Timing of hypertonic saline inhalation for cystic fibrosis

Mark Elkins; Ruth Dentice

doi:10.1002/14651858.CD008816.pub4

. 2020 Feb 28;2020(2):CD008816. doi: 10.1002/14651858.CD008816.pub4

Timing of hypertonic saline inhalation for cystic fibrosis

Mark Elkins ^1,^✉, Ruth Dentice ²

Editor: Cochrane Cystic Fibrosis and Genetic Disorders Group

PMCID: PMC7046936 PMID: 32107770

Abstract

Background

Inhalation of hypertonic saline improves sputum rheology, accelerates mucociliary clearance and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review.

Objectives

To determine whether the timing of hypertonic saline inhalation (in relation to airway clearance techniques or in relation to time of day) has an impact on its clinical efficacy in people with cystic fibrosis.

Search methods

We identified relevant randomised and quasi‐randomised controlled trials from the Cochrane Cystic Fibrosis Trials Register, the Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings.

Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register: 28 February 2019.

Selection criteria

Any trial of hypertonic saline in people with cystic fibrosis where timing of inhalation was the randomised element in the study protocol with either: inhalation up to six hours before airway clearance techniques compared to inhalation during airway clearance techniques compared to inhalation up to six hours after airway clearance techniques; or morning compared to evening inhalation with any definition provided by the author.

Data collection and analysis

Both authors independently assessed the trials identified by the search for potential inclusion in the review. The certainty of the evidence was assessed using GRADE.

Main results

The searches identified 104 trial reports which represented 51 trials, of which three cross‐over trials (providing data on 77 participants) met our inclusion criteria. We present three comparisons: inhalation before versus during airway clearance techniques; inhalation before versus after airway clearance techniques; and inhalation during versus after airway clearance techniques. One trial (50 participants), given its three‐arm design, was eligible for all three comparisons. No trials compared morning versus evening inhalation of hypertonic saline.

The evidence from the three trials was judged to be of low quality downgraded for limitations (high risk of bias due to blinding) and indirectness (all participants are adults, and therefore not applicable to children). Intervention periods ranged from one treatment to three treatments in one day. There were no clinically important differences between the timing regimens of inhaling hypertonic saline before, during or after airway clearance techniques in the mean amount of improvement in lung function or symptom scores (77 participants), with the between‐group comparisons being non‐significant (low‐certainty evidence). While there may be little or no difference in the rating of satisfaction when hypertonic saline was inhaled before versus during the airway clearance techniques (64 participants) (with the 95% confidence interval including the possibility of both a higher and lower rating of satisfaction), satisfaction may be lower on a 100‐mm scale when inhaled after the airway clearance techniques compared to before: mean difference (MD) 20.38 mm (95% confidence interval (CI) 12.10 to 28.66) and when compared to during the techniques, MD 14.80 mm (95% CI 5.70 to 23.90). Perceived effectiveness showed similar results: little or no difference for inhalation before versus during airway clearance techniques (64 participants); may be lower when inhaled after the airway clearance techniques compared to before, MD 10.62 (95% CI 2.54 to 18.70); and also when compared to during the techniques, MD 15.60 (95% CI 7.55 to 23.65). There were no quality of life or adverse events reported in any of the trials.

Authors' conclusions

Timing of hypertonic saline inhalation makes little or no difference to lung function (low‐certainty evidence). However, inhaling hypertonic saline before or during airway clearance techniques may maximise perceived efficacy and satisfaction. The long‐term efficacy of hypertonic saline has only been established for twice‐daily inhalations; however, if only one dose per day is tolerated, the time of day at which it is inhaled could be based on convenience or tolerability until evidence comparing these regimens is available.

The identified trials were all of very short intervention periods, so longer‐term research could be conducted to establish the effects arising from regular use, which would incorporate the influence of changes in adherence with long‐term use, as well as generating data on any adverse effects that occur with long‐term use.

Plain language summary

The timing of inhalation of hypertonic saline in people with cystic fibrosis

Review question

We reviewed the evidence about whether the timing (in relation to airway clearance techniques or in relation to time of day) of hypertonic saline (a strong, sterile, salt water solution) through a nebuliser improves the physical properties of sputum, stimulates cough, improves clinical outcomes (such as lung function), and improves the perceived effect of airway clearance techniques in cystic fibrosis. This is an update of a previously published Cochrane Review.

Background

Regular inhalation of hypertonic saline improves the clinical outcomes of people with cystic fibrosis. It is not certain whether it is better to inhale hypertonic saline before, during or after clearing the airways with physical techniques, nor whether it is better to inhale it in the morning or in the evening. We looked for trials that compared these different timing regimens.

Search date

The evidence is current to: 28 February 2019.

Study characteristics

The review included three studies with 77 people with cystic fibrosis aged between 18 and 64 years of age. The studies looked at the impact of the timing of hypertonic saline inhalation in relation to airway clearance techniques. The studies reported immediate outcomes after inhalation of hypertonic saline before, during or after physical airway clearance techniques. All studies were short, involving only one to three treatments of each timing regimen.

