Nebuliser systems for drug delivery in cystic fibrosis

  • Review
  • Intervention

Authors


Abstract

Background

Nebuliser systems are used to deliver medications to control the symptoms and the progression of lung disease in people with cystic fibrosis. Many types of nebuliser systems are available for use with various medications; however, there has been no previous systematic review which has evaluated these systems.

Objectives

To evaluate effectiveness, safety, burden of treatment and adherence to nebulised therapy using different nebuliser systems for 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 of relevant journals and abstract books of conference proceedings. We searched the reference lists of each study for additional publications and approached the manufacturers of both nebuliser systems and nebulised medications for published and unpublished data.

Date of the most recent search: 15 Oct 2012.

Selection criteria

Randomised controlled trials or quasi-randomised controlled trials comparing nebuliser systems including conventional nebulisers, vibrating mesh technology systems, adaptive aerosol delivery systems and ultrasonic nebuliser systems.

Data collection and analysis

Two authors independently assessed studies for inclusion. They also independently extracted data and assessed the risk of bias. A third author assessed studies where agreement could not be reached.

Main results

The search identified 40 studies with 20 of these (1936 participants) included in the review. These studies compared the delivery of tobramycin, colistin, dornase alfa, hypertonic sodium chloride and other solutions through the different nebuliser systems. This review demonstrates variability in the delivery of medication depending on the nebuliser system used. Conventional nebuliser systems providing higher flows, higher respirable fractions and smaller particles decrease treatment time, increase deposition and may be preferred by people with CF, as compared to conventional nebuliser systems providing lower flows, lower respirable fractions and larger particles. Nebulisers using adaptive aerosol delivery or vibrating mesh technology reduce treatment time to a far greater extent. Deposition (as a percentage of priming dose) is greater than conventional with adaptive aerosol delivery. Vibrating mesh technology systems may give greater deposition than conventional when measuring sputum levels, but lower deposition when measuring serum levels or using gamma scintigraphy. The available data indicate that these newer systems are safe when used with an appropriate priming dose, which may be different to the priming dose used for conventional systems. There is an indication that adherence is maintained or improved with systems which use these newer technologies, but also that some nebuliser systems using vibrating mesh technology may be subject to increased failures.

Authors' conclusions

Clinicians should be aware of the variability in the performance of different nebuliser systems. Technologies such as adaptive aerosol delivery and vibrating mesh technology have advantages over conventional systems in terms of treatment time, deposition as a percentage of priming dose, patient preference and adherence. There is a need for long-term randomised controlled trials of these technologies to determine patient-focused outcomes (such as quality of life and burden of care), safe and effective dosing levels of medications and clinical outcomes (such as hospitalisations and need for antibiotics) and an economic evaluation of their use.

Résumé scientifique

Systèmes de nébulisation pour l'administration de médicaments dans la mucoviscidose

Contexte

Les systèmes de nébulisation sont utilisés pour administrer des médicaments destinés à contrôler les symptômes et la progression de la maladie pulmonaire chez les personnes atteintes de mucoviscidose. De nombreux types de systèmes de nébulisation peuvent être utilisés avec différents médicaments ; toutefois, aucune revue systématique antérieure n'a évalué ces systèmes.

Objectifs

Évaluer l'efficacité, la sécurité d'emploi, les contraintes du traitement et l'observance du traitement nébulisé en utilisant différents systèmes de nébulisation chez des personnes atteintes de mucoviscidose.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d'essais cliniques du groupe Cochrane sur la mucoviscidose et autres maladies génétiques constitué de références identifiées lors de recherches exhaustives dans les bases de données électroniques, de recherches manuelles de revues pertinentes et de résumés d'actes de conférence. Nous avons effectué des recherches dans les références bibliographiques de chaque étude pour trouver des publications supplémentaires et avons rencontré les fabricants à la fois des systèmes de nébulisation et des médicaments nébulisés pour obtenir des données publiées et non publiées.

Date de la recherche la plus récente : 15 octobre 2012.

Critères de sélection

Les essais contrôlés randomisés ou quasi-randomisés comparant des systèmes de nébulisation y compris les nébuliseurs classiques, les systèmes utilisant une technologie de tamis vibrant, les systèmes d'administration d'aérosol adaptative et les générateurs ultrasonores.

Recueil et analyse des données

Deux auteurs ont évalué de manière indépendante les études en vue de leur inclusion. Ils ont également extrait les données et évalué le risque de biais de manière indépendante. Un troisième auteur a évalué les études lorsqu'aucun accord n'a pu être atteint.

Résultats principaux

La recherche a identifié 40 études parmi lesquelles 20 ont été incluses (1936 participants) dans la revue. Ces études ont comparé l'administration de tobramycine, colistine, dornase alfa, chlorure de sodium hypertonique et d'autres solutions par les différents systèmes de nébulisation. Cette revue révèle une variabilité dans l'administration du médicament en fonction du système de nébulisation utilisé. Les systèmes de nébulisation classiques générant des débits plus forts, des fractions respirables plus grandes et des particules plus petites réduisent la durée du traitement, augmentent la quantité de médicament qui se dépose et peuvent avoir la préférence des personnes atteintes de mucoviscidose, comparés aux systèmes de nébulisation classiques générant des débits plus faibles, des fractions respirables plus petites et des particules plus grosses. Les nébuliseurs utilisant l'administration d'aérosol adaptative ou la technologie de tamis vibrant réduisent la durée du traitement de façon considérable. La quantité de médicament déposée (en pourcentage de dose d'amorçage) est supérieure au dépôt classique obtenu avec l'administration d'aérosol adaptative. Les systèmes utilisant la technologie de tamis vibrant peuvent permettre un dépôt plus important que les systèmes classiques lors de la mesure des niveaux des expectorations, mais un dépôt plus faible lors de la mesure des taux sériques ou en utilisant la gamma scintigraphie. Les données disponibles indiquent que ces systèmes plus récents sont sans danger quand ils sont utilisés avec une dose d'amorçage appropriée, qui peut être différente de la dose d'amorçage utilisée pour les systèmes classiques. Il existe une indication que l'observance est maintenue ou améliorée avec les systèmes utilisant ces technologies plus récentes, mais aussi que certains systèmes de nébulisation utilisant une technologie de tamis vibrant peuvent avoir tendance à être en panne plus souvent.

Conclusions des auteurs

Les cliniciens devraient être conscients de la variabilité dans les performances des différents systèmes de nébulisation. Les technologies telles que l'administration d'aérosol adaptative et la technologie de tamis vibrant offrent des avantages par rapport aux systèmes classiques en termes de durée du traitement, de dépôt en pourcentage de la dose d'amorçage, de préférence des patients et d'observance du traitement par les patients. Il est nécessaire de mener des essais contrôlés randomisés à long terme portant sur ces technologies pour déterminer les critères de jugement axés sur le patient (tels que la qualité de vie et les contraintes des traitements), les niveaux d'administration sûrs et efficaces de médicaments et les critères cliniques (tels que les hospitalisations et le besoin d'antibiothérapie) et une évaluation économique de leur utilisation.

Plain language summary

Nebulisers for giving medication in cystic fibrosis

Nebulisers change a liquid medication into a mist so it can be breathed in. There are different types of nebuliser systems and no review has yet considered whether any nebuliser is better than another.

1. Conventional nebuliser systems - a machine sucks air in and pushes it out at high speed; a tube attaches the machine to a chamber holding the medication where the air breaks it up into a mist. The mist of medication is delivered constantly.

2. Adaptive aerosol delivery nebuliser systems - use conventional technology as described above, but also monitor breathing and deliver the mist of medication only while the person is breathing in.

3. Adaptive aerosol delivery nebuliser systems with vibrating mesh technology - monitor breathing and deliver the mist of medication only while the person is breathing in and use vibrating mesh technology, as described below, to change the liquid medication into a mist.

4. Vibrating mesh technology nebuliser systems - move the liquid medication through a metal mesh to break up the liquid into a mist where each drop is a similar size; they deliver the mist of medication constantly.

5. Ultrasonic nebuliser systems - use a crystal to vibrate the liquid medication at a high-frequency to break up the liquid medication into a mist; they deliver the mist of medication constantly.

We included 20 studies (1936 participants) in this review which compared the delivery of tobramycin, colistin, dornase alfa, hypertonic sodium chloride and other nebulised medications through the different types of nebuliser. Some conventional nebuliser systems have faster air flows and smaller medication droplets. These systems decrease treatment time and deliver more medication into the lung than other conventional nebulisers which have slower air flows and larger medication droplets. Nebulisers using newer technologies, e.g. adaptive aerosol delivery or vibrating mesh technology, deliver the medication faster and may deliver more of the medication into the lung. These systems appear safe when used with the correct amount of medication, which may be different to that used in a conventional nebuliser system. Some studies suggest that people with cystic fibrosis may prefer these newer systems and may take more of their medication when using them. More research is needed into what dose of medication is needed and how these newer nebuliser technologies affect quality of life, burden of treatment, additional treatment needed and treatment costs.

