (Fauroux 1999). In this trial tidal volume increased from mean (SD) 0.42 (0.01) litres to 1.0 (0.02) litres after the NIV physiotherapy session, but there were no data provided for the control session (Fauroux 1999).

Respiratory rate was reported in one trial (Fauroux 1999). In this trial respiratory rate was reported to be significantly lower during NIV than during chest physiotherapy (no data available) (Fauroux 1999).

Airway resistance (% predicted) was reported in one trial (Fauroux 1999). Comparing chest physiotherapy with NIV there was no statistical difference post treatment between groups for airway resistance MD -9.00 (95% CI -31.35 to 13.35) (Fauroux 1999).

2. Measures of gas exchange

This was reported in four trials during airway clearance sessions (Fauroux 1999; Holland 2003; Kofler 1998; Placidi 2006). In the first trial the same outcome measure for saturation of haemoglobin with oxygen in arterial blood (SpO2) was measured and recorded in numerous ways: mean oxygen saturation (mSpO2); the largest fall expressed in the absolute value of SpO2 (nadirSpO2); the largest fall expressed as the difference with the SpO2 just before the manoeuvre (*SpO2max); the mean of *SpO2 max during the whole chest physiotherapy (*SpO2 mean) (Fauroux 1999). We have chosen to report on one of these i.e. *SpO2 mean. Indices of oxygenation were significantly lower during chest physiotherapy than during NIV, *SpO2mean MD 1.00 (95% CI 0.29 to 1.71) (Fauroux 1999).

The second trial reported the change in SpO2 during treatment. There was a significantly greater improvement in SpO2 following NIV versus chest physiotherapy including PEP, MD 1.16% (95% CI 0.08 to 2.24) (Kofler 1998).

In the third trial, Holland reported that mean (P < 0.001) and minimum SpO2 (P = 0.007) were significantly lower during standard treatment than during NIV treatment. Addition of NIV resulted in a significant reduction in the proportion of treatment time with SpO2 < 90% (P = 0.001) (Holland 2003).

In the fourth trial by Placidi , there was no significant difference in SpO2 after airway clearance between chest physiotherapy including directed cough and NIV, MD -0.20% (95% CI -0.74 to 1.14), nor between chest physiotherapy including PEP and NIV, MD -0.10% (95% CI -0.98 to 0.78) (Placidi 2006).

3. Respiratory symptom scores and sputum production

Sputum production was reported in three trials (Fauroux 1999; Holland 2003; Placidi 2006). There was no significant difference in the amount of wet weight sputum expectorated during NIV and during chest physiotherapy including directed coughing, MD -0.69g (95% CI -3.06 to 1.67) (Fauroux 1999; Holland 2003; Placidi 2006) or with chest physiotherapy including PEP, MD -1.54g (95% CI -3.96 to 0.89) (Fauroux 1999; Holland 2003; Placidi 2006). Ten out of 16 participants considered expectoration was easier with NIV, four out of 16 participants did not perceive any difference and two participants did not expectorate (Fauroux 1999).

In the trial by Placidi, no significant difference in dry weight sputum between chest physiotherapy including directed cough and NIV was found, MD -0.09g (95% CI -0.56 to 0.38), nor between chest physiotherapy including PEP and NIV, MD -0.06g (95% CI -0.46 to 0.34) (Placidi 2006).

Fatigue was reported in two trials (Fauroux 1999; Placidi 2006). In the Fauroux trial, 15 out of 16 participants felt less tired after the NIV session compared to standard therapy (Fauroux 1999). Participants in the Placidi trial also reported being less tired following NIV compared to PEP (Placidi 2006).

Borg breathlessness score was reported in one trial; there was no statistical difference in Borg breathlessness score post-treatment, MD -0.43 (95% CI -1.46 to 0.60) (Holland 2003).

4. Exercise tolerance

No trials looked at exercise tolerance.

5. Impact on health resources

No trials looked at health resources.

6. Measures of nocturnal polysomnography

No trials looked at nocturnal polysomnography.

7. Effect on nutrition and weight

No trials looked at nutrition and weight.

8. Measures of right-sided cardiac function

No trials looked at right-sided cardiac function.

9. Cost

No trials looked at cost.

10. Adherence to treatment and preference

All four trials included information about subjective response to NIV in comparison to other airway clearance techniques. In three trials more participants stated that they preferred NIV to another method of airway clearance (Fauroux 1999; Holland 2003; Kofler 1998). In the first trial, 14 out of 16 participants stated that they preferred NIV to chest physiotherapy and two participants had no preference (Fauroux 1999). In the second trial, 15 out of 26 participants preferred treatment with NIV, eight out of 26 stated that they preferred standard treatment and three had no preference (Holland 2003). In the third trial, 12 out of 20 participants preferred NIV, five out of 20 participants preferred PEP and three out of 20 participants had no preferences (Kofler 1998). In the Placidi trial, no statistical difference in subjective effectiveness scores between chest physiotherapy including PEP and NIV were seen (Placidi 2006). Physiotherapy preference was reported in one trial (Fauroux 1999). The physiotherapists found it easier to perform chest physiotherapy while the person was on NIV in 14 out of 16 participants and did not perceive any difference in two participants (Fauroux 1999).

11. Adverse events

No trials reported on adverse events.

The role of NIV in overnight ventilation

There are three trials included under this intervention: two single-night trials (Gozal 1997; Milross 2001) and one short-term trial (Young 2008).

Primary outcomes
1. Mortality

No trials looked at mortality.

2. Quality of life

One short term trial looked at quality of life.

One short-term trial looked at quality of life using the CF specific quality of life questionnaire (Young 2008). There was no significant difference in the chest symptom score between NIV and oxygen, MD 3.0 (95% CI -15.73 to 21.73) and the transitional dyspnoea index score, MD 1.4 (95% CI -0.29 to 3.09).There was no significant difference in the chest symptom score between NIV and room air, MD 7.00 (95% CI -11.73 to 25.73); however, in the original trial this was reported as significant P < 0.002. There was a significant difference in the transitional dyspnoea index score between NIV and room air, MD 2.90 (95% CI 0.71 to 5.09).

3. Symptoms of sleep disordered breathing

One short-term trial looked at symptoms of sleep disordered breathing.