Key results

While outcomes such as lung function did not show any difference between the regimens, people with cystic fibrosis perceived that inhaling hypertonic saline before or during airway clearance techniques may be more effective and satisfying than inhaling hypertonic saline after airway clearance. No studies comparing morning and evening inhalation were found. The long‐term efficacy of hypertonic saline has only been established for twice‐daily inhalations; however, if only one dose per day is tolerated, the time of day at which it is inhaled could be based on convenience or tolerability until further evidence is available.

Quality of the evidence

Overall, the quality of the evidence was low. The only issues perhaps affecting the quality related to the fact that it was not possible for participants to be blinded to the treatment they received. However, because the studies were short‐term and most of the significant results were based on perceived efficacy, timing of administration of hypertonic saline needs further study.

Summary of findings

Background

Description of the condition

Cystic fibrosis (CF) is the most common life‐limiting autosomal recessive disorder amongst Caucasians (Cutting 2002). Mucociliary clearance is impaired in CF (Robinson 1996; Robinson 1997). Cystic fibrosis‐related pulmonary disease is the major cause of morbidity and mortality (Buzzetti 2009).

Description of the intervention

Hypertonic saline is a sterile salt‐water solution delivered as a nebulised therapy, usually at a concentration of between 3% and 10% (composition by mass). Traditionally, volumes of 3 mL to 10 mL are nebulised (Elkins 2006c; Wark 2018). Long‐term use is recommended (Button 2016).

Each dose of hypertonic saline is usually nebulised immediately prior to airway clearance, but other timing regimens are sometimes used in clinical practice. The clinical effect of hypertonic saline could be affected by the timing of its delivery in relation to physical airway clearance techniques (before, during or after) or in relation to time of day (morning or evening).

How the intervention might work

Hypertonic saline has been shown to accelerate mucociliary clearance in the CF airway (Robinson 1996; Robinson 1997). Three mechanisms are believed to contribute to this improvement in mucociliary clearance. The first is restoration of the depleted airway surface liquid volume, which peaks almost immediately after a dose, but which may be sustained for several hours (Donaldson 2006). The other mechanisms are improvement in the rheology of the mucus (King 1997; Wills 1997), and stimulation of cough (Robinson 1996; Robinson 1997). The overall effect on mucus clearance is presumably responsible for the significant clinical improvements including lung function, quality of life (QoL), and ease of expectoration with regular use of the therapy (Elkins 2006b; Eng 1996). A Cochrane Review of nebulised hypertonic saline for CF concluded that improvements in forced expiratory volume at one second (FEV₁) were demonstrated over two to four weeks of therapy and QoL and pulmonary exacerbation rates were improved compared to placebo interventions over 48 weeks of treatment (Wark 2018).

In the controlled studies that established the efficacy of hypertonic saline (Elkins 2006c; Eng 1996; Robinson 1996; Robinson 1997), each dose was nebulised immediately before the administration of airway clearance techniques. However, other timing regimens may have advantages. Nebulisation of hypertonic saline during airway clearance techniques could save time. It also may capitalise on the immediate peak in the airway surface liquid volume. Nebulisation after airway clearance techniques may capitalise on the reduction in airway obstruction by mucus and therefore allow delivery of the hypertonic saline to a greater portion of the bronchial tree.

In the clinical trials that established the efficacy of the regular use of hypertonic saline (Donaldson 2006; Elkins 2006c; Eng 1996), at least two doses per day were used. However, some individuals can tolerate (or for other reasons elect to use) only one dose per day. For these people, nebulising the dose at a particular time of the day may affect its efficacy. Given that spontaneous mucociliary clearance is faster during waking hours than sleep (Bateman 1978), morning inhalation of hypertonic saline may capitalise on faster daytime mucociliary clearance and on the mucus‐clearing effects of daytime activities such as exercise (Wolff 1977). Some people with CF find evening inhalation more convenient or report that it improves ease of expectoration the following morning. Since mucociliary clearance and coughing are suppressed overnight, evening inhalation of hypertonic saline may increase its dwell time in the airways, possibly increasing its clinical efficacy.

Why it is important to do this review

Despite the theoretical rationales presented to justify the investigation of alternative timing regimens in the previous section, it is also possible that any timing regimen may have adverse effects on the efficacy, tolerability and convenience of the treatment and on the duration of the airway clearance session. For example, nebulisation of hypertonic saline during airway clearance techniques could increase the complexity of the overall session of airway clearance, perhaps requiring modified equipment. Nebulisation after airway clearance techniques presumably delivers the hypertonic saline more directly to the exposed airway epithelium, rather than an overlying mucus layer, which may reduce tolerability. Evening delivery may increase nocturnal coughing and sleep disturbance. Therefore, it is important to review well‐designed research that compares the regimens.

There is a high treatment burden associated with CF for both people with the disease and for care providers. Hypertonic saline inhalation adds to the duration of the overall treatment regimen. Therefore, even if the various timing regimens have equal clinical efficacy, it is important that the review also investigates whether the interventions differ in their effects on the duration of the overall airway clearance session, in their convenience and in their side effects.