Résumé simplifié

Nébuliseurs pour administrer le traitement dans la mucoviscidose

Les nébuliseurs transforment un médicament liquide en aérosol afin de pouvoir l'inhaler. Il existe différents types de systèmes de nébulisation et aucune revue n'a encore évalué si un nébuliseur est plus efficace qu'un autre.

1. Les systèmes de nébulisation classiques : un dispositif aspire l'air et l'expulse à grande vitesse ; un tube relie le dispositif à une chambre contenant le médicament d'où l'air le pulvérise en aérosol. L'aérosol de médicament est délivré en continu.

2. Les systèmes de nébulisation pour l'administration d'aérosol adaptative : ils utilisent une technologie classique décrite ci-dessus, mais contrôlent aussi l'inspiration et administrent l'aérosolthérapie uniquement quand la personne l'inspire.

3. Les systèmes de nébulisation pour l'administration d'aérosol adaptative équipés de la technologie de tamis vibrant : ils contrôlent l'inspiration et administrent l'aérosolthérapie uniquement quand la personne l'inspire et utilisent une technologie de tamis vibrant, comme décrit ci-dessous, pour convertir le médicament liquide en aérosol.

4. Les systèmes de nébulisation équipés de la technologie de tamis vibrant  : ils déplacent le médicament liquide à travers un tamis métallique pour pulvériser le liquide en aérosol dans lequel toutes les gouttelettes ont une taille similaire ; ils administrent l'aérosolthérapie en continu.

5. Les générateurs ultrasonores : ils utilisent un cristal pour faire vibrer le médicament liquide à haute fréquence afin de pulvériser le médicament liquide en aérosol ; ils administrent l'aérosolthérapie en continu.

Nous avons inclus 20 études (1936 participants) dans cette revue qui ont comparé l'administration de tobramycine, colistine, dornase alfa, chlorure de sodium hypertonique et d'autres médicaments nébulisés par les différents types de nébuliseur. Certains systèmes de nébulisation classiques ont des débits d'air plus forts et des gouttelettes de médicament plus petites. Ces systèmes réduisent la durée du traitement et délivrent une quantité de médicament plus importante dans le poumon que d'autres nébuliseurs classiques qui génèrent des débits d'air plus faibles et des gouttelettes de médicament plus grosses. Les nébuliseurs intégrant des technologies plus récentes, par exemple l'administration d'aérosol adaptative ou la technologie de tamis vibrant, administrent le médicament plus rapidement et peuvent délivrer une quantité de médicament plus importante dans le poumon. Ces systèmes semblent sans danger quand ils sont utilisés avec la quantité correcte de médicament, qui peut être différente de celle utilisée dans les systèmes de nébulisation classiques. Certaines études laissent entendre que les personnes atteintes de mucoviscidose pourraient préférer ces systèmes plus récents et pourraient inspirer une plus grande quantité de médicament quand elles les utilisent. D'autres recherches doivent être menées pour déterminer la dose de médicament qui est nécessaire et la manière dont ces dernières technologies de nébuliseur affectent la qualité de vie, les contraintes du traitement, la nécessité d'un traitement supplémentaire et les coûts du traitement.

Notes de traduction

Traduit par: French Cochrane Centre 17th May, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Background

Description of the condition

Cystic fibrosis (CF) is the most common autosomal recessive condition present in the Caucasian population, accounting for one in 2500 births (CFF 2006). It is a multi-system, progressive disorder characterised by abnormal ion transport leading to viscid secretions affecting the pancreas and the respiratory, gastrointestinal and reproductive systems (Hodson 2000). The major cause of morbidity and mortality is the respiratory component of the condition (Buzzetti 2009). Dysfunction of the cystic fibrosis transmembrane conductance regulator in the CF airway epithelium causes abnormal ion transport which in turn leads to depleted airway surface liquid volume, mucus dehydration, decreased mucus transport and mucus plugging of the airways providing an environment for bacterial infection (Zhang 2009). This process sets up a cycle of infection and inflammation leading to airway damage and progressive loss of respiratory function (Cantin 1995; Konstan 1997). In 1938, 70% of babies with CF died within the first year of life. More recent data suggests that median survival has increased to between 37 and 41 years of age as a result of improvements in conventional therapy (CFF 2011; CF Trust 2010). Nebulised treatment has been a key element of these therapies, but at the cost of increased burden of care for people with CF and their families (Halfhide 2005).

Description of the intervention

Nebuliser therapy is commonly used in the care of people with CF to deliver medications including bronchodilators, corticosteroids, antibiotics, mucolytics, osmotics and antifungals. Conventional nebulisation systems consist of an air compressor combined with a chamber to hold and deliver the medication as an aerosol to the individual. Treatments may take time periods from a few minutes up to 40 minutes to nebulise depending on the volume and viscosity of medication and the nebulisation system used. Nebulised therapy is therefore a large, and often time-consuming, aspect of treatment for those with CF. Studies suggest that the mean (SD) time taken to complete daily treatment for CF is 108 (58) minutes, with nebulised treatments taking up more time (mean 41 minutes) than any other type of treatment (Sawicki 2009).  Burden of treatment, measured by the Cystic Fibrosis Questionnaire – revised (CFQ-R), is also shown to increase with increasing nebulised treatment (Sawicki 2009).

Ultrasonic nebuliser systems have been available for some time and may reduce treatment times. They use a piezoelectric crystal which vibrates rapidly to produce aerosol particles, but may not be suitable for nebulising some types of medication, for example dornase alfa. Newer generation nebuliser systems utilise new technologies including adaptive aerosol delivery (AAD) and vibrating mesh technology (VMT). In AAD the nebuliser adapts to individual breathing patterns by monitoring pressure changes through the mouthpiece and decreases drug loss by delivering timed pulses of aerosol during the first 50% to 80% of inhalation only until a preset dose is achieved. With VMT, vibration is utilised to move the liquid medication through a perforated mesh in order to create homogeneous sized particles for inhalation. These technologies may be used in isolation or in combination within nebuliser systems to reduce treatment times and may have other benefits such as more consistent dosing, quieter treatments, smaller and more portable equipment and the ability to monitor adherence to treatment.

Why it is important to do this review

Many systems for nebulisation of medication are now available and there is no systematic review which evaluates the effectiveness, safety, burden of treatment and adherence to nebulised therapy using the different systems. There is confusion as to the most appropriate nebuliser system for use by people with CF and, as new and often expensive therapies emerge, these issues become even more important.

Objectives

To assess the effectiveness, safety, cost and impact of use (e.g. burden of care, adherence, quality of life) of the different nebuliser systems available when used with people with CF.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials or quasi-randomised controlled trials where there was sufficient evidence that intervention and control groups were similar at baseline.

Types of participants

People with CF, diagnosed according to Rosenstein (Rosenstein 1998), including all ages with any degree of disease severity. Studies with participants enrolled during a period of stability or during a respiratory exacerbation and those studies where aerosolised medications were used as a single-dose, acutely or as long-term maintenance therapy were all considered.

Types of interventions

Nebuliser systems were compared for delivery of each of the following:

  1. tobramycin;

  2. colistin;

  3. dornase alfa;

  4. hypertonic sodium chloride;

  5. other aerosolised medications.

For each medication conventional systems were compared with any other identified aerosol delivery system listed below, or with another type of conventional system (post hoc change). For this purpose we considered conventional systems to be a compressor combined with a jet nebuliser, including open vent jet systems and breath-assisted open vent systems.

Systems for comparison were:

  1. different types of conventional system (for example open-vent jet system versus breath-assisted open-vent jet system) (post hoc change);

  2. adaptive aerosol delivery (AAD) nebuliser systems (post hoc change);

  3. AAD incorporating vibrating mesh technology (VMT) nebuliser systems;

  4. vibrating mesh technology systems;

  5. ultrasonic nebuliser systems.

Conventional

Conventional nebuliser systems consist of a compressor coupled with a nebuliser chamber. The compressor entrains room air, compresses it to a higher pressure and emits the air at a given flow rate. The air enters the nebuliser chamber and passes through a small hole, a venturi, beyond which the air expands rapidly creating a negative pressure; this draws the medication up a feeding tube where it is atomised into particles. The particle sizes are variable, larger particles will impact on the baffle within the nebuliser chamber and onto the walls of the chamber and be returned back to the well of the chamber to be re-nebulised. The smaller particles will be continuously released from the nebuliser chamber during both inspiration and expiration of the person using the nebuliser system.

There are three main types of conventional nebuliser system: the jet nebuliser; the open-vent jet nebuliser; and the breath-assisted open-vent jet nebuliser. The jet nebuliser works continuously as described above. Open-vent jet nebulisers incorporate an open vent to allow extra air to be sucked into the chamber during inspiration. This results in greater air flow through the chamber and so greater densities of smaller respirable particles over a shorter period of time. Breath-assisted open-vent jet systems use a valve system to allow air to be drawn in during inspiration as per the open-vent design. During expiration the valve closes and the flow of air through the chamber is decreased to that coming from the compressor only. This decreases the amount of particles released during expiration and therefore decreases medication wastage (O'Callaghan 1997). One last adaptation of compressor and nebuliser systems is holding chambers. This is a chamber which is attached to the nebuliser and aerosol generated continuously by the nebuliser is held within the chamber. A negative pressure is created within the chamber during inspiration causing a valve to open and air to be entrained. This air picks up aerosol and delivers it to the person breathing in. An expiratory valve diverts expired air away from the chamber and the chamber continues to fill with aerosol. Holding chambers are designed to reduce medication wastage (O'Callaghan 1997).