In the Young trial, daytime sleepiness was measured as a primary outcome (Young 2008).There was no significant difference in the daytime Epworth sleepiness score between NIV and oxygen, MD 00.0 (95% CI -5.57 to 5.57) and NIV and air, MD 00.0 (95% CI -5.07 to 5.07). There was no significant difference in the daytime sleepiness global Pittsburg sleep quality index (PSQI) score between NIV and oxygen, MD 00.0 (95% CI - 2.62 to 2.62) and NIV and room air, MD -1.0% (95% CI -4.04 to 2.04).

Secondary outcomes
1. Lung function

One single-night trial reported on lung function (Milross 2001). As can be seen from the graphs, several results were non-significant and these have not been reported in the text.

The data for one trial have been entered into the analysis using GIV (Milross 2001). There was a significant difference in minute ventilation (VI) in favour of NIV between NIV and oxygen and between NIV and room air during REM sleep, MD 1.48 L/m (95% CI 0.74 to 2.22) and MD 1.56 L/m (95% CI 0.05 to 3.07) respectively (Milross 2001). However, in the original trial these differences did not reach statistical significance. There was also a significant difference in VI between NIV and room air during NREM sleep, MD 1.04 L/m (95% CI 0.37 to 1.17) (Milross 2001).

There was a significant difference in tidal volume (VT) between NIV and oxygen during REM sleep MD 0.08 L (95% CI 0.04 to 0.12). There was also a significant difference in VT between NIV and room air during REM sleep, MD 0.10 L (95% CI 0.04 to 0.16). There was a significant difference in VT between NIV and oxygen during NREM sleep MD 0.03 L (95% CI 0.01 to 0.05) (Milross 2001).

There was a significant difference in respiratory rate during REM sleep between NIV and oxygen, MD -1.84bpm (95% CI -3.25 to -0.43) and between NIV and room air, MD -2.64 (95% CI -3.70 to -1.58) (Milross 2001).

One short-term trial reported on lung function (Young 2008).There was no significant difference in lung function: FEV1 % predicted between NIV and oxygen, MD 1.00% (95% CI -8.13 to 10.13) and NIV and room air, MD 1.00% (95% CI -8.62 to 10.62); FVC % predicted between NIV and oxygen, MD 4.00% (95% CI -11.22 to 19.22) and NIV and room air, MD 4.00% (95% CI -10.32 to 18.30) (Young 2008). There was no significant difference in mean respiratory rate during slow wave sleep between NIV and oxygen, MD -6.00 breaths per minute (b/m) (95% CI -22.7 to 10.7) and NIV and room air, MD 0.00 b/m (95% CI -5.07 to 5.07).

2. Measures of gas exchange

See 'Measures of nocturnal polysomnography'.

The short-term trial looked at awake arterial blood gases (Young 2008). There was no significant difference in: pH between NIV and oxygen, MD 0.00 (95% CI -0.03 to 0.03) and NIV and room air, MD 0.01 (95% CI -0.02 to 0.04); PaCO2 between NIV and oxygen, MD -1.00 mmHg (95% CI -7.10 to 5.10) and NIV and room air, MD -2.00 mmHg (95% CI -8.10 to 4.10); PaO2 between NIV and oxygen, MD -4.00 mmHg (95% CI -13.43 to 5.43) and NIV and room air, MD -2.00 mmHg (95% CI -8.58 to 4.58); HCO3 between NIV and oxygen, MD 0.00 mmol/l (95% CI -3.14 to 3.14) and NIV and room air, MD 0.00 mmol/L (95% CI -2.55 to 2.55); SaO2 % between NIV and oxygen, MD -2.00 % (95% CI -6.06 to 2.06) and NIV and room air, MD -1.00 % (95% CI -4.62 to 2.62).

3. Sputum production

No trials looked at sputum production.

4. Exercise tolerance

One short-term trial looked at exercise tolerance.

The Young trial also looked at exercise tolerance (Young 2008). There was no significant difference in the modified shuttle walk test (MSWT) between NIV and oxygen, MD 56.00 m (95% CI -76.74 to 188.74). There was a significant difference in the MSWT between the NIV and room air intervention, MD 83.00 m (95% CI 21.50 to 144.50) (Young 2008).

5. Impact on health resources

No trials looked at health resources.

6. Measures of nocturnal polysomnography

Two single-night trials looked at measures of sleep polysomnography (Gozal 1997; Milross 2001).

Total sleep time (TST) was reported in one trial (Gozal 1997). There was no statistical difference in TST in NIV compared to supplemental oxygen, MD 4.00 min (95% CI -29.39 to 37.39) and there was no statistical difference in TST when NIV was compared to room air, MD 12.00 min (95%CI -33.56 to 57.56) (Gozal 1997).

There was no statistical difference in time spent in REM sleep, MD -13.00 min (95% CI -43.25 to 17.25) or time in REM sleep expressed as a % TST, MD -3.00 (95% CI -9.88 to 3.88) when NIV was compared with supplemental oxygen (Gozal 1997). In the original trial, REM sleep and REM expressed as a percentage of TST was significantly greater in the NIV night than in the room air night but there was no statistical difference in REM duration between the NIV and oxygen night (Gozal 1997). In Data and analyses, when NIV was compared with room air there was no statistical difference in time spent in REM sleep, MD 10.00 min (95% CI -13.37 to 33.37) or time in REM sleep % TST, MD 3.00 min (95% CI -1.67 to 7.67) (Gozal 1997).

Sleep latency was reported in two single-night trials (Gozal 1997; Milross 2001). There was no statistical difference in sleep latency with NIV compared to supplemental oxygen, MD 2.93 min (95%CI -0.32 to 6.19) and there was no statistical difference in sleep latency between NIV and room air, MD -2.63 min (95%CI -7.37 to 2.11) (Gozal 1997; Milross 2001).

The Gozal trial measured nocturnal oxygen saturation. There was no statistically significant difference between mean SpO2 for NIV compared with supplemental oxygen during either REM sleep, MD -2.00% (95% CI -4.88 to 0.88) or NREM sleep, MD -1.00% (95% CI -2.79 to 0.79); although in the original trial SpO2 was significantly lower during REM and NREM sleep on the NIV night. For NIV compared with room air, mean SpO2 was significantly greater in the NIV group during REM sleep, MD 9.00% (95% CI 2.91 to 15.09) and NREM sleep, MD 5.00% (95% CI 0.69 to 9.31) although this difference was not significant in the primary trial (Gozal 1997).