This is an update of a previously published Cochrane Review (Elkins 2012; Elkins 2016).

Objectives

To determine whether the timing of hypertonic saline inhalation, in relation to physical airway clearance techniques or time of day, has an impact on objective and subjective measures of clinical efficacy and tolerability in people with CF.

Methods

Criteria for considering studies for this review

Types of studies

Randomised trials (published and unpublished). Both random allocation and quasi‐random allocation (e.g. where there is alternate allocation to groups) were included. Parallel and cross‐over trials were eligible.

Types of participants

People of all ages and of both sexes with CF diagnosed by genetic testing or evidence on sweat chloride or nasal potential difference, including all degrees of disease severity.

Types of interventions

Nebulised hypertonic saline, where timing of inhalation was the randomised element in the study protocol:

hypertonic saline inhalation up to six hours before airway clearance techniques, compared to inhalation during airway clearance techniques;
hypertonic saline inhalation up to six hours before airway clearance techniques, compared to up to six hours after airway clearance techniques;
hypertonic saline inhalation during airway clearance techniques, compared to up to six hours after airway clearance techniques;
morning compared to evening inhalation with any definition provided by the author. If not defined, we accepted midnight to midday as morning and midday to midnight as evening.

Note: many individuals perform two treatments with physical airway clearance techniques each day. Even if these treatments are performed as far as possible from each other (i.e. 12 hours apart), any threshold greater than six hours would mean that the hypertonic saline labelled ‘before’ would actually be closer to ‘after’ the previous treatment with physical airway clearance techniques. Therefore, six hours is the broadest threshold possible to capture all potentially relevant trials. However, some of the mechanisms by which timing may affect the outcome are short‐lived. Therefore, a sensitivity analysis is performed that only considers trials where the hypertonic saline is within 30 min of the techniques (seeSensitivity analysis).

The timing regimen could be a single treatment or could be maintained for any duration.

Hypertonic saline treatment had to be a minimum of a single dose of at least 3% concentration. If studies mentioned co‐interventions (such as bronchodilators and other inhaled medications), these were permitted provided they were the same on all trial days and taken either before or after the period during which hypertonic saline and airway clearance techniques were used.

Airway clearance techniques (ACT) had to be a minimum of 10 minutes in duration and include at least one of the following:

postural drainage with percussion and vibration (PDPV). In other reviews this has been described as conventional chest physiotherapy (CCPT) (Elkins 2006c; Main 2009; van der Schans 2009);
active cycle of breathing techniques (ACBT).This comprises relaxation or breathing control, forced expiration technique (FET), thoracic expansion exercises and may include postural drainage or percussion (Robinson 2010);
autogenic drainage (AD). This breathing technique uses high expiratory flow rates at varying lung volumes to enhance mucus clearance while avoiding airway closure;
positive expiratory pressure (PEP) (Elkins 2006a);
oral oscillatory devices that provide oscillating PEP (such as the Flutter, Cornet and Acapella) or intrapulmonary percussive ventilation, which provides continuous oscillation of the air pressure in the airways via the mouth (Morrison 2009);
thoracic oscillating devices applied via a vest to provide external chest wall oscillation (Morrison 2009);
exercise prescribed for the purpose of airway clearance either independently or as an adjunct to other techniques.

Types of outcome measures

Primary outcomes

Lung function, i.e., change in lung function (measured in litres or % predicted). If change values are unavailable, final post‐treatment values will be used. Values in litres and in % predicted will be analysed separately.
1. forced expiratory volume at one second (FEV₁)
2. forced vital capacity (FVC)
Patient‐reported outcomes, using validated scales or subjective reporting measures
1. measures of QoL
2. symptom scores (including cough, tolerability, subjective ease of clearance, or treatment satisfaction)

Secondary outcomes

Measures of sputum clearance, including measures of mucociliary clearance (assessed by radioactive tracer clearance) and objective measures of sputum volume
Measures of exercise capacity (either maximal or submaximal where measured directly, or by a standard field test)
Mortality (all cause or CF‐related, analysed separately)
Other pulmonary parameters
1. forced expiratory flow between 25% and 75% of the vital capacity (FEF_25‐75)
2. maximal instantaneous forced flow when 25% of the FVC remains to be exhaled (MEF₂₅)
3. total lung capacity (TLC)
4. residual volume (RV)
5. functional residual capacity (FRC)
6. lung clearance index (LCI)
Frequency of exacerbations of respiratory infection (where a clear definition is described demonstrating an increase in symptoms or a decline in pulmonary function)
1. admission rates to hospital (defined as either number of inpatient hospital admissions or days as a hospital inpatient)
2. courses of IV antibiotics (whether received in hospital or in the home)
3. outpatient treatments (presentations to hospital, unscheduled visits to the doctor)
Adherence to inhaled therapies, airway clearance techniques, and other therapies
Adverse effects such as bronchospasm, cough and acute decline in pulmonary function

Search methods for identification of studies

A comprehensive search strategy was formulated in an attempt to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).

Electronic searches

We identified relevant trials from the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register using the term 'hypertonic saline'.