A large number of conventional compressor and nebuliser combinations are available and these combinations have differing characteristics in terms of aerosol particle size, nebulisation time and mass of medication delivered (Higgenbottam 1997). Conventional nebulisation systems tend to be cheaper than the alternatives and are less prone to reliability or delivery problems (or both) due to poor cleaning and maintenance. They are, however, noisy and bulky and therefore less portable; they also produce variable particle sizes and have a larger residual volume as compared to alternative systems, so leading to more wastage of medication.

AAD

Two nebuliser systems, the Halolite® and Prodose®, were the first and second generation of nebuliser systems to utilise AAD. These systems are no longer available as they have been superseded by an AAD nebuliser system incorporating vibrating mesh technology (VMT); the I-Neb AAD system®. With AAD, pressure changes relating to airflow are continuously analysed and timed pulses of aerosol (during the first 50% to 80% of inspiration only) are delivered based on the prior three breaths until the preset dose; an actuation, is delivered. This eliminates wastage of medication during exhalation which occurs with continuously delivering nebulisers and optimises deposition. These systems were designed to give optimal efficiency and therefore require an alteration in the priming dose of medication used as compared to conventional nebuliser systems.

AAD incorporating VMT

One nebuliser system, the I-Neb AAD system®, utilises VMT and AAD in combination in order to optimise deposition and treatment times. As detailed above, AAD occurs along with the use of VMT, as detailed below. Inhalation technique is assessed; the nebuliser system will not operate unless correctly set up and used at the appropriate angle. The system also stores adherence and delivery data such as treatment date, time, duration and completeness of dose which can be downloaded by the clinician or the person using the I-Neb using software supplied by Philips (Insight®). These nebuliser systems were designed to give optimal efficiency and therefore require an alteration in the priming dose of medication used as compared to conventional nebuliser systems.

VMT

This technology aerosolises medication utilising a vibrating, perforated mesh to generate particles. This is achieved by using a piezoelectric element which either vibrates a transducer horn or which is annular and encircles the mesh causing it to vibrate. Both methods result in medication being pumped through the perforated mesh creating homogenous particles. Some meshes are created with an electroplating technique which forms tapered holes and others by precision laser-drilling (Kesser 2009). Vibrating mesh systems are silent, portable (being small and battery powered), fast and produce more homogenously-sized particles as compared to conventional systems. There are a number of systems available. The Omron MicroAir®, the Aerogen Aeroneb Go®, and the Pari eFlow Rapid® were designed to be similar in efficiency to conventional breath-enhanced nebulisers by using larger particle sizes, a system housing which causes a high residual dose within the nebuliser system, or a medication reservoir with a larger residual volume. Other nebuliser systems were designed to give optimal efficiency and may therefore require an alteration in the priming dose of medication used. The Aerogen OnQ®, Aerodose®, Aeroneb Pro® and Solo®, Pari eFlow® and Philips I-Neb® aim to deliver medication more efficiently and quicker. Some VMT systems are currently available for clinical use while others have only been utilised in research. A number of VMT systems use the piezoelectric crystal technology associated with ultrasonic nebulisers (see below) to create the vibration necessary to pump medication through a mesh.

Ultrasonic nebulisers

Ultrasonic nebulisers utilise a piezoelectric crystal which vibrates creating standing waves within the surface of the medication, droplets move away from the crests of these waves becoming an aerosol. Large particles impact on a baffle to be re-nebulised in the same way as jet nebulisers. Ultrasonic nebulisers may be smaller and are quieter and quicker than conventional systems. There is controversy, however, as to whether they are suitable to nebulise certain medications.

Types of outcome measures

Primary outcomes
  1. Treatment time (for single nebulised treatment)

  2. Quality of life (as measured by e.g. the Cystic Fibrosis Questionnaire (CF-Q) (Henry 2003) or Cystic Fibrosis Quality of Life (CFQoL) (Gee 2000) both validated measures of quality of life in people with CF)

  3. Deposition (as measured by radio labelling or by serum, sputum or urine levels of the studied medication) (post hoc change to consider sputum and urine levels)

Secondary outcomes
  1. Adherence (percentage of prescribed treatment taken)

  2. Burden of care (as measured by a validated tool)

  3. Adverse events

  4. Respiratory function tests

    1. force expiratory volume at one second (FEV1)

    2. forced vital capacity (FVC)

    3. forced mid-expiratory flow (FEF25-75)

  5. Respiratory exacerbations

    1. time to next exacerbation (measured in days and as defined by Rosenfeld 2001)

    2. total exacerbations within study period

  6. Need for additional antibiotic treatment during study period

    1. oral

    2. intravenous

  7. Cost (including nebuliser system, consumables and medication costs where a particular brand is required in order to use the nebuliser system)

  8. Patient satisfaction and preference with nebuliser system (e.g. weight, dimensions, time taken to clean equipment, noise levels, power supply, average number of doses per fully charged batteries, cleaning regimen, nebuliser system and consumables availability, customer support, etc.)

  9. Nebuliser system reliability

Search methods for identification of studies

Electronic searches

The authors identified relevant studies from the Cochrane CF and Genetic Disorders Group's CF Trials Register using the terms: aerosol delivery AND nebuliser.

The CF Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (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 the Journal of Cystic Fibrosis. Unpublished work is identified by searching 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 CF Trials Register: 15 Oct 2012.

Searching other resources

The authors searched the reference lists of each included study for additional publications. They contacted the authors of identified studies for further study details or for information on other published or unpublished studies. They approached the manufacturers of each type of nebuliser system assessed and also manufacturers of the medications identified to provide details of any studies or any data relevant to this review. They emphasised that they wished to access both published and unpublished work, with results which were either positive or negative for the manufacturer.

Data collection and analysis

Selection of studies

Two authors (TD and PW) independently reviewed all citations and abstracts identified by the search to determine which of the papers assessed they would include. Where the two authors disagreed, they resolved this by consensus; a third author (NM) was available to review the paper if consensus was not possible. They recorded any areas of disagreement. The authors excluded non-RCTs, although they did include randomised cross-over studies. The authors also excluded studies comparing nebuliser versus inhaler systems.

Data extraction and management

Two authors (TD and PW) independently performed data extraction and recorded data using Review Manager (RevMan 2011). The authors recorded any areas of disagreement which occurred. They noted details of randomisation, allocation concealment, degree of blinding, inclusion and exclusion criteria, participant type (for example adult or paediatric), and dropouts and withdrawals and how these were accounted for. For short-term studies (up to and including four weeks), the authors reported outcomes for single-intervention studies separately; then reported outcomes at one week, between one and two weeks, more than two weeks to three weeks, more than three weeks to four weeks. For long-term studies (over four weeks), they reported outcomes at three months, six months, twelve months and annually thereafter. They presented other time points reported in the included studies as appropriate.

Some included studies compared more than two nebulisers of the same type (e.g. conventional) for administering the same drug. In these cases, for parallel studies, the authors presented the data for each combination of comparisons on the same graph. For cross-over studies, this is not possible and we have presented the data in an additional table.

For studies that did not present data in an appropriate form to enter into the meta-analysis, where possible the authors calculated the standard deviations (SDs) from the standard errors (SEs) or the confidence intervals (CIs) presented in the published papers.

Assessment of risk of bias in included studies

The authors assessed the risk of bias using the tool described within the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Generation of allocation sequence

The authors considered this as having a low risk of bias if a computer algorithm or a similar process based on chance was used to randomise participants to treatment groups. They identified this as having a high risk of bias for sequences which could be attributed to prognosis, degree of disease severity, age etc. They considered studies as having an unclear risk of bias where the generation of allocation sequence was not identified.

Concealment of allocation

The authors considered concealment of allocation to have a low risk of bias where it was not possible for the investigators to foresee the allocation of participants to a particular treatment group, for example centralised or pharmacy-controlled randomisation, pre-numbered or coded identical containers administered serially to participants, on-site locked computer system, or sequentially numbered, sealed, opaque envelopes. They considered the concealment of allocation to have a high risk of bias if the investigator was able to predict the allocation, for example, alternation; the use of case record numbers, dates of birth or day of the week. They graded the risk of bias as unclear if the concealment of allocation was not described.

Blinding

The authors reported on the degree of blinding employed in each study. Given the specific systems for nebulisation considered within this review, the blinding of the investigator and participants was generally not possible; however, blinding of the person analysing the data was possible. The risk of bias generally increases when few people are blinded to an intervention, thus the risk of bias was higher if the data analyst was not blinded.