The Milross trial compared the percentage of time spent with SpO2 > 90% during TST, REM and NREM and these data have been entered into the analysis using GIV (Milross 2001). When NIV was compared with supplemental oxygen, there was no statistically significant difference during TST, MD -2.54 min (95% CI -9.59 to 4.50); REM sleep, MD 0.65 min (95% CI -8.94 to 10.25); or in NREM sleep, MD -0.84 min (95% CI -7.95 to 6.26). The SpO2 > 90% during TST was significantly lower on room air compared with NIV, MD 27.58 min (95% CI 7.83 to 47.33) and during REM sleep, MD 34.53 min (95% CI 15.00 to 54.06). The original trial reports that the SpO2 >90% during TST and REM sleep was significantly lower on the room air night versus the oxygen or NIV night. There was a significant difference in percentage of time spent with SpO2 > 90% in NREM between NIV and room air, MD 26.21 (95% CI 6.24 to 46.18). (Milross 2001). However, the original trial reported that there was no significant difference in percentage of time spent with SpO2 >90% in NREM during the NIV night or the oxygen night and the room air night.

In the trial by Gozal, transcutaneous carbon dioxide (TcCO2) on the NIV night was significantly lower than in the oxygen night during REM sleep, MD -1.90mmHg (95% CI -2.55 to -1.25) and during NREM, MD -1.40 mmHg (95% CI -2.19 to -0.61) (Gozal 1997). TcCO2 in the NIV night was also significantly lower during REM, WMD -0.90 mmHg (95%CI -1.62 to -0.18) and during NREM, MD -0.70 mmHg (95%CI -1.15 to -0.25) than in the room air night.

TcCO2 during sleep was expressed in terms of change during different phases of sleep in the Milross trial (Milross 2001). The change in TcCO2 from NREM to REM in the NIV night was significantly less than in the oxygen night , MD -2.60 mmHg (95% CI -4.05 to -1.16) and the room air night, WMD -2.31 mmHg (95% CI -3.30 to -1.32) (Milross 2001). The original report states that NIV with oxygen "significantly attenuated the rise in TcCO2 seen with REM sleep compared with both supplemental oxygen and room air" (Milross 2001). In two trials, TcCO2 during sleep was also expressed in terms of maximum TcCO2 between NIV treatment and either oxygen (Milross 2001) or room air (Milross 2001; Young 2008). Comparing NIV to oxygen there was no significant difference between the two nights, MD -2.08 mmHg (95% CI -10.64 to 6.48) (Milross 2001). Comparing NIV to room air, there was a significant difference in maximum nocturnal TcCO2, MD -8.49 mmHg (95% CI -15.74 to -1.23) (Milross 2001).

Milross reports that in the NIV night the number of episodes of hypopnoeas per hour were significantly lower than in the oxygen night, relative rate (RR) 0.02 (95% CI 0.01 to 0.06); likewise, these were significantly lower in the NIV night than the room air night, RR 0.02 (95% CI 0.01 to 0.05) (Milross 2001).

One six-week trial looked at measures of sleep polysomnography (Young 2008).

Total sleep time (TST) was reported in one short-term trial (Young 2008). There was no statistical difference in TST in NIV compared to supplemental oxygen, MD -22.00 min (95% CI -55.19 to 11.19) and there was no statistical difference in TST when NIV was compared to room air, MD 25.00 min (95%CI -69.57 to 19.57).

In the trial by Young there was no statistical difference in time in REM sleep expressed as a % TST, MD 2.00 min (95% CI -5.10 to 9.10) when NIV was compared with supplemental oxygen or time in REM sleep expressed as a % TST, MD 2.00 (95% CI -5.59 to 9.59) when NIV was compared with room air.

There was no statistical difference in sleep latency with NIV compared to supplemental oxygen, MD -5.00 min (95%CI -19.17 to 9.17) and there was no statistical difference in sleep latency between NIV and room air, MD -3.00 min (95%CI -19.88 to 13.88).

There was no significant difference with regard to nocturnal hypoxia for TST with SpO2 < 90% when comparing NIV with oxygen: MD 13.00 % (95% CI -12.95 to 38.95) or NIV with room air, MD -25.00 (95% CI -66.9 to 16.9); for mean SpO2 for TST when comparing NIV with oxygen, MD -1.00 % (95%CI -3.62 to 1.62) or NIV with room air, MD 3.00 (95% CI -1.04 to 7.04).

There was significantly higher levels of hypercapnia in the oxygen group when comparing NIV with oxygen: maximum PtCO2 TST, MD -14.00 mmHg (95% CI -23.22 to -4.78); mean PtCO2 TST MD -9.00 mmHg (95%CI -17.23 to -0.77). There were significantly higher levels of hypercapnia in the room air group when comparing NIV with room air: maximum PtCO2 TST MD -16.00 mmHg (-30.15 to -1.85) but no significance difference between the two groups for mean PtCO2 TST MD -9.0 mmHg (95% CI -19.05 to 1.05).

There was also a significant difference in mean change PtCO2 and mean change PaCO2 for NIV compared to oxygen: mean change PtCO2 , MD -2.80 mmHg (95% CI -5.53 to -0.77); mean change PaCO2 , MD -7.30 mmHg (95% CI -11.51 to -3.09). There was a significant difference in mean change PtCO2 for NIV compared to room air, MD -2.20 mmHg (95% CI -4.32 to -0.8) but no significant difference for mean change PaCO2 for NIV compared to room air, MD -3.30mmHg (95% CI -6.73 to 0.13).

There was no significant difference in mean heart rate when NIV was compared to oxygen, MD -6.00 beats/min (95% CI -22.7 to 10.7); NIV compared to room air, MD -9.00 beats/min (95% CI -22.4 to 4.48) whereas in the original paper a significant difference was reported (P = 0.05).

7. Effect on nutrition and weight

No trials looked at nutrition and weight.

8. Measures of right-sided cardiac function

No trials looked at right-sided cardiac function.

9. Cost

No trials looked at cost.

10. Adherence to treatment and preference

One single-night trial looked at preference of treatment (Gozal 1997).