The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library), weekly searches of MEDLINE, a search of Embase to 1995 and the prospective handsearching of two journals ‐ Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work was identified by searching the abstract books of relevant conferences, including the 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 Cochrane Cystic Fibrosis and Genetic Disorders Group's website.

Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register: 28 February 2019.

In addition, we searched the Physiotherapy Evidence Database (PEDro) (Michaleff 2011) and the WHO International Clinical Trials Registry Platform for all years available (Appendix 1; Appendix 2). Date of last search: 21 February 2019.

Searching other resources

We hand‐searched the biennial Australia and New Zealand CF Conference Proceedings from 1995 to 2017.

We contacted trial authors, experts and manufacturers of hypertonic saline to identify additional trials.

We searched the reference lists of the included studies.

Data collection and analysis

Selection of studies

Both authors (RD, ME) independently selected the trials to be included in the review. We performed initial screening by title and abstract, and reviewed the full text for studies remaining after the initial screening phase. We resolved disagreements by discussion. We excluded irrelevant records and have presented the details of these excluded trials and the reasons for exclusion in tabular form (Characteristics of excluded studies).

Data extraction and management

Each author independently extracted data from the included studies using a standardised data extraction form. We resolved any disagreements by discussion. Where data were absent or difficult to interpret in the presented form, the authors contacted the trial investigators to gain the information required to evaluate risk of bias in the trial and to facilitate data analysis. Data extraction was also carried out at the editorial base for the Dentice trial given we (the Cochrane Review authors) are also two of the trial authors (Dentice 2012).

Assessment of risk of bias in included studies

We independently determined the risk of bias for each trial using published and unpublished data from the trial investigators, following the domain‐based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1 (Higgins 2011). The risk of bias was also carried out at the editorial base for the Dentice trial given we (the Cochrane Review authors) are also two of the trial authors (Dentice 2012). We assessed the following domains as either low risk, unclear risk, or high risk of bias:

sequence generation;
allocation concealment;
blinding (of participants, personnel and outcome assessors);
incomplete outcome data;
selective outcome reporting;
other sources of bias.

We resolved any disagreements by discussion. In addition, each author independently rated each trial on the PEDro Scale (Maher 2003; de Morton 2009), using published and unpublished data from the trial investigators. The PEDro Scale was chosen because it has acceptably high reliability for individual ratings and for consensus ratings (Maher 2003; Shiwa 2011). It has undergone extensive validation including convergent and construct validity and the appropriateness of the scoring system has been justified with Rasch analysis (de Morton 2009). The PEDro Scale is also widely used and understood by physiotherapists (Elkins 2013). The Cochrane Risk of Bias tool has reliability that ranges from poor to slight (Armijo‐Olivo 2012; Hartling 2009; Hartling 2013).

Measures of treatment effect

For dichotomous data we planned to use the risk ratio (RR) with 95% confidence intervals (95% CIs) as a measure of treatment effect with an intention‐to‐treat analysis. An intention‐to‐treat analysis means that, where participants did not receive treatment as allocated, and were measures of outcomes were available, the analysis was performed as if participants received the treatment to which they were allocated. We considered a trial to have analysed by intention to treat if the report explicitly states that all participants received treatment or control conditions as allocated. Mortality and adverse events were the only dichotomous outcomes.

For continuous data we planned to record the difference in mean change from baseline and standard deviation (SD) (or standard errors (SE)) for each group, or the final group means and SDs if change data are unavailable. We planned to calculate a pooled estimate of treatment effect using the mean difference (MD) with 95% CIs.

However, given that both of the included trials were cross‐over in design, we used the generic inverse variance method. Where the MD and SE of the MD were available, we entered these directly into the meta‐analysis. Where only group means and SDs were available, we calculated the MD by subtraction of one group mean from the other. We imputed the SD of the differences from that obtained from the data in a similar trial, taking into account the paired nature of the data. We then calculated SEs using the formula: imputed SD / √n.

Unit of analysis issues

We incorporated data from cross‐over trials into meta‐analysis using the generic inverse variance method, involving expression of data in terms of the paired mean differences between treatments and their SE. We calculated these values either from paired individual patient data provided by authors, or by calculation of mean differences between interventions and their SE from means, SDs and P values reported in the manuscript (Elbourne 2002). We intended to combine data from parallel‐designed trials with those from cross‐over trials in the meta‐analyses, but only cross‐over trials were obtained. If necessary, we intended to calculate the SEs in parallel trials from the MDs between treatments and their CIs, but only cross‐over trials were obtained.

Dealing with missing data

Where data were absent or difficult to interpret in the presented form, we contacted the trial investigators in an attempt to obtain the data in a form that would facilitate data analysis. Had we not been able to obtain the data, our plan was to analyse only the available data (available‐case analysis). Additional data were obtained from the authors of the van Ginderdeuren trial (Van Ginderdeuren 2011). Additional data were sought from the authors of the O'Neill trial (O'Neill 2016) and data were received for all requested outcomes.