Incomplete outcome data

The authors judged a study to be at low risk of bias from incomplete outcome data if there were either no missing outcome data (all participants included in the analysis are exactly those who were randomized into the study) or any missing data or withdrawals were unlikely to be directly related to the intervention, for example if the participant moved away. They judged a study to have an unclear risk of bias if the number of participants randomized into each intervention group was not clearly reported, or numbers completing study not clearly reported. They judged the study to have a high risk of bias if the proportion of incomplete outcome data across groups was not balanced across intervention groups or if reasons for withdrawal or dropout were not given.

Selective reporting

The authors judged there to be a low risk of bias from the selective reporting of data if all pre-specified outcomes were reported adequately. They judged there to be an unclear risk of bias if insufficient information was available to make a judgement of either low or high risk. They judged there to be a high risk of bias if not all pre-specified outcomes were reported at all, or non-significant results were not reported; also, if there was non-reporting of outcomes that would very likely have been recorded (e.g. reporting of FVC but not FEV1).

Other sources of bias

Fifteen studies identified as suitable for inclusion were randomised cross-over studies. The authors assessed the risk of bias for cross-over studies as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and considered:

  1. whether the cross-over design was suitable;

  2. whether there was a carry-over effect;

  3. whether only first-period data were available;

  4. incorrect analysis; and

  5. comparability of results with those from parallel-group studies.

Measures of treatment effect

For binary outcome measures, the authors assessed data on the number of participants with each outcome event, by allocated treated group, irrespective of compliance and whether or not the individual was later thought to be ineligible or otherwise excluded from treatment or follow-up. They calculated a pooled estimate of the treatment effect for each outcome across studies using the risk ratio (RR) and 95% CIs where appropriate.

For continuous outcomes, they recorded either mean relative change from baseline for each group or mean post-treatment or intervention values and their SDs (presented separately). Where SEs were reported, the authors calculated the SDs where possible. They calculated a pooled estimate of treatment effect by calculating the mean difference (MD) and 95% CIs. If outcomes were reported using different units of measurement, the authors calculated the standardised mean difference (SMD) and 95% CIs.

They considered studies identifying interventions of varying duration separately; those of up to four weeks being short term and those over four weeks long term. They included single-dose interventions as most deposition data were of this data type.

For time-to-event outcomes included in the review, the authors planned to obtain a mixture of logrank and Cox model estimates from the studies. They planned to combine results using the generic inverse variance method as they would have converted the logrank estimates into log hazard ratios and SEs as detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This was not required during analysis of the data obtained from the included papers.

The authors reported results for both individual studies and meta-analyses with a point estimate together with an associated CI. The point estimate gave magnitude and direction of effect as compared with control and the CI indicated the certainty or uncertainty of this estimate.

Unit of analysis issues

Cross-over studies are those in which each individual receives both treatments in random order. The advantage of this design is that the effect of treatments can be compared within each participant. This is appropriate when within-participant variation is small compared to that between participants, and can allow studies with a smaller number of participants to be conducted. The design is not suitable when the condition of participants is not stable over time, or when the effect of one treatment can 'carry over' from one period to the next. This carry over may be minimised with an adequate wash-out period. The issue of participant stability is obviously pertinent to the CF patient group. A meta-analysis can be conducted if, in the original data, the relevant estimates of treatment effect with SEs are provided. For future updates of the review, where estimates are not available and the authors cannot retrieve the information from the authors, they will consult a statistician for the best way of reporting these data.

The authors identified 11 of the 15 cross-over studies were suitable for inclusion in the analysis, considered the methods recommended by Elbourne to combine results from these cross-over studies (Elbourne 2002) and treated the data as we would for parallel studies.

Dealing with missing data

The authors have reported on whether the original investigators employed an intention-to-treat analysis (analysis based on the initial treatment allocation, not on the treatment eventually administered). They have assessed whether the numbers and reasons for dropouts and withdrawals in all intervention groups are described or whether it is specified that there were no dropouts or withdrawals. They contacted the primary investigators of any identified study where data they required for analysis was not published in the published paper.

Assessment of heterogeneity

The greater the consistency between the primary studies in a meta-analysis, the more generalisable are the results. Heterogeneity refers to the genuine differences between studies rather than those that occur by chance. When the authors are able to include and combine more studies in future updates, they will test for heterogeneity using the I2 statistic (Higgins 2003). They will use a simplified categorization of heterogeneity such that they consider heterogeneity to be low if the I2value is up to 25%, moderate up to 50%, high up to 75% and very high over 75%.

Assessment of reporting biases

The authors attempted to minimise publication bias by directly contacting manufacturers of nebuliser systems for data from all studies, regardless of positive or negative outcome, carried out with the specified medications and using the identified nebuliser systems. Had they been able to combine at least 10 studies, they planned to assess publication bias using a funnel plot analysis, bearing in mind that there are other reasons for funnel plot asymmetry, which would require caution in interpretation. The authors assessed selective reporting by comparing study protocols to final publications where possible, in order to make sure that all outcomes measured were reported. Where this was not possible, they compared the measurements identified within the methods section of the paper with the measurements reported on within the results section.

Data synthesis

The authors analysed the included data using a fixed-effect model. They planned to employ a random-effects model if they identified moderate or high degrees of heterogeneity (as defined above).

Subgroup analysis and investigation of heterogeneity

As there were insufficient studies, the authors were unable to perform the planned subgroup analysis for children (up to 16 years) compared to adult (16 and older) and by disease severity. There are a number of ways of measuring disease severity and new methods are being developed as the decline in respiratory function slows over time in the CF population. However, spirometry has been an accepted standard in disease monitoring (Davies 2009) and provides a simple classification system for the purposes of this review. In future revisions, and when sufficient studies are available for subgroup analysis, the authors intend to describe disease severity as severe (FEV1 below 30% predicted), moderate (FEV1 between 31% and 60% predicted) and mild (FEVover 60% predicted) (Davies 2009).

Sensitivity analysis

The authors will perform sensitivity analyses when they are able to include a sufficient number of studies in the future. Where they identify moderate or high degrees of heterogeneity, they will test the robustness of their findings by performing a sensitivity analysis excluding studies with higher risk of bias (i.e. quasi-randomised). They will consider all sources of bias.

Results

Description of studies

Results of the search

Of the 40 studies identified through the Cochrane Group's CF Trials Register, 20 studies including 1936 participants met the inclusion criteria (Byrne 2003; Clavel 2007; Devadason 1997; Devadason 2001; Dodd 2002; Eisenberg 1997; Elkins 2006; Fiel 1995; Geller 1998; Geller 2003; Griese 2009; Hubert 2009; Kastelik 2002; Köhler 2003; Lenney 2011; Marshall 1994; Newman 1988; Shah 1997; Thomas 1991; Westerman 2008). One publication provided by a company was included (Conway 2002), which was an additional publication taken from the study by Dodd (Dodd 2002). A total of 16 studies were excluded (Conway 1993; Crowther Labiris 1999; Dolovich 2005; Faroux 2000; Hung 1995; Johnson 2006; Kovaleva 2001; Laube 2000; Mallol 1996; Mallol 1997; Militz 2008; Moss 2005; Mulrennan 2004; Podolec 2001; Potter 2008; Vanlaethem 2008). Four studies were listed as 'Studies awaiting classification' as further information is required to decide upon inclusion or to gain enough outcome data (Denk 2009; Govoni 2012; Haeussermann 2006; McCormack 2011). All other additional data, from companies and identified following searches of reference lists of identified studies from the original search, either did not reach the inclusion criteria for this review or had already been identified. We contacted the primary investigators of any identified study where data we required for analysis were not presented in the published paper. We have not yet received any responses.

The process of the search and study selection is documented in the PRISMA diagram (Figure 1).

Figure 1.

Study flow/ PRISMA diagram.

Included studies

A total of 20 studies are included in this review. Where studies included participants with CF and healthy participants only data from those participants with CF have been used within the review (Kastelik 2002; Lenney 2011). Details of the included studies are presented grouped according to the drug being delivered. Below is a table showing the comparison of different systems for different drugs with the number of relevant included studies shown in brackets.

NebuliserConventionalVMTUltrasonicAAD
Conventional

Tobramycin (3)

Dornase alfa (4)

Salbutamol (1)

Radio-labelled saline (1)

Radio-active carbenicillin (1)

Tobramycin (4)

Radio-labelled amiloride (1)

Sodium cromoglycate (1)

Colistin (2)

Dornase alfa (1)

Radio-labelled saline (1)

VMTTobramycin (4)   
Ultrasonic

Radio-labelled amiloride (1)

Sodium cromoglycate (1)

   
AAD

Colistin (2)

Dornase alfa (1)

Radio-labelled saline (1)

   
1. Nebuliser systems for delivering tobramycin

Seven studies assessed nebuliser systems for delivering tobramycin (Clavel 2007; Eisenberg 1997; Geller 2003; Griese 2009; Hubert 2009; Lenney 2011; Westerman 2008). Six of these are published as full papers (Clavel 2007; Eisenberg 1997; Geller 2003; Hubert 2009; Lenney 2011; Westerman 2008) and one as abstract only (Griese 2009). One three-arm cross-over study compared two conventional systems used with the same compressor to an ultrasonic nebuliser, but the results of the conventional arms versus the ultrasonic arm of this study are not presented within this review because the priming dose for the ultrasonic nebuliser was variable, so that it is unclear whether any differences between the treatment arms are due to the priming dose or due to the nebuliser system (Eisenberg 1997).