Gozal reports that four out of six participants preferred oxygen to NIV despite morning headache being present in two participants following the oxygen night (Gozal 1997).

The Young trial looked at preference of treatment and reports that four participants rated oxygen as the most comfortable, whilst two rated oxygen and air equally comfortable (Young 2008). Four participants preferred oxygen as long-term therapy whilst three preferred NIV. No participants selected air as their preferred treatment (Young 2008).

11. Adverse events

No trials reported adverse events though one short-term trial reported negative effects (Young 2008).

One participant developed a spontaneous pneumothorax while on air which was considered coincidental. Two participants complained of aerophagia with NIV which resolved with a reduction in IPAP by 2 cmH20 (Young 2008).

Discussion

Six randomised cross-over trials comparing single sessions of NIV to another intervention have been published that meet the inclusion criteria for this review (Fauroux 1999; Gozal 1997; Holland 2003; Kofler 1998; Milross 2001; Placidi 2006). One further short-term trial examined the outcome of nocturnal NIV over a longer period of six weeks (Young 2008). Four trials focused on the role of NIV as a method of airway clearance (Fauroux 1999; Holland 2003; Kofler 1998; Placidi 2006) and three trials focused on the role of NIV as a method of overnight ventilatory support (Gozal 1997; Milross 2001; Young 2008). One of the trials is in abstract form only (Kofler 1998).

All of the trials were randomised cross-over trials and although the existence of a carry-over effect was only investigated in one trial (Holland 2003), each trial included a washout period between the interventions. None of the trials were double-blinded. However, this quality issue must be considered in the context of the difficulty of blinding NIV trials. It was only clear in one trial that the outcome measurements were performed by an independent assessor, who was not involved in the delivery of the interventions (Holland 2003). All of the trials used random allocation; although only two trials provided details on the specific procedures used (Placidi 2006; Young 2008). These quality issues affect the internal validity of the trials. The external validity of these trials is limited by the fact that six of the trials in the review only assess the efficacy of a single treatment session of NIV and do not study the longer term efficacy or safety of NIV.

In a single physiotherapy session the use of NIV led to easier airway clearance in participants with stable moderate to severe disease. Airway clearance may be easier and participants may prefer to use NIV for airway clearance treatment. We were unable to find any evidence that NIV increases sputum expectoration or improves lung function. There is some evidence that the introduction of NIV to airway clearance preserved muscle strength and improved expiratory muscle strength. No deleterious effects on small airway function were observed.

In terms of overnight ventilatory support in a single nocturnal treatment session, NIV offers benefits over oxygen or room air. Nocturnal hypoventilation is an early marker of respiratory deterioration in advanced CF and can lead to the development of daytime hypercapnia. By attenuating the decrease in VT and improving ventilation during sleep NIV decreases hypoventilation in people with moderate to severe lung disease. Nocturnal SpO2 may be increased by NIV and oxygen or oxygen alone, but the increase in SpO2 with NIV and oxygen is likely to occur without a concomitant increase in TcCO2 as seen when people receive oxygen alone. The respiratory rate on the NIV night was significantly lower in REM sleep than on the room air or oxygen nights. In the trial by Gozal four out of six participants reported that they preferred oxygen therapy overnight to NIV and oxygen (Gozal 1997). Milross found only one participant in the group of 13 who was unable to tolerate sufficiently high pressures to improve nocturnal ventilation (Milross 2001).

In terms of a longer period of overnight ventilation (six weeks), NIV further demonstrated an improvement in nocturnal hypercapnic levels as well as a meaningful clinically important difference in peak exercise capacity and exertional dyspnoea when compared to room air. Young identifies the improvement of peak exercise capacity as important as it is a predictor of survival in adults and children with CF (Young 2008). However, the intervention over this time period did not lead to a change in sleep architecture, lung function or awake hypercapnic levels. Neurocognitive function  was not an outcome measure reported in our review; however, Young did test neurocognition and found no significant change with any treatment.

It is important to note that Young did not address the issue of NIV in combination with oxygen as opposed to NIV alone. The combination of NIV and oxygen is more commonly considered in clinical practice in people with CF and severe lung disease (Young 2008). In this six-week trial four participants preferred oxygen as long-term therapy, three preferred NIV and none selected air as their preferred long-term therapy (Young 2008).

Overall, the results demonstrate NIV improves the physiological markers of early respiratory failure following a single nocturnal treatment session, with improvements in exercise tolerance, selected aspects of quality of life and nocturnal carbon dioxide levels when used over a longer period. Nocturnal respiratory support with NIV has important implications for the people with CF and advanced lung disease and may attenuate the early effects and progression of respiratory failure. Further investigations over longer time courses are warranted to determine if these changes will be sustained or have any influence on clinical outcomes. Which subgroups benefit most from NIV intervention also needs to be established.

Authors' conclusions

Implications for practice

We have found there is some limited evidence to support the use of NIV as a clinical treatment in people with CF. NIV may be a useful adjunct to other airway clearance techniques particularly in people with CF who have difficulty expectorating sputum, where fatigue or respiratory muscle weakness is an issue. The trials in this review demonstrate that NIV, when used with overnight oxygen improves gas exchange during sleep to a greater extent than oxygen therapy alone in people with moderate to severe CF. Use of NIV over a six-week period provided benefits over oxygen and room air for those people with CF who experience daytime hypercapnia in terms of exercise tolerance, dyspnoea and nocturnal gas exchange. This effect of NIV has been demonstrated in only one clinical trial.

Implications for research

There is a need for long-term multicentre randomised controlled trials which are adequately powered to assess the impact of NIV on quality of life and clinical disease progression when used as an adjunct to airway clearance or as a method of overnight ventilation. At the protocol stage and when conducting short-term trials the power of the trial should be considered. There is also a need to further establish the role of NIV in exercise in CF and which subgroups would benefit most from NIV intervention. Although it would be impossible to double blind future trials, it would be important to undertake blind assessment of the participants to ensure good quality trials. Future trials should use outcome measures which are considered important by people with CF such as health-related quality of life and dyspnoea. Future trials must also assess the impact of NIV use on both people with CF and their carers in terms of practical difficulties, such as inconvenience, noise, intrusiveness and travel restrictions.