Assessment of heterogeneity

We visually inspected forest plots for overlap of the CIs and estimated statistical heterogeneity using the I² value (Higgins 2003). Given that thresholds for the interpretation of I² can be misleading (since the importance of inconsistency depends on several factors) we chose a rough guide to interpretation as follows: moderate heterogeneity was defined as an I² value of 30% to 60%, substantial heterogeneity was defined as an I² value of 50% to 90%, and considerable heterogeneity was defined as an I² value of 75% to 100%. The P value from the chi‐squared test was also used to interpret the importance of the observed value of I². Clinical heterogeneity was also assessed by considering differences in trial designs and participants characteristics.

Assessment of reporting biases

If we had included sufficient trials in the review, we planned to assess publication bias using a funnel plot. If we suspected outcome reporting bias, we planned to contact trial investigators to clarify whether they measured and analysed certain outcomes and obtained the data. However, only two eligible trials were obtained; this was fewer than the recommended number of studies to construct a funnel plot so we were unable to assess whether outcome reporting bias was likely.

Data synthesis

We analysed the following between‐group comparisons where possible:

hypertonic saline inhalation up to six hours before airway clearance techniques, compared to inhalation during airway clearance techniques;
hypertonic saline inhalation up to six hours before airway clearance techniques, compared to up to six hours after airway clearance techniques;
hypertonic saline inhalation during airway clearance techniques, compared to up to six hours after airway clearance techniques;
morning compared to evening inhalation with any definition provided by the author. If not defined, we accepted midnight to midday as morning and midday to midnight as evening.

We performed meta‐analyses using a fixed‐effect model. However, if we had observed substantial heterogeneity, we planned to use a random‐effects model. We planned to further explore heterogeneity in the planned subgroup analyses.

Subgroup analysis and investigation of heterogeneity

We planned a subgroup analysis for different concentrations of hypertonic saline inhalation: low hypertonic concentrations (3% to 5%); medium (6% to 7%); and high (8% to 10%). We also planned to perform a subgroup analysis for intervention duration: less than two weeks; two to eight weeks; and greater than eight weeks. However, the included studies did not permit these analyses.

Sensitivity analysis

We planned to conduct sensitivity analyses to assess the robustness of the review results by repeating the analyses with the following adjustments:

exclusion of trials with unclear or inadequate sequence generation;
exclusion of trials with unclear or inadequate allocation concealment;
exclusion of trials that scored less than 5 out of 10 on the PEDro Scale (Maher 2003);
modifying the definition of 'before' and 'after' airway clearance techniques to within 30 minutes of the techniques;
with and without cross‐over trials.

However, the included studies did not permit these analyses.

Summary of findings tables

In a post hoc change, we have presented three summary of findings tables, one for each comparison (Table 1; Table 2; Table 3). We have included the following outcomes: FEV₁, FVC, measures of QoL, symptom scores, measures of sputum clearance, lung clearance index and adverse events.

Summary of findings for the main comparison. Inhalation before compared with during airway clearance techniques for cystic fibrosis.

Inhalation before compared with during airway clearance techniques for cystic fibrosis
Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: inhalation before airway clearance techniques Comparison: inhalation during airway clearance techniques
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Inhalation during airway clearance techniques	Inhalation before airway clearance techniques
FEV₁ % predicted Follow‐up: before treatment to ˜2 hours later	Not reported¹	The mean FEV₁ (% predicted) was 0.56% higher (0.48% lower to 1.60% higher) in the inhalation before airway clearance techniques.	NA	63 (2 studies)	⊕⊕⊖⊖ low^2,3	FEV₁ (L) also showed no statistically significant difference between groups. Participants received both inhalation approaches as cross‐over design.
FVC % predicted Follow‐up: before treatment to 2 hours later	Not reported¹	The mean FVC (% predicted) was 2.09% higher (0.08% higher to 4.11% higher) in the inhalation before airway clearance techniques.	NA	50 (1 study)	⊕⊕⊖⊖ low^2,3	FEV₁ (L) showed no statistically significant difference between groups. Participants received both inhalation approaches as cross‐over design.
QoL	Outcome not reported.		NA	NA	NA
Symptom scores	See comments.		NA	76 (3 studies)	⊕⊕⊖⊖ low^2,3	All of the symptom scores suggest no statistically significant difference between the groups. This outcome includes a range of symptom scores from many different studies but number of participants contributing to each symptom score varies.
Measures of sputum clearance: sputum wet weight immediately (g)	Not reported¹	The mean wet weight of sputum during the application of the intervention was 0.26 g lower (4.79 g lower to 4.27 g higher) in the inhalation before airway clearance techniques.	NA	26 (2 studies)	⊕⊕⊖⊖ low^2,3	The mean wet weight of sputum for the 24 hours following treatment suggests no statistically significant difference between the groups. Participants received both inhalation approaches as cross‐over design.
LCI Follow‐up: 90 minutes later	Not reported¹	The mean LCI was 0.02 lower (0.63 lower to 0.59 higher) in the inhalation before airway clearance techniques.	NA	13 (1 study)	⊕⊕⊖⊖ low^2,3	The mean LCI immediately after treatment suggests no statistically significant difference between the groups. Participants received both inhalation approaches as cross‐over design.
Adverse events	Outcome not reported.		NA	NA	NA
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; FEV₁: forced expiratory volume at 1 second; FVC: forced vital capacity; LCI: lung clearance index; MD: mean difference; QoL: quality of life
GRADE Working Group grades of evidence  High certainty: further research is very unlikely to change our confidence in the estimate of effect.  Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low certainty: we are very uncertain about the estimate.