Study design

Six studies were of cross-over design (Clavel 2007; Eisenberg 1997; Geller 2003; Hubert 2009; Lenney 2011; Westerman 2008) and one was of parallel design (Griese 2009). The duration of the studies ranged from single doses (Clavel 2007; Eisenberg 1997; Geller 2003; Lenney 2011; Westerman 2008) to 28 days (Griese 2009). Five studies stated that they were multi-centre involving: 10 centres (Eisenberg 1997; Griese 2009); nine centres (Geller 2003); two centres (Lenney 2011); and the number of centres was not stated in one study (Hubert 2009). Studies took place in France (Clavel 2007; Hubert 2009), the USA (Eisenberg 1997; Geller 2003), the UK (Lenney 2011); the Netherlands (Westerman 2008) and Germany and Poland (Griese 2009).

Participants

The number of participants in the studies ranged from 10 (Clavel 2007; Westerman 2008) to 68 (Eisenberg 1997). There was one single paediatric study where participants were under six years of age (Clavel 2007) and three studies were in adults only (Hubert 2009; Lenney 2011; Westerman 2008). Three studies included both adults and children (Eisenberg 1997; Geller 2003; Griese 2009), one of which split the age ranges of the paediatric (8 to 17 years old) and adult populations (18 to 42 years old) (Griese 2009). Six studies reported on gender splits. These were 6 male, 4 female (Clavel 2007); 32 male, 28 female (Eisenberg 1997); 19 male, female 30 (Geller 2003); 15 male, 10 female (Hubert 2009); 4 male, 3 female (Lenney 2011)and 6 male,4 female (Westerman 2008). One study did not report on the gender of the participants (Griese 2009).

Interventions

Three studies compared two types of conventional system for use with tobramycin 300 mg/5 ml (Clavel 2007; Eisenberg 1997; Westerman 2008). Clavel assessed the Pari LC plus® with Pari Turboboy® versus NL9M with the atomiser BoxPlus, both systems were used with a facemask (Clavel 2007). Eisenberg compared the Sidestream® and the Pari LC Plus® , both of which used with the same compressor (DeVilbiss Pulmoaide) (Eisenberg 1997). Westerman compared different compressors (the Porta-neb® and the CR60® ) used with the same nebuliser (Pari LC plus®) (Westerman 2008).

Four studies compared conventional to VMT systems (Geller 2003; Griese 2009; Hubert 2009; Lenney 2011). All four studies used the Pari LC plus® as the conventional system to deliver tobramycin 300 mg/5 ml, but the VMT systems differed: one study used the AeroDose® with 30, 60 or 90 mg tobramycin (Geller 2003); one study used an investigational eFlow with 150 mg/1.5 ml tobramycin (Griese 2009); and the remaining two studies both used the eFlow rapid® with tobramycin 300 mg/5 ml (Hubert 2009; Lenney 2011).

Outcomes measured

All studies reported on tobramycin levels: two reported urine levels (Clavel 2007; Geller 2003); four reported sputum levels (Eisenberg 1997; Geller 2003; Griese 2009; Hubert 2009); and six reported serum levels (Eisenberg 1997; Geller 2003; Griese 2009; Hubert 2009; Westerman 2008; Lenney 2011). Lenney also measured deposition by gamma scintigraphic imaging (Lenney 2011). Additionally, two studies reported on pharmacokinetics (Lenney 2011; Westerman 2008). One study reported blood urea nitrogen and creatinine levels (Geller 2003). All studies reported on nebulisation time, Eisenberg also reported on the number of breaths required to complete the treatment (Eisenberg 1997). Five studies reported on respiratory function pre- and post-dose (Eisenberg 1997; Geller 2003; Hubert 2009; Lenney 2011; Westerman 2008). Six studies reported on adverse events (Eisenberg 1997; Geller 2003; Griese 2009; Hubert 2009; Lenney 2011; Westerman 2008), one study on patient experience which was assessed by a questionnaire (Westerman 2008) and one on adherence to the treatment regimen (Hubert 2009). One study measured osmolality of medication residue in the nebuliser as compared to an ampoule of medication in order to determine the effect of jet nebulisation on the solution (Westerman 2008).

2. Nebuliser systems for delivering colistin

Two studies compared conventional systems to AAD systems for use with colistin (Byrne 2003; Dodd 2002). One of these is only available in abstract form (Dodd 2002).

Study design

One study was of cross-over design (Byrne 2003); the second study was of parallel design (Dodd 2002). The Byrne study was completed in two parts: initially participants received a single dose via each nebuliser system in random order and at visits at least one week apart; then there was a seven-day washout period followed by seven days of treatment via one system then a further seven-day washout followed by seven days using the other system (Byrne 2003). In the parallel Dodd study, participants received the intervention for 182 days (Dodd 2002). One study was single centre and carried out in the UK (Byrne 2003), while one was multicentre across centres in Australia, Canada, the USA and Europe (Dodd 2002).

Participants

Both studies recruited a mixed adult and paediatric cohort (Byrne 2003; Dodd 2002). Byrne stated that the participants were aged 7 to 23 years (mean 14.1 years); Dodd reported the median age of participants as being 17 years (Dodd 2002). The studies differed in size; Byrne reported on 15 participants (Byrne 2003) and Dodd reported on 259 participants (Dodd 2002). Neither study reported the gender split.

Interventions

Both studies used the Halolite® AAD nebuliser system (Byrne 2003; Dodd 2002). Byrne used the conventional system of the Pari LC plus® with Pariboy®. Dodd did not specify the actual system used in comparison, but described it as "a conventional high-output system" (Dodd 2002).

Outcomes measured

Both studies reported on treatment time and respiratory function (Byrne 2003; Dodd 2002). In addition Byrne reported on radio-labelled deposition, sputum colistin levels and sputum Pseudomonas aeruginosa load (Byrne 2003). Dodd additionally reported on days of antibiotic use, exacerbation frequency, time to first exacerbation, safety, adherence to prescription, compliance with device and patient experience (Dodd 2002).

3. Nebuliser systems for delivering dornase alfa

Five studies assessed nebuliser systems for use with dornase alfa (Devadason 2001; Elkins 2006; Fiel 1995; Geller 1998; Shah 1997). Two of these were only available in abstract form (Devadason 2001; Elkins 2006); the other three were published as full papers (Fiel 1995; Geller 1998; Shah 1997).

Study design

Two studies were of cross-over design (Devadason 2001; Elkins 2006) and three were of parallel design (Fiel 1995; Geller 1998; Shah 1997). One parallel study had three treatment arms (Fiel 1995). Study duration ranged from single-dose studies (Devadason 2001; Elkins 2006) to 15 days (Fiel 1995). Two studies were single centre (Devadason 2001; Elkins 2006), three multicentre: over 26 sites (Fiel 1995); 41 sites (Geller 1998); and over three sites (Shah 1997). Two studies were carried out in Australia (Devadason 2001; Elkins 2006), one in the USA (Fiel 1995), one in the USA and Canada (Geller 1998) and one in the UK (Shah 1997).

Participants

The number of participants ranged from 10 (Elkins 2006) to 749 (Geller 1998). One study stated that adults only were recruited (Shah 1997); while a further study was undertaken in an adult CF unit (although specific age was not stated) (Elkins 2006). The remaining two studies recruited both adults and children (Fiel 1995; Geller 1998). Gender splits were reported as: 51% male (Fiel 1995); 53% to 54% male in each study arm (Geller 1998); 87 male and 84 female participants (Shah 1997). The remaining two studies did not report the gender split (Devadason 2001; Elkins 2006).

Interventions

Four studies compared two different conventional systems (Elkins 2006; Fiel 1995; Geller 1998; Shah 1997) and one study compared a conventional system to an AAD system (Devadason 2001).

Elkins compared the Pari LC star® to the Pari LC plus® both with 2.5 mg/2.5ml dornase alfa (Elkins 2006). Fiel compared the DeVilbiss Pulmo-Aide® compressor in combination with the Marquest Acorn II® nebulizer to the Hudson T Updraft® and to the Pari LC plus® with a Pariboy® compressor all using a dose of 2.5 mg/2.5 ml dornase alfa (Fiel 1995). Geller compared a Medicaid Durable Sidestream® with a MobilAir® compressor to the Hudson T Updraft® nebuliser with a DeVilbiss Pulmo-Aide® compressor using a dose of 2.5 mg/2.5 ml dornase alfa (Geller 1998). Shah compared the Hudson T Updraft® II nebuliser with the Pulmo-Aide® compressor to the Sidestream® nebuliser with a CR50 compressor using a dose of 2.5 mg/2.5 ml dornase alfa (Shah 1997).

Devadason compared the Pari LC plus® using a dose of 2.5 mg/2.5 ml dornase alfa to the Halolite® system with 1.25 mg/1.25 ml dornase alfa (Devadason 2001).