In the Young trial despite the benefits outlined above, nocturnal hypoxaemia persisted in the NIV group and in the oxygen group. Therfore further research is needed to establish if a combination of NIV and oxygen is more effective in the long term.

Acknowledgements

The authors thank Dr Peter Wark and Professor Rosalind Smyth for editorial advice. The authors would also like to thank Ashley Jones who has advised on the statistics in previous updated versions of the review.

Data and analyses

Download statistical data

Comparison 1. NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Lung function - chest physiotherapy including directed cough3 Std. Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 FEV13118Std. Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.41, 0.31]
1.2 FVC3118Std. Mean Difference (IV, Fixed, 95% CI)0.02 [-0.35, 0.38]
1.3 FEF25-753118Std. Mean Difference (IV, Fixed, 95% CI)-0.03 [-0.39, 0.33]
2 Lung function - chest physiotherapy including PEP3 Std. Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 FEV13118Std. Mean Difference (IV, Fixed, 95% CI)-0.06 [-0.43, 0.30]
2.2 FVC3118Std. Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.37, 0.35]
2.3 FEF25-753118Std. Mean Difference (IV, Fixed, 95% CI)-0.00 [-0.36, 0.36]
3 Respiratory muscle strength (cmH20)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 PImax1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 PEmax1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Airway resistance % predicted1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
5 Oxygen saturation during airway clearance (%)1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
6 Oxygen saturation during airway clearance (change in SpO2 % during treatment)1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
7 Oxygen saturation after airway clearance (SpO2) - chest physiotherapy including directed cough1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
8 Oxygen saturation after airway clearance (SpO2) - chest physiotherapy including PEP1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
9 Sputum wet weight (g) - chest physiotherapy including directed cough3118Mean Difference (IV, Fixed, 95% CI)-0.69 [-3.06, 1.67]
10 Sputum wet weight (g)- chest physiotherapy including PEP3118Mean Difference (IV, Fixed, 95% CI)-1.54 [-3.96, 0.89]
11 Sputum dry weight (g) - chest physiotherapy including directed cough1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
12 Sputum dry weight (g)- chest physiotherapy including PEP1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
13 Breathlessness1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
Analysis 1.1.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 1 Lung function - chest physiotherapy including directed cough.

Analysis 1.2.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 2 Lung function - chest physiotherapy including PEP.

Analysis 1.3.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 3 Respiratory muscle strength (cmH20).

Analysis 1.4.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 4 Airway resistance % predicted.

Analysis 1.5.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 5 Oxygen saturation during airway clearance (%).

Analysis 1.6.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 6 Oxygen saturation during airway clearance (change in SpO2 % during treatment).

Analysis 1.7.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 7 Oxygen saturation after airway clearance (SpO2) - chest physiotherapy including directed cough.

Analysis 1.8.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 8 Oxygen saturation after airway clearance (SpO2) - chest physiotherapy including PEP.

Analysis 1.9.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 9 Sputum wet weight (g) - chest physiotherapy including directed cough.

Analysis 1.10.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 10 Sputum wet weight (g)- chest physiotherapy including PEP.

Analysis 1.11.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 11 Sputum dry weight (g) - chest physiotherapy including directed cough.

Analysis 1.12.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 12 Sputum dry weight (g)- chest physiotherapy including PEP.

Analysis 1.13.

Comparison 1 NIV versus other methods of airway clearance (chest physiotherapy including directed cough or PEP), Outcome 13 Breathlessness.

Comparison 2. NIV in overnight ventilation compared to oxygen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 CFQoL chest symptom score1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 CFQoL transitional dyspnoea index1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Symptoms of Sleep Disordered Breathing1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 Epworth Sleepiness Scale (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Global PSQI (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Lung function during sleep1 Mean Difference (Fixed, 95% CI)Totals not selected
4.1 VI (L/m) while awake (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 VI (L/m) during REM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 VI (L/m) during NREM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4.4 VT (L) while awake (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4.5 VT (L) during REM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4.6 VT (L) during NREM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
5 Lung function while awake1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 FEV1% predicted (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 FVC % predicted (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Respiratory rate (breaths/min)1 Mean Difference (Fixed, 95% CI)Totals not selected
6.1 RR while awake (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 RR during REM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 RR during NREM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean Respiratory Rate (breaths/min)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 ABG: pH1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 ABG: PaO2 (mmHg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
9.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10 ABG: PaCO2 (mmHg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
10.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
11 ABG: HCO3 (mmol/L)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
11.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12 ABG: SaO2 (%)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
12.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
13 Exercise performance (MSWT) (metres)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
13.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
14 Total sleep time (min)2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
14.1 Single night1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
14.2 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
15 REM sleep architecture2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
15.1 REM (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
15.2 REM %TST (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
15.3 REM % TST (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
16 Sleep latency (min)3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
16.1 Single night238Mean Difference (IV, Fixed, 95% CI)2.93 [-0.32, 6.19]
16.2 Up to 3 months115Mean Difference (IV, Fixed, 95% CI)-5.0 [-19.17, 9.17]
17 Nocturnal oxygen saturation (%)2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
17.1 Mean SpO2 REM (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
17.2 Mean SpO2 NREM (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
17.3 Mean SpO2 for TST (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
17.4 TST with SpO2 < 90% (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
18 Nocturnal oxygen saturation (%)1 Mean Difference (Fixed, 95% CI)Totals not selected
18.1 Percentage TST SpO2>90%1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
18.2 Percentage REM SpO2>90%1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
18.3 Percentage NREM SpO2>90%1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
19 Nocturnal TcCO2 (mmHg2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
19.1 TcCO2 during REM (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
19.2 TcCO2 during NREM (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
19.3 Mean change PtCO2 (mmHg) (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
19.4 Mean change PaCO2 (mmHg) (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
20 Nocturnal TcCO2 (mmHg)1 Mean Difference (Fixed, 95% CI)Totals not selected
20.1 Mean change TcCO2 NREM to REM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
20.2 Maximum TcCO2 (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
21 Nocturnal TcCO2 TST (mmHg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
21.1 Mean PtCO2 TST (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
21.2 Maximum PtCO2 TST (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
22 Hypopneas1 Relative rate (Fixed, 95% CI)Totals not selected
22.1 Single night1 Relative rate (Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 1 CFQoL chest symptom score.