Inhalation before compared with after airway clearance techniques for cystic fibrosis
Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: inhalation before airway clearance techniques Comparison: inhalation after airway clearance techniques
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Inhalation after airway clearance techniques	Inhalation before airway clearance techniques
FEV₁ % predicted Follow‐up: before treatment to 2 hours later	Not reported¹	The mean FEV₁ (% predicted) was 0.75% higher (0.45% lower to 1.95% higher) in the inhalation before airway clearance techniques.	NA	50 (1 study)	⊕⊕⊖⊖ low^2,3	FEV₁ (L) also showed no statistically significant difference between groups. Participants received both inhalation approaches as cross‐over design.
FVC % predicted Follow‐up: before treatment to 2 hours later	Not reported¹	The mean FVC (% predicted) was 1.66% higher (1.42% lower to 4.74% higher) in the inhalation before airway clearance techniques.	NA	50 (1 study)	⊕⊕⊖⊖ low^2,3	FVC (L) showed no statistically significant difference between groups. Participants received both inhalation approaches as cross‐over design.
QoL	Outcome not reported.		NA	NA	NA
Symptom scores	See comments.		NA	50 (1 study)	⊕⊕⊖⊖ low^2,3	Three symptom scores have been presented: Perceived efficacy shows a statistically significant difference in favour of inhalation before airway clearance techniques (MD 10.62; 95% CI 2.54 to 18.70) Tolerability showed no statistically significant difference between groups. Satisfaction shows a statistically significant difference in favour of inhalation before airway clearance techniques, MD 20.38 (95% CI 12.10 to 28.66)
Measures of sputum clearance	Outcome not reported.		NA	NA	NA
LCI	Outcome not reported		NA	NA	NA
Adverse events	Outcome not reported		NA	NA	NA
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; FEV₁: forced expiratory volume at 1 second; FVC: forced vital capacity; LCI: lung clearance index; MD: mean difference; QoL: quality of life
GRADE Working Group grades of evidence  High certainty: further research is very unlikely to change our confidence in the estimate of effect.  Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low certainty: we are very uncertain about the estimate.

Inhalation during compared with after airway clearance techniques for cystic fibrosis
Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: inhalation during airway clearance techniques Comparison: Inhalation after airway clearance techniques
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Inhalation after airway clearance techniques	Inhalation during airway clearance techniques
FEV₁ % predicted Follow‐up: before treatment to 2 hours later	Not reported¹	The mean FEV₁ (% predicted) was 0.03% lower (1.19% lower to 1.12% higher) in the inhalation during airway clearance techniques.	NA	50 (1 study)	⊕⊕⊖⊖ low^2,3	FEV₁ (L) also showed no statistically significant difference between groups. Participants received both inhalation approaches as cross‐over design.
FVC % predicted Follow‐up: before treatment to 2 hours later	Not reported¹	The mean FVC (% predicted) was 0.44% lower (3.34% lower to 2.46% higher) in the inhalation during airway clearance techniques.	NA	50 (1 study)	⊕⊕⊖⊖ low^2,3	FVC (L) also showed no statistically significant difference between groups. Participants received both inhalation approaches as cross‐over design.
QoL	Outcome not reported.		NA	NA	NA
Symptom scores	See comments.		NA	50 (1 study)	⊕⊕⊖⊖ low^2,3	Three symptom scores have been presented: Perceived efficacy shows a statistically significant difference in favour of inhalation during airway clearance techniques, MD 15.60 (95% CI 7.55 to 23.65) Tolerability showed no statistically significant difference between groups. Satisfaction shows a statistically significant difference in favour of inhalation during airway clearance techniques, MD 14.80 (95% CI 5.70 to 23.90)
Measures of sputum clearance	Outcome not reported.		NA	NA	NA
LCI	Outcome not reported.		NA	NA	NA
Adverse events	Outcome not reported.		NA	NA	NA
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; FEV₁: forced expiratory volume at 1 second; FVC: forced vital capacity; LCI: lung clearance index; MD: Mean difference; QoL: quality of life
GRADE Working Group grades of evidence  High certainty: further research is very unlikely to change our confidence in the estimate of effect.  Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low certainty: we are very uncertain about the estimate.

Date	Event	Description
24 February 2020	New citation required but conclusions have not changed	The conclusions have not been not changed, however, one recommendation for future research has been added.
24 February 2020	New search has been performed	A search of the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register identified seven potentially‐eligible references to five trials, one was an additional reference to a study already awaiting classification (O'Neill 2016), which has now been included in the review.