Outcomes measured

Three studies reported on respiratory function (Fiel 1995; Geller 1998; Shah 1997). Three studies reported on nebulisation time (Elkins 2006; Geller 1998; Shah 1997). Two studies reported aerosol or nebuliser characteristics (Geller 1998; Shah 1997) and Devadason additionally reported on lung deposition and environmental drug loss (Devadason 2001). Adverse events were reported in three studies (Fiel 1995; Geller 1998; Shah 1997).

4. Nebuliser systems for delivering hypertonic sodium chloride

No RCTs were found assessing the delivery of hypertonic sodium chloride using different types of nebuliser system.

5. Nebuliser systems for delivering other aerosolised medications

Six studies, all published as full papers, assessed different nebuliser systems for the delivery of other nebulised medications (Devadason 1997; Kastelik 2002; Köhler 2003; Marshall 1994; Newman 1988; Thomas 1991).

Study design

All six studies were of cross-over design using a single dose of each intervention (Devadason 1997; Kastelik 2002; Köhler 2003; Marshall 1994; Newman 1988; Thomas 1991). Five studies were single centre (Kastelik 2002; Köhler 2003; Devadason 1997; Marshall 1994; Newman 1988) and it was unclear whether one study was single or multicentre (Thomas 1991). Three studies were carried out in the UK (Kastelik 2002; Newman 1988; Thomas 1991), two in Australia (Devadason 1997; Marshall 1994) and one in Germany (Köhler 2003).

Participants

Two studies were in children alone, aged 10 to 16 years (Marshall 1994) and 3 to 16 years (Devadason 1997). Three studies were in adults only aged 19 to 42 years (Kastelik 2002), 22 to 48 years (Newman 1988) and specific ages were not given in the third study (Thomas 1991). One study recruited both adults and children (Köhler 2003). The Kastelik study recruited a mixture of healthy participants and people with CF, although we only report data for participants with CF (Kastelik 2002). All studies were small with numbers of participants ranging from a minimum of six (Kastelik 2002) to a maximum of 18 (Devadason 1997). The gender split was reported in all studies: six males and no females (Kastelik 2002); six males and two females (Thomas 1991); nine males and nine females (Devadason 1997); six males and six females (Marshall 1994); five males and two females (Newman 1988); and six males and four females (Köhler 2003).

Interventions

Three studies compared two conventional nebuliser systems (Devadason 1997; Marshall 1994; Newman 1988). None of the studies compared the same systems delivering the same drugs. Devadason compared the delivery of salbutamol 2.5 mg/2.5 ml via Marquest Acorn II® conventional jet nebuliser used with and without mizer storage chamber versus two venturi nebulisers (Ventstream® and PARI LC plus®) (Devadason 1997). Marshall compared the Marquest Acorn II® with mouthpiece versus Marquest Acorn II® with mizer for the delivery of technetium radio-labelled saline (Marshall 1994). Newman compared the Turret® nebuliser with Maxi®compressor versus the Inspiron® nebuliser with Traveller® compressor for the delivery of radioactive carbenicillin (Newman 1988).

One study compared a conventional system (Pari LC plus®) to an AAD system (Halolite®) for the delivery of radio-labelled saline (Kastelik 2002).

The remaining studies compared conventional systems to ultrasonic systems (Köhler 2003; Thomas 1991). Thomas compared the System 22 Acorn® (Medic-Aid Ltd) combined with a CR60® compressor (Medic-Aid Ltd) to the ultrasonic system the Fisoneb® (Fisons, Medix) to deliver radio-labelled amiloride (Thomas 1991). Köhler compared the Parimaster/LC plus turbo® with the Multisonic compact® to deliver sodium cromoglycate (SCG) (Köhler 2003).

Outcome measures

All studies reported on deposition (Devadason 1997; Kastelik 2002; Köhler 2003; Marshall 1994; Newman 1988; Thomas 1991). This was generally reported as lung deposition, except for one study which reported inspiratory filter deposition (Devadason 1997) and a second which reported urinary SCG levels to indicate lung deposition (Köhler 2003). Two studies reported on the delivered dose (Kastelik 2002; Marshall 1994) and two reported the amount of medication retained in the nebuliser at the end of treatment (Devadason 1997; Köhler 2003). Two studies reported on the nebulisation time (Devadason 1997; Köhler 2003). Two studies reported on adverse events and respiratory function (Kastelik 2002; Thomas 1991). One study reported on patient preference (Thomas 1991).

Excluded studies

Of the 16 excluded studies, one identified study was not an RCT (Mulrennan 2004), two were in vitro studies and did not consider the nebuliser comparisons in patients (Johnson 2006; Potter 2008) and 11 did not compare one form of nebuliser system to another nebuliser system (Conway 1993; Crowther Labiris 1999; Dolovich 2005; Faroux 2000; Hung 1995; Kovaleva 2001; Laube 2000; Mallol 1996; Mallol 1997; Moss 2005; Vanlaethem 2008). A further two studies were excluded because authors were unable to provide sufficient data to allow a decision to be made on eligibility (Militz 2008; Podolec 2001).

Risk of bias in included studies

Allocation

Generation of sequence

We judged one study to have a low risk of bias as the methods of sequence generation were described (Fiel 1995). Nineteen studies were described as being randomised; however, the methods of randomisation were not stated and therefore we considered these studies to have an unclear risk of bias (Byrne 2003; Clavel 2007; Devadason 1997; Devadason 2001; Dodd 2002; Eisenberg 1997; Elkins 2006; Geller 1998; Geller 2003; Griese 2009; Hubert 2009; Kastelik 2002; Köhler 2003; Lenney 2011; Marshall 1994; Newman 1988; Shah 1997; Thomas 1991; Westerman 2008).

Allocation concealment

Nineteen of the 20 studies did not report on how the allocation was concealed, hence we deemed these to have an unclear risk of bias (Byrne 2003; Clavel 2007; Devadason 1997; Devadason 2001; Dodd 2002; Eisenberg 1997; Elkins 2006; Fiel 1995; Geller 1998; Geller 2003; Griese 2009; Hubert 2009; Kastelik 2002; Lenney 2011; Marshall 1994; Newman 1988; Shah 1997; Thomas 1991; Westerman 2008). One study stated alternation as an allocation method and was therefore graded as high risk (Köhler 2003).

Blinding

Byrne reports shielding the patient from the nebuliser system, but it is unclear whether the researchers were blinded to the nebuliser systems and in view of this we considered an unclear risk of bias was appropriate (Byrne 2003). Two studies report lead shielding around the nebuliser (Kastelik 2002; Newman 1988); however, it was unclear whether the participants, researchers or both were blinded, therefore we also considered an unclear risk of bias to be appropriate here. One study was described as open therefore there was no blinding (Westerman 2008) and we so considered it high risk. In the remaining 16 studies, no descriptions of blinding were documented, therefore we considered them to have a high risk of bias (Clavel 2007; Devadason 1997; Devadason 2001; Dodd 2002; Eisenberg 1997; Elkins 2006; Fiel 1995; Geller 1998; Geller 2003; Griese 2009; Hubert 2009; Köhler 2003; Lenney 2011; Marshall 1994; Shah 1997; Thomas 1991).

Incomplete outcome data

We considered 15 studies to have a low risk of bias as they either provided full reasons for incomplete data or confirmed that the data were complete (Byrne 2003; Clavel 2007; Devadason 1997; Eisenberg 1997; Fiel 1995; Geller 1998; Geller 2003; Hubert 2009; Kastelik 2002; Köhler 2003; Lenney 2011; Marshall 1994; Newman 1988; Thomas 1991; Westerman 2008). Seven studies did not report on missing data, four of these were in abstract form only (Devadason 2001; Dodd 2002; Elkins 2006; Griese 2009) and we considered them to have an unclear or high risk of bias. Although presented as a full paper, Shah did not report on some data and again we considered this study to have a high risk of bias (Shah 1997).

Selective reporting

We compared the 'Methods' section with the 'Results' section in every study to ensure that each outcome was reported on. Sixteen studies reported on every outcome identified in the methods section and were so assigned a low risk of selective reporting bias (Clavel 2007; Devadason 1997; Devadason 2001; Eisenberg 1997; Elkins 2006; Fiel 1995; Geller 1998; Geller 2003; Hubert 2009; Köhler 2003; Lenney 2011; Marshall 1994; Newman 1988; Shah 1997; Thomas 1991; Westerman 2008).

One study reported on all outcomes stated in the methods section; but for FEV1 stated that there were no significant changes in post-dose with either nebuliser system and did not give actual data, so the risk of bias due to selective reporting was judged to be unclear (Byrne 2003). LIkewise, a further study reported on all stated outcomes, but for respiratory function tests simply stated there were no significant changes and did not provide any data (Kastelik 2002).

One study presented data in the results section for outcomes not identified in the methods and also presented limited details of methods and was so assigned a high risk of bias (Griese 2009). One further study was assigned a high risk of bias as it did not fully report on all outcomes listed in the methods (Dodd 2002). Instead a statement was given that there was no statistically significant difference for any secondary outcome variable. We intend to contact the authors of these studies for further information regarding their methods and results and will include these in any future review update.