Analysis 2.2.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 2 CFQoL transitional dyspnoea index.

Analysis 2.3.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 3 Symptoms of Sleep Disordered Breathing.

Analysis 2.4.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 4 Lung function during sleep.

Analysis 2.5.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 5 Lung function while awake.

Analysis 2.6.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 6 Respiratory rate (breaths/min).

Analysis 2.7.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 7 Mean Respiratory Rate (breaths/min).

Analysis 2.8.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 8 ABG: pH.

Analysis 2.9.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 9 ABG: PaO2 (mmHg).

Analysis 2.10.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 10 ABG: PaCO2 (mmHg).

Analysis 2.11.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 11 ABG: HCO3 (mmol/L).

Analysis 2.12.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 12 ABG: SaO2 (%).

Analysis 2.13.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 13 Exercise performance (MSWT) (metres).

Analysis 2.14.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 14 Total sleep time (min).

Analysis 2.15.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 15 REM sleep architecture.

Analysis 2.16.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 16 Sleep latency (min).

Analysis 2.17.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 17 Nocturnal oxygen saturation (%).

Analysis 2.18.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 18 Nocturnal oxygen saturation (%).

Analysis 2.19.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 19 Nocturnal TcCO2 (mmHg.

Analysis 2.20.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 20 Nocturnal TcCO2 (mmHg).

Analysis 2.21.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 21 Nocturnal TcCO2 TST (mmHg).

Analysis 2.22.

Comparison 2 NIV in overnight ventilation compared to oxygen, Outcome 22 Hypopneas.

Comparison 3. NIV in overnight ventilation compared to room air
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 CF QoL chest symptom score1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 CF QoL traditional dyspnoea index score1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Symptoms of sleep disordered breathing1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 Epworth sleepiness scale (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Global PSQI (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Lung function during sleep1 Mean Difference (Fixed, 95% CI)Totals not selected
4.1 VI while awake (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 VI during REM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 VI during NREM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4.4 VT while awake (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4.5 VT during REM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4.6 VT during NREM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
5 Lung function while awake1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 FEV1% predicted (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 FVC % predicted (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Respiratory rate(breaths/min) during sleep1 Mean Difference (Fixed, 95% CI)Totals not selected
6.1 RR while awake (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 RR during REM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 RR during NREM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mean respiratory rate1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 ABG: pH1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 ABG: PaO2 (mmHg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
9.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10 ABG: PaCO2 (mmHg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
10.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
11 ABG: HCO3 (mmol/L)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
11.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12 ABG: SaO2 (%)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
12.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
13 Exercise performance (metres)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
13.1 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
14 Total sleep time (min)2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
14.1 Single night1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
14.2 Up to 3 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
15 REM sleep architecture2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
15.1 REM (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
15.2 REM %TST (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
15.3 REM % TST (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
16 Sleep latency3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
16.1 Single night238Mean Difference (IV, Fixed, 95% CI)-2.63 [-7.37, 2.11]
16.2 At 6 weeks115Mean Difference (IV, Fixed, 95% CI)-3.00 [-19.88, 13.88]
17 Nocturnal oxygen saturation (%)2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
17.1 Mean SpO2 REM (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
17.2 Mean SpO2 NREM (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
17.3 Mean SpO2 for TST (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
17.4 TST for SpO2 < 90% (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
18 Nocturnal oxygen saturation (%)1 Mean Difference (Fixed, 95% CI)Totals not selected
18.1 Percentage TST SpO2 > 90% (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
18.2 Percentage REM SpO2 > 90% (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
18.3 Percentage NREM SpO2 > 90% (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
19 Nocturnal TcCO2 (mmHg)2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
19.1 TcCO2 during REM (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
19.2 TcCO2 during NREM (single night)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
19.3 Mean change PtCO2 (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
19.4 Mean change PaCO2 (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
20 Nocturnal TcCO2(mmHg)1 Mean Difference (Fixed, 95% CI)Totals not selected
20.1 Mean change TcCO2 NREM to REM (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
20.2 Maximum TcCO2 (single night)1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
21 Nocturnal TcCO2 TST (mmHg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
21.1 Mean PtCO2 TST (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
21.2 Max PtCO2 TST (up to 3 months)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
22 Hypopneas1 Relative rate (Fixed, 95% CI)Totals not selected
22.1 Single night1 Relative rate (Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 1 CF QoL chest symptom score.

Analysis 3.2.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 2 CF QoL traditional dyspnoea index score.

Analysis 3.3.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 3 Symptoms of sleep disordered breathing.

Analysis 3.4.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 4 Lung function during sleep.

Analysis 3.5.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 5 Lung function while awake.

Analysis 3.6.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 6 Respiratory rate(breaths/min) during sleep.

Analysis 3.7.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 7 Mean respiratory rate.

Analysis 3.8.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 8 ABG: pH.

Analysis 3.9.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 9 ABG: PaO2 (mmHg).

Analysis 3.10.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 10 ABG: PaCO2 (mmHg).

Analysis 3.11.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 11 ABG: HCO3 (mmol/L).

Analysis 3.12.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 12 ABG: SaO2 (%).

Analysis 3.13.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 13 Exercise performance (metres).

Analysis 3.14.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 14 Total sleep time (min).

Analysis 3.15.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 15 REM sleep architecture.

Analysis 3.16.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 16 Sleep latency.

Analysis 3.17.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 17 Nocturnal oxygen saturation (%).

Analysis 3.18.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 18 Nocturnal oxygen saturation (%).

Analysis 3.19.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 19 Nocturnal TcCO2 (mmHg).

Analysis 3.20.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 20 Nocturnal TcCO2(mmHg).

Analysis 3.21.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 21 Nocturnal TcCO2 TST (mmHg).

Analysis 3.22.

Comparison 3 NIV in overnight ventilation compared to room air, Outcome 22 Hypopneas.

What's new

Last assessed as up-to-date: 14 March 2013.

DateEventDescription
24 March 2014AmendedContact details updated.