Date	Event	Description
20 December 2016	New search has been performed	Changes have been made throughout the review. Two new trials have been included in the review (Dentice 2012; Van Ginderdeuren 2011).
20 December 2016	New citation required and conclusions have changed	Previously there were no trials included in the review; however, for this update, two trials have been included (with a total of 63 participants) (Dentice 2012; Van Ginderdeuren 2011).

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 FEV₁ (L)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
2 FEV₁ (% pred)	2	Mean Difference (Fixed, 95% CI)	0.56 [‐0.48, 1.60]
3 FVC (L)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
4 FVC (% pred)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
5 Coughs (n)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
6 Dyspnoea (mm)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
7 Tolerability (mm)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
8 Perceived efficacy (mm)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
9 Ease (mm)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
10 Ease rated by therapist (mm)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
11 Satisfaction (mm)	2	Mean Difference (Fixed, 95% CI)	4.91 [‐1.58, 11.41]
12 Satisfaction rated by therapist (mm)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
13 Sputum wet weight immediately (g)	2	Mean Difference (Fixed, 95% CI)	‐0.26 [‐4.79, 4.27]
14 Sputum wet weight next 24 hours (g)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
15 FEF_25‐75 (% pred)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
16 FRC immediately (L)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
17 FRC at 90 min (L)	1	Mean Difference (Fixed, 95% CI)	Totals not selected
18 LCI immediately	1	Mean Difference (Fixed, 95% CI)	Totals not selected
19 LCI at 90 min	1	Mean Difference (Fixed, 95% CI)	Totals not selected

Methods	Randomised, cross‐over trial with concealed allocation, intention‐to‐treat analysis and blinded assessors; investigating the impact of timing of hypertonic saline inhalation in relation to airway clearance techniques. The inhalation blocks were for one day. The three treatments of the allocated timing regimen were performed on each of the three trial days, with no washout day.
Participants	50 adults (mean age 31 years, SD 10, range 18 ‐ 64 years) with a confirmed diagnosis of cystic fibrosis who were clinically stable with an FEV₁ within 10% of the best recorded value in the last 6 months. This trial excluded people who were hypertonic saline naïve or previously intolerant, a lung transplant recipient, colonised with Burkholderia cepacia complex, not clinically stable, haemoptysis greater than 60 mL within the last month, thrombocytopenia or pregnancy.
Interventions	4 mL of 6% hypertonic saline was nebulised via an LC Star nebuliser 3 times per day with the allocated timing regimen for that day. Hypertonic saline was nebulised immediately before or after airway clearance or during (with blocks of inhalation and pauses for airway clearance). The airway clearance technique was optimised for each participant on recruitment to the trial and was standardised for all 3 trial days.
Outcomes	The primary outcome was the change in FEV₁ and FVC (in litres and percentage of the predicted value) recorded prior to and two hours following the middle treatment session of each trial day. Symptom scores at the end of each intervention arm were also recorded: perceived effectiveness, tolerability and satisfaction rated on a 100 mm visual analogue scale. Adverse events and adherence were also recorded.
Notes	PEDro Score: 8/10 [Eligibility criteria: yes; random allocation: yes; concealed allocation: yes; baseline comparability: yes; blind participants: no; blind therapists: no; blind assessors: yes; adequate follow up: yes; intention‐to‐treat analysis: yes; Between‐group comparisons: yes; point estimates and variability: yes. Note: eligibility criteria item does not contribute to total score].
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random allocation list.
Allocation concealment (selection bias)	Low risk	Sealed opaque envelopes.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Stated "no withdrawals" and intention‐to‐treat analysis used.
Selective reporting (reporting bias)	Low risk	Consistent with the prospectively registered trial protocol.
Other bias	Low risk	None identified.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Participants were unblinded to the timing regimen.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Outcome assessors were blinded.

Methods	Randomised cross‐over trial. The physiotherapist collecting the outcome measures was blinded.
Participants	14 adults with CF recruited, 13 completed the trial (mean (SD) age 33 years (12), FEV₁% predicted 51 (22), LCI (no. turnovers) 14 (4)).
Interventions	ACTs after HTS inhalation or ACTs during HTS inhalation on alternate days. Between days 10 – 14 of intravenous antibiotic course during a pulmonary exacerbation. ACT treatment consisted of 10 cycles of active cycle of breathing technique using an Acapella^®.
Outcomes	Participants completed a multiple breath washout (MBW) test to obtain LCI and spirometry (FEV₁) at baseline and 90 min post treatment. Sputum collection during 90 min, ease of clearance and satisfaction with treatment was also recorded. Wilcoxon test was used and P < 0.05 was considered significant.
Notes	PEDro Score: 8/10 [Eligibility criteria: yes; random allocation: yes; concealed allocation: yes; baseline comparability: yes; blind participants: no; blind therapists: no; blind assessors: yes; adequate follow up: yes; intention‐to‐treat analysis: yes; Between‐group comparisons: yes; point estimates and variability: yes. Note: eligibility criteria item does not contribute to total score].
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was electronically generated.
Allocation concealment (selection bias)	Low risk	The random allocation list was concealed by an administrator independent of the trial.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	One participant was lost to follow‐up.
Selective reporting (reporting bias)	Low risk	Consistent with the prospectively registered trial protocol.
Other bias	Low risk	None identified.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Participants were unblinded to the timing regimen.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Outcome assessors were blinded.