Other potential sources of bias

We were unable to exclude the possibility of publication bias but as previously described we aimed to limit this.

Fifteen of the studies identified as suitable for inclusion were randomised cross-over studies (Byrne 2003; Clavel 2007; Devadason 1997; Devadason 2001; Eisenberg 1997; Elkins 2006; Geller 2003; Hubert 2009; Kastelik 2002; Köhler 2003; Lenney 2011; Marshall 1994; Newman 1988; Thomas 1991; Westerman 2008). It was unclear whether the cross-over design was suitable for two of these studies as they were available as abstracts only and did not present sufficient information to ascertain this (unclear risk of bias) (Devadason 2001; Elkins 2006). We deemed that there was no carry-over effect in ten of the studies. Two abstracts provided insufficient information to ascertain this (Devadason 2001; Elkins 2006) and three further studies did not describe a washout period (Devadason 1997; Newman 1988; Thomas 1991); hence these five studies had an unclear risk of bias. There were no studies where only first-period data were available. We were unable to fully assess the appropriateness of the statistical analysis in two studies (Devadason 2001; Elkins 2006), but the remaining thirteen appeared appropriate. Ten of the studies gave results comparable with those from a parallel-group study, we require further information to be sure of this for the remaining six studies (Devadason 1997; Devadason 2001; Elkins 2006; Newman 1988; Thomas 1991). We intend to contact the authors to obtain this information to include in a future update. One study was deemed to have a high risk of bias since it was a difficult participant group for both consistent administration of nebuliser and for full urine collection (Clavel 2007).

Effects of interventions

The effects of using different types of nebuliser to deliver each medication we have described in the previous section are discussed below. We only present comparisons and outcomes for which eligible studies have been identified and for which information is reported.

Nebuliser systems for delivering tobramycin

Seven studies are included in this intervention (Clavel 2007; Eisenberg 1997; Geller 2003; Griese 2009; Hubert 2009; Lenney 2011; Westerman 2008).

Conventional versus conventional system

Three studies compared one type of conventional system with a second type of conventional system (Clavel 2007; Eisenberg 1997; Westerman 2008).

Primary outcomes
1. Treatment time

Data for all studies were reported as medians and ranges and so we were unable to present these in a meta-analysis (Clavel 2007; Eisenberg 1997; Westerman 2008). We have contacted the authors and hope to include this data in a meta-analysis in a future update should we obtain means and SDs from the study investigators. Clavel reported a decreased nebulisation time with the NL9M®, median (range) 12 min (10 min to 19 min), versus the Pari LC plus®, median (range) 22 min (13 min to 28 min) (Clavel 2007). Eisenberg reported that treatment time was significantly shorter using the Pari LC Plus® (median (range) 10 (5 to 17) min) than with the Sidestream® (median (range) 15 (10 to 27) min) (P < 0.001). The number of breaths needed to complete the treatment was also significantly less with the Pari LC Plus® (median (range) 135 (43 to 358) breaths) versus the Sidestream® (median (range) 235 (50 to 514) breaths) (Eisenberg 1997). Westerman found a decreased nebulisation time using the CR60®, median (range) 13.2 (11.1 to 15.8) min as compared to use of the Porta-neb®, median (range) 16.1 (11.8 to 19.4) min) (Westerman 2008).

3. Deposition

Again, all studies presented median values with ranges precluding the construction of a meta-analysis. We have contacted the authors and hope to include these data in a meta-analysis in a future update should we obtain means and SDs from the study investigators. The Clavel study used urinary tobramycin levels, which were low and variable, as an indicator of pulmonary deposition (Clavel 2007). The study found similar levels for each nebuliser, median 2.6 mg for Pari LC plus® and 2.2 mg for NL9M® , but found great variation between children and also between one nebulisation session and another in the same child (Clavel 2007). Eisenberg measured sputum tobramycin concentrations and found median (SD) peak sputum concentrations to be greater for the Pari LC Plus® (452 (663) µg/g) than the sidestream® (393 (402) µg/g) although there was greater variation in the concentrations found following administration through the Pari LC Plus®. Eisenberg also reported that serum concentrations of tobramycin did not exceed the stated safety limits for any participant using any of the nebuliser systems (Eisenberg 1997). In the Westerman study, tobramycin serum concentrations were measured post-dose (Westerman 2008). The outcomes Cmax (maximum tobramycin concentration) and AUC (area under the curve) were greater using the CR60® indicating a potential for better pulmonary deposition: Cmax being median (range) 0.7 (0.53 to 2.49) with CR60® and 0.54 (0.41 to 1.95) using the Porta-neb®; and AUC was median (range) 2.54 (1.98 to 6.65) for CR60® versus median (range) 2.01 (1.55 to 6.18) with Porta-neb® (Westerman 2008).

Secondary outcomes
3. Adverse events

Clavel reported no adverse events for those using either nebuliser (Clavel 2007). Eisenberg reported two episodes of asymptomatic bronchoconstriction (greater than 15% drop in FEV1) following the administration of tobramycin with the Pari LC Plus®, RR 0.20 (95% CI 0.01 to 4.08) (Analysis 1.1); while the Westerman study reported bronchoconstriction in three participants; two using the Porta-neb® and one using the CR60®, RR 0.50 (95% CI 0.05 to 4.67) (Analysis 1.2). Westerman also reported subjective chest tightness in seven participants; with more participants using the CR60® reporting this than those using the Porta-neb®, although actual numbers are not given (Westerman 2008). Eisenberg recorded two further adverse events as related to the underlying respiratory disease, one participant with increased cough and haemoptysis six days following administration through the Sidestream®, RR 3.00 (95% CI 0.12 to 72.20) (Analysis 1.3) ; and one with chest pain one day following administration through Pari LC Plus®, RR 0.33 (95% CI 0.01 to 8.02) (Analysis 1.4).

4. Respiratory function tests

Clavel did not report this measure as the participant group were aged 10 to 63 months (Clavel 2007). Eisenberg demonstrated a small and clinically insignificant decrease in FEV1 post-treatment for both delivery systems; the Sidestream® the Pari LC Plus®, MD -0.40% predicted (95% CI -2.42 to 1.62) (Analysis 1.5). Westerman used respiratory function only as an indicator of bronchoconstriction therefore this is reported in the adverse events section (Westerman 2008).

8. Patient satisfaction and preference with nebuliser system

Clavel and Eisenberg did not report participant or parental satisfaction (Clavel 2007; Eisenberg 1997). Westerman identified a statistically non-significant preference for the CR60® compressor due to shorter administration times with seven out of ten participants preferring the CR60®, RR 2.33 (95% CI 0.83 to 6.54) (Analysis 1.6).

Conventional system versus VMT

Four studies reported on this comparison (Geller 2003; Griese 2009; Hubert 2009; Lenney 2011). The data presented within this review for the Lenney study are for only those participants with CF.

Primary outcomes
1. Treatment time (for single nebulised treatment)

The Geller single-dose study showed a significantly shorter treatment time with the AeroDose® (a VMT nebuliser system) when using a priming dose of 90 mg (giving an equivalent dose to 300 mg tobramycin through a conventional nebuliser system) when compared to the conventional nebuliser system of a Pari LC plus®, MD 9.70 min (95% CI 8.15 to 11.25) (Analysis 2.1). The second single-dose study found a median nebulisation time of seven minutes with the eFlow rapid® (VMT nebuliser) versus 20 minutes with a conventional nebuliser in participants with CF. Where interruptions in dosing were included (e.g. stopping the dose to cough) these times were eight minutes with the eFlow® (VMT nebuliser) versus 20 minutes with a conventional nebuliser in participants with CF (Lenney 2011). As Lenney only stated the median time, these data could not be included in the meta-analysis. We have contacted the author for further data to include in the meta-analysis in a future update of this review.

Two studies reported results at up to one week (Griese 2009; Hubert 2009) and pooled data show a significantly reduced treatment time using VMT nebulisers compared to conventional nebulisers, MD 11.14 min (95% CI 10.15 to 12.12) (Analysis 2.1).

One study reported data for the time-point between two and three weeks (Hubert 2009). The mean treatment time was shorter using the VMT nebuliser, MD 6.80 min (95% CI 4.31 to 9.29) (Analysis 2.1). This difference between the first and second time point may represent slowing of the mesh over time for VMT nebuliser systems (Hubert 2009).

3. Deposition

a. Serum

Two studies reported data for single doses for serum Cmax of tobramycin (Geller 2003; Lenney 2011). Pooled data favoured the conventional nebuliser system, MD SMD 0.48 (95% CI 0.06 to 0.90) (Analysis 2.2). There is a moderate to high value of I 2 for this analysis (55%) signifying high heterogeneity between the two studies. This may be due to the differing VMT nebuliser systems used in each study (AeroDose® (Geller 2003) and eFlow rapid® (Lenney 2011)) or to the differing priming doses used (90 mg (Geller 2003) versus 300 mg (Lenney 2011)).