History

Protocol first published: Issue 4, 2000
Review first published: Issue 2, 2003

DateEventDescription
14 March 2013New search has been performedA search of the Cochrane Cystic Fibrosis & Genetic Disorders Group's Cystic Fibrosis register did not identify any new references eligible for inclusion in this review.
14 March 2013New citation required but conclusions have not changedNo new references were included in this update of the review, hence the conclusions remain the same.
22 May 2012AmendedContact details updated.
29 March 2011New search has been performedA search of the Group's Cystic Fibrosis Trials Register identified three new references which were potentially eligible for this review. One of these was an additional reference to an already included study (Young 2008). Two references were excluded (Fauroux 2000; Riethmueller 2006).
26 April 2010AmendedContact details updated.
30 September 2008New citation required but conclusions have not changedAshley Jones has stepped down as co-author.
12 June 2008New search has been performedA search of the Group's Cystic Fibrosis Trials Register identified that the previously included 2006 abstract has now been published as a full paper (Young 2008).
12 June 2008AmendedConverted to new review format.
18 February 2008AmendedThere have been some corrections to the graph labels in the following graphs: 01 01, 01 02, 01 09, 01 10, 01 11, 01 12, 02 04, 03 07.
22 August 2007New search has been performed

The sleep data from the Milross trial, which appeared in the graphs removed in the previous update of the review, have now been more appropriately analysed using GIV methodology and are presented in this update.

A new search identified seven new references to six studies. One of these references was to an already included study (Holland 2003). Of the remaining six references to five studies, three have not been included as they were not randomised controlled trials in which a form of pressure preset or volume preset NIV versus no NIV was used in people with acute or chronic respiratory failure in CF and they have been added to the excluded studies section (Falk 2006; Fauroux 2004; Greenough 2004). Two studies were included as they fulfilled inclusion criteria (Placidi 2006; Young 2006).

22 August 2007New citation required and conclusions have changedSubstantive amendment
23 May 2004New search has been performed

Amanda Piper and joined the review team as a second co-author.

A new search identified four new references. One trial (Holland 2003) has been included and three trials have been excluded (Fauroux 2001; Serra 2000; Serra 2002).

Contributions of authors

The title for the protocol was conceived by the Cochrane Cystic Fibrosis and Genetic Disorders Group.

Both F. Moran and J. Bradley designed and assisted in writing the protocol and the review.

A. Piper has reviewed and contributed to the updated versions of the review.

F. Moran acts as guarantor of the review.

Declarations of interest

Amanda Piper was a clinical consultant to ResMed Australia until 2004. She has also been involved in: educational activities sponsored by manufacturers of bilevel devices (Mayo Healthcare, Australia; Weinmann, Germany; Air Liquide, Australia; ResMed, Australia); industry-sponsored research (ResMed, Australia) and has received equipment for research projects from distributors of bilevel equipment (Air Liquide, Australia; Mayo Healthcare, Australia).

Fidelma Moran and Judy Bradley received a NIPPY3 ventilator for a research clinical trial from Respicare.

Differences between protocol and review

In a post hoc change we have defined short-term trials as those with a duration less than three months. We decided to analyse single-night interventions separately from other short-term trials as we did not feel it appropriate to combine them with other longer trials.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Fauroux 1999

MethodsRandomised, cross-over trial.
Participants16 participants with CF. Stable participants.
Mean (SD) age 13 (4) years.
Interventions

Order of intervention was randomised.
Session 1: CPT (10 to 15 forced expiration manoeuvres separated by rest periods) and inspiratory PSV via nasal mask using pressure support generator.
Session 2: CPT with no PSV.

Sessions 20 minutes. Time between sessions unclear - paper states sessions were conducted on two different days at the same time of day by same physiotherapist.

OutcomesFVC; FEV1; PEF; FEF 25%; FEF50%; FEF25-75%; airway resistance; SpO2; RR; PI max; PE max; FEF25-75; sputum weight; subjective participants impressions of fatigue, ease sputum clearance; participant preference (1 = worse to 3 = marked preference).
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStates order of intervention was randomised, but no details given.
Allocation concealment (selection bias)Unclear riskNot discussed.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskIn one trial, participants' subjective impressions were evaluated by individuals who were not involved in the trial and were unaware of the treatment regimen; but it was not reported who was responsible for collecting and weighing secretions and lung function testing.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants were accounted for.
Selective reporting (reporting bias)Low riskAll outcome measures were reported.
Other biasLow riskMethods of statistical analysis were described.

Gozal 1997

MethodsRandomised, cross-over trial.
ParticipantsSix participants with CF and moderate to severe lung disease and significant gas exchange abnormalities during sleep. Stable participants.
Mean (SD) age 22.3 (4.7) years (range 13 - 28 years). Mean (SD) FEV1% predicted 29.4 (3.4).
InterventionsOrder of intervention was randomised.
Three nights within a 15-day period.
Session 1: Room air Session 2: Night-time low flow O2.
Session 2: Night-time bilevel NIPPV with supplemental O2.
OutcomesTST; Sleep latency; NREM; NREM %TST; REM min; REM %TST; undetermined % TST; total arousals; arousal index; SaO2; TcCO2.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStated as randomised, methods not discussed.
Allocation concealment (selection bias)Unclear riskNot discussed.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipants were obviously aware of the intervention being administered; however, all were reportedly unaware of the purpose of the trial with participants and sleep technicians blinded to the results until completion of the third night.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk2 participants dropped out due to non-tolerance of NIV; it was not explicitly stated that intention-to-treat was not used, but results are based on the remaining 6 participants who completed the trial.
Selective reporting (reporting bias)Low riskAll outcome measures were reported.
Other biasUnclear riskMethods of statistical analysis were described.

Holland 2003

MethodsRandomised cross-over trial.
Participants26 participants with CF and moderate to severe disease. Acute participants.
Mean (SD) age 27.04 (6.42) years.
Mean (SD) FEV1% predicted 33.85 (11.85).
Interventions

Order of intervention was randomised on days 3 and 4 of hospital admission.
Session 1: CPT by ACBT i.e. (thoracic expansion x6, breathing control) x2, forced expiration technique and cough as required.

Session 2: ACBT as above with NIV - EPAP 4 - 5 cmH2O, IPAP 10 - 12 cmH20 with heated humidification entrained.