Study	Reason for exclusion
Adde 2004	Intervention not related to the timing of hypertonic saline inhalation.
Amin 2010	Intervention not related to the timing of hypertonic saline inhalation.
Amin 2016	Intervention not related to the timing of hypertonic saline inhalation.
Aquino 2012	Intervention not related to the timing of hypertonic saline inhalation.
Balinotti 2015	Intervention not related to the timing of hypertonic saline inhalation.
Ballmann 2002	Intervention not related to the timing of hypertonic saline inhalation.
Brivio 2013	Intervention not related to the timing of hypertonic saline inhalation.
Brown 2010	Intervention not related to the timing of hypertonic saline inhalation.
Buonpensiero 2010	Intervention not related to the timing of hypertonic saline inhalation.
Cardinale 2003	Intervention not related to the timing of hypertonic saline inhalation.
Chadwick 1997	Intervention not related to the timing of hypertonic saline inhalation.
Corcoran 2017	Intervention not related to the timing of hypertonic saline inhalation.
De Cono 2008	Intervention not related to the timing of hypertonic saline inhalation.
Dentice 2013	Intervention not related to the timing of hypertonic saline inhalation.
Donaldson 2003	Intervention not related to the timing of hypertonic saline inhalation.
Donaldson 2006	Intervention not related to the timing of hypertonic saline inhalation.
Donaldson 2013	Intervention not related to the timing of hypertonic saline inhalation.
Dwyer 2013	Intervention not related to the timing of hypertonic saline inhalation.
Elkins 2006c	Intervention not related to the timing of hypertonic saline inhalation.
Elkins 2006d	Intervention not related to the timing of hypertonic saline inhalation.
Eng 1996	Intervention not related to the timing of hypertonic saline inhalation.
Furnari 2012	Intervention not related to the timing of hypertonic saline inhalation.
Grasemann 2005	Did not involve administration of hypertonic saline.
Grasemann 2013	Did not involve administration of hypertonic saline.
Grieve 2003	Intervention not related to the timing of hypertonic saline inhalation.
Gupta 2012	Intervention not related to the timing of hypertonic saline inhalation.
Herrero 2016	Different airway clearance techniques in the two study arms confound the comparison of the effects of timing.
Hofmann 1997	Intervention not related to the timing of hypertonic saline inhalation.
Homola 2013	Intervention not related to the timing of hypertonic saline inhalation.
Kobylyansky 2000	Intervention not related to the timing of hypertonic saline inhalation.
Laube 2009	Intervention not related to the timing of hypertonic saline inhalation.
Mainz 2015	Intervention not related to the timing of hypertonic saline inhalation.
Nenna 2017	Intervention not related to the timing of hypertonic saline inhalation.
Palacio 2014	Intervention not related to the timing of hypertonic saline inhalation.
Riedler 1996	Intervention not related to the timing of hypertonic saline inhalation.
Robinson 1996	Intervention not related to the timing of hypertonic saline inhalation.
Robinson 1997	Intervention not related to the timing of hypertonic saline inhalation.
Robinson 1999	Intervention not related to the timing of hypertonic saline inhalation.
Ros 2012	Intervention not related to the timing of hypertonic saline inhalation.
Rosenfeld 2012	Intervention not related to the timing of hypertonic saline inhalation.
Ruiz 2012	Intervention not related to the timing of hypertonic saline inhalation.
Stahl 2017	Intervention not related to the timing of hypertonic saline inhalation.
Suri 2002	Intervention not related to the timing of hypertonic saline inhalation.
Suri 2007	Intervention not related to the timing of hypertonic saline inhalation.
Teper 2012	Intervention not related to the timing of hypertonic saline inhalation.
Vanlaethem 2008	Intervention not related to the timing of hypertonic saline inhalation.

PERMALINK

Timing of hypertonic saline inhalation for cystic fibrosis

Mark Elkins

Ruth Dentice

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings tables

Summary of findings for the main comparison. Inhalation before compared with during airway clearance techniques for cystic fibrosis.

Summary of findings 2. Inhalation before compared with after airway clearance techniques for cystic fibrosis.

Summary of findings 3. Inhalation during compared with after airway clearance techniques for cystic fibrosis.

Results

Description of studies

Results of the search

Included studies

1.

Trial characteristics

Participants

Interventions

Outcomes measures

Excluded studies

Risk of bias in included studies

2.

Allocation

Generation of sequence

Concealment of allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Inhalation before versus during airway clearance techniques

Primary outcomes

1. Lung function

a. FEV1

1.1. Analysis.

1.2. Analysis.

b. FVC

1.3. Analysis.

1.4. Analysis.

2. Patient‐reported outcomes

a. QoL

b. Symptom scores

1.5. Analysis.

a. FEV₁

a. FEF_25‐75

a. FEV₁

a. FEV₁