OutcomesFVC; FEV1; FEF25-75; PiMax; PeMax; SpO2; sputum weight; Borg breathlessness score; participant preference.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStates order of intervention was randomised, but no details given.
Allocation concealment (selection bias)Unclear riskNot discussed.
Blinding (performance bias and detection bias)
All outcomes
Low riskAn independent data collector who was blinded to the treatment order obtained all measurements.
Incomplete outcome data (attrition bias)
All outcomes
Low riskInformation provided about one drop out at the start of testing.
Selective reporting (reporting bias)Low riskAll outcome measures were reported.
Other biasUnclear riskMethods of statistical analysis were described.

Kofler 1998

MethodsRandomised, cross-over trial.
Participants20 participants with CF. No detail on whether participants are in acute or stable state, but participants have mean (SD) S-K score of 80.8 (15.3) indicating that they have mild disease.
Mean age 15.25 years (range 6 - 23) years.
Interventions

Order of intervention was randomised.
Session 1: PEP treatment (no details of PEP treatment).
Session 2: bilevel positive airway pressure (BiPaP) treatment.

Treatment sessions on 2 successive days. Time between 2 sessions is 1 day.

OutcomesFEV1; FVC; SaO2; FEF25-75; MEF50; FEF25-75; participant preference.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStates order of intervention was randomised, but no details given.
Allocation concealment (selection bias)Unclear riskNot discussed.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskData collection was not described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants were accounted for.
Selective reporting (reporting bias)Unclear riskNot clear whether all outcomes measured were reported in this abstract.
Other biasUnclear riskMethods of statistical analysis were not described.

Milross 2001

MethodsRandomised, cross-over trial.
Participants13 participants with CF with severe lung disease.
Mean (SD) age 26 (5.9) years.
Mean (SD) FEV1 % predicted, 31.7(10.6); awake PaO2 range 53-77 mmHg; PaCO2 ≥ 45 mmHg; mean (SD) BMI 20 (3) kgm2.
Interventions

Order of intervention randomised.
Night 1: Room air and low-level CPAP (4 - 5 cm H2O).
Night 2: Oxygen (1.4 +/- 0.9L/min to maintain SaO2 ≥ 90%) and low-level CPAP (4 - 5 cm H2O).
Night 3: BVS +/- oxygen (0.7+/-0.9 L/min to maintain SaO2 ≥ 90%).

3 nights within a 1-week period. Time between nights unclear.

OutcomesVI, VT; RR; respiratory disturbance indices; SaO2 TcCO2.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStated as randomised, methods not discussed.
Allocation concealment (selection bias)Unclear riskNot discussed.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence of blinding of assessors, investigators or participants.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts.
Selective reporting (reporting bias)Low riskAll outcome measures were reported.
Other biasUnclear riskMethods of statistical analysis were described.

Placidi 2006

MethodsRandomised, cross-over trial.
Participants17 participants with CF. Severe lung disease. Acute participants.
Mean (SD) age 27 (7) years; mean (SD) FEV1% predicted 25 (6); mean (SD) BMI 18 (3) kg/m2; mean (SD) MIP% predicted 87 (17); mean (SD) wet weight sputum 5 (5) g.
InterventionsOrder of intervention randomised. Treatment twice daily for 70 mins for 2 days per intervention.
Intervention 1 directed cough;
Intervention 2 mask PEP;
Intervention 3 mask CPAP;
Intervention for NIV with IPAP 8 - 12 cmH20; EPAP 4 cmH20.
OutcomesSputum wet and dry weight; number spontaneous coughs; FEV1; mean SpO2; participants subjective impression of the effectiveness and fatigue induced by each treatment.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation of treatment order was done according to the Latin square design which provided a balanced assignment to each treatment and a balance in the sequence of treatments.
Allocation concealment (selection bias)Unclear riskNot discussed.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskReported data collection but not who was responsible for weighing sputum or collating subjective impressions induced by the treatment.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll participants were accounted for.
Selective reporting (reporting bias)Low riskAll outcome measures were reported.
Other biasUnclear riskMethods of statistical analysis were described.

Young 2008

  1. a

    Full abbreviations list can be found in "Additional Tables" (Table 1)

MethodsRandomised, cross-over trial.
Participants8 participants with CF. Moderate and severe lung disease. No details on whether participants are in acute or stable state.
Mean (SD) age 37 (8) years. Mean (SD) FEV1% predicted 35 (8). Mean (SD) BMI 21.1 (2.6) kg/m2. Mean (SD) PaCO2 52 (4) mmHg.
InterventionsOrder of intervention was randomised with a 2-week washout period; 6 weeks of nocturnal air (placebo), oxygen and NIV.
Outcomes

CF specific QoL questionnaire; daytime sleepiness; exertional dyspnoea; awake and asleep gas exchange; sleep architecture; lung function; peak exercise capacity. Neurocognitive function (PVT :mean; error; lapse); stroop color & word test; trail making test; controlled oral word association; digital span test were reported in the online supplement. They are not reported in this review as they were not relevant to the aims of this review.

Post treatment assessments were carried out during a period of clinical stability i.e. no current need for hospitalisation or intravenous antibiotics.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated Latin square design.
Allocation concealment (selection bias)Low riskSealed in sequentially numbered opaque envelopes by a person not involved in the trial and opened as each participant was enrolled.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipants remained blinded as to whether they were receiving oxygen or room air only.
Incomplete outcome data (attrition bias)
All outcomes
Low riskOne withdrawal after randomisation due to a pneumothorax. One withdrawal from NIV group due to mask discomfort (NIV n=7; O2 n=8).
Selective reporting (reporting bias)Low riskAll outcome measures were reported.
Other biasLow riskMethods of statistical analysis were described.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    NIV: non-invasive ventilation

Elkins 2004This trial did not compare NIV to increase minute ventilation and is not linked to the outcome measures in this review.
Falk 2006This trial did not use NIV.
Fauroux 2000This trial did not compare NIV with other management for acute or chronic respiratory failure.
Fauroux 2001This is not a randomised controlled trial of NIV versus no NIV.
Fauroux 2004This trial did not compare NIV with other management for acute or chronic respiratory failure.
Greenough 2004This trial did not use NIV.
Piper 1992This is not a randomised controlled trial.
Regnis 1994This is not a randomised controlled trial.
Riethmueller 2006This trial did not use NIV.
Serra 2000This is not a randomised controlled trial of NIV versus no NIV.
Serra 2002This is not a randomised controlled trial of NIV versus no NIV.

Ancillary