Two studies compared serum tobramycin levels at up to one week (Griese 2009; Hubert 2009). Pooled data show a combined significant MD favouring conventional systems, SMD 0.38 (95% CI 0.02 to 0.74) (Analysis 2.2); Griese reports mg/ml and Hubert reports µg/ml. However, it should be noted that Hubert found that with the use of both types of nebuliser, tobramycin pre-dose serum levels did not exceed 2 µg/ml or Cmax 12 µg/ml, which were levels defined as potentially causing increased systemic toxicity (Hubert 2009).

Hubert reported on serum Cmax at day 15, there was no significant difference in serum levels of tobramycin with VMT versus a conventional nebuliser, SMD 0.09 (95% CI -0.51 to 0.68) (Analysis 2.2).

Three studies reported data for serum AUC (Geller 2003; Hubert 2009; Lenney 2011). After a single dose, two studies reported that serum concentrations of tobramycin were higher for conventional nebulisation than VMT (Geller 2003), MD 1.22 µg h/ml (95% CI 0.45 to 1.98) (Analysis 2.3).

At up to one week, Hubert demonstrated that there was no significant difference between VMT and conventional nebulisers, MD 1.00 µg/hr/ml (95% CI -0.18 to 2.18) (Analysis 2.3).

b. Sputum

Three studies reported sputum Cmax (Geller 2003; Griese 2009; Hubert 2009). The single-dose study reported comparable sputum concentrations of tobramycin when comparing VMT and conventional nebuliser systems, MD 27.65 µg/g (95% CI -370.64 to 425.94) (Geller 2003). The priming dose differences (90 mg tobramycin for the VMT arm and 300 mg for the conventional arm) should be noted and where a dose-normalised sputum Cmax was calculated, this showed greater deposition with VMT, SMD -1.05 (95% CI -1.51 to -0.58) (Analysis 2.4).

Two studies reported on this outcome at up to one week (Griese 2009; Hubert 2009) and found the nebuliser systems to be comparable, SMD -0.15 (95% CI -0.51 to 0.20) (Analysis 2.4).

At the two- to three-week time point, Hubert found that deposition was greater with VMT, SMD -0.48 (95% CI -1.09 to 0.14) (Analysis 2.4). The difference seen between the two time points in the Hubert study was due to an extreme outlier for sputum deposition measures at day 15, which occurred in this person for delivery via both the Pari LC plus® and for the eFlow rapid®.

Two studies reported data for sputum AUC and again found comparable results between nebulisers (Geller 2003; Hubert 2009). Geller reported results for a single dose, MD 195.93 μg h/g (95% CI -385.37 to 777.23) (Analysis 2.5). Hubert compared sputum tobramycin levels at day 1 and day 15 of the study (Hubert 2009). At day 1 sputum AUC was comparable between nebuliser systems, MD -177.00 μg h/g (95% CI -1326.84 to 972.84) (Analysis 2.5) and at day 15 comparable again, MD -1790.00 μg h/g (95% CI -5037.13 to 1457.13) (Analysis 2.5). It should be noted that Hubert and Geller both identified high variability in tobramycin levels between participants when using either type of nebuliser system.

c. Gamma scintigraphy

Lenney reported lung deposition, measured by gamma scintigraphic imaging of radiolabelled tobramycin. This paper reported a median (SD) percentage of metered dose despite it being usual to report mean with SD or median with interquartile range depending on the distribution of the data. The median (SD) for those with CF was 8.9 (0.8)% for eFlow rapid® versus 15.1 (6.0)% for LC plus® (Lenney 2011). We intend to contact the authors to clarify the statistics used and will report this in a future review update.

Secondary outcomes
1. Adherence

One study reported on adherence to the prescribed regimen (Hubert 2009). There was no significant difference found in adherence levels between conventional and VMT use, MD 0.67 % (95% CI -1.07 to 2.40) (Analysis 2.6). All adherence levels were found to be high at over 96% throughout. This may be due to the clinical trial setting and also the method used to measure adherence; ampoule return. This result may therefore not apply to the long-term clinical situation.

3. Adverse events

Three studies reported adverse events (Geller 2003; Griese 2009; Hubert 2009). After a single dose (Geller 2003), the difference between conventional and VMT nebulisation for adverse events was not statistically significant, RR 1.04 (95% CI 0.37 to 2.89) (Analysis 2.7). The paper describes the adverse events (cough, wheeze, chest tightness, urticarial reaction) included in these statistics, but does not present them by event type (Geller 2003).

At the two- to three-week time point (Hubert 2009), there was no significant difference between nebuliser systems, RR 1.26 (95% CI 0.86 to 1.86) (Analysis 2.7). Again, the paper reported total numbers of adverse events (headache, cough, dyspnoea, abdominal pain), but did not report the number of specific adverse events.

Griese reported there were fewer side effects with the VMT (Pari eFlow rapid®) treatment than with the conventional nebuliser treatment (Pari LC plus®), but did not provide data suitable for meta-analysis (Griese 2009). The relevant authors have been contacted for further data in order to add further detail to this section in future updates of this review.

4. Respiratory function tests

Hubert assessed respiratory function pre- and 30 minutes post-nebulisation at day 1 and day 15 of the study (Hubert 2009). Geller also assessed respiratory function pre- and 30 minutes post-nebulisation for each single dose given (Geller 2003).

a. FEV1

Only Geller reported on bronchospasm involving a greater than a 10% reduction in FEV1 and identified a total of 24 instances in 15 participants during the study (Geller 2003). When comparing the conventional nebuliser group with the VMT 90 mg group (giving an equivalent dose to 300 mg tobramycin through a conventional nebuliser system), the risk of bronchospasm of greater than 10% of FEV1 was not significant, RR 1.46 (95% CI 0.49 to 4.34) (Analysis 2.8). Geller also identified two episodes of bronchospasm involving a greater than a 20% reduction in FEV1 during the study (Geller 2003). One of these episodes was in a participant using conventional nebulisation and the other following delivery of 60 mg tobramycin via VMT. When data are entered in the graphs, the result is not statistically significant, RR 1.96 (95% CI 0.08 to 46.76) (Analysis 2.9).

Hubert reported on only those participants who had a greater than 20% reduction in FEV1 and identified no bronchospasm in participants either using conventional or using vibrating mesh nebulisers (Hubert 2009).

9. Nebuliser system reliability

Three studies reported no nebuliser system malfunctions (Griese 2009; Hubert 2009; Lenney 2011). In the Geller study, 10 participants experienced malfunction in the Aerodose® group (VMT); there were no malfunctions with the conventional nebuliser system, RR 0.09 (95% CI 0.01 to 1.53) (Analysis 2.10).

Conventional versus ultrasonic

One study compared conventional versus ultrasonic systems for delivering tobramycin (Eisenberg 1997). The results of the conventional versus ultrasonic arm of this study are not presented within this review as the priming dose was variable, 600 mg tobramycin in 30 ml but with an additional 15 ml of tobramycin added until 200 inhalations were complete. This variability means that it is unclear whether differences between the arms are due to the priming dose or due to the nebuliser system.

Nebuliser systems for delivering colistin

Two studies are included in this intervention, both compared a conventional system to AAD (Byrne 2003; Dodd 2002). One was a short-term cross-over study where each intervention arm was seven days with a seven-day washout period in between (Byrne 2003). The second study was a long-term study of six months (Dodd 2002).

Conventional system versus AAD
Primary outcomes
1. Treatment time

Only the short-term study reported on this outcome and demonstrated that the mean (SD) time to nebulise was less with the AAD system (Halolite®), than with a conventional system (Pari LC plus®) (Byrne 2003), MD 84.50 min (95% CI 41.62 to 127.38) (Analysis 3.1). However, the pre-set dose of the AAD system delivered a smaller mean (SD) volume of medication than the conventional system as a single dose, 0.55 (0.24) ml for the AAD system compared to 2.29 (0.34) ml for the conventional system from a priming dose of 3 ml for both systems (Byrne 2003).

3. Deposition

One study reported on this outcome and found that mean (SD) lung deposition, as measured by radiolabelled colistin in sputum, was higher with a conventional nebuliser system as compared to an AAD nebuliser system (Byrne 2003), MD 6.04 MBq (95% CI 4.29 to 7.79) (Analysis 3.2). However, the mean (SD) dosage used by the AAD system was significantly less (P <0.0001) than that used by the conventional system, 0.55 (0.24) ml used by AAD versus 2.29 (0.34) ml used by the conventional system. If calculated as a percentage of the amount of drug used, mean (SD) uptake was significantly higher for the AAD system as compared to the conventional nebuliser system, MD -11.04% (95% CI -21.07 to -1.01) (Analysis 3.3). Peripheral deposition was found to be comparable between the two systems with a MD of 1.34% (SE 1.14%) although raw data were not given.

Secondary outcomes
1. Adherence

This outcome was only reported by the long-term study (Dodd 2002). Dodd assessed adherence defined as doses initiated by the participant versus those prescribed (Dodd 2002). Compliance was also assessed, defined as doses taken correctly as compared to those initiated. Dodd found an improved adherence level in participants using an AAD system; mean adherence was 62% of prescribed nebulisers as compared to 47% in those using a conventional system. A higher level of doses correctly taken was also found in the group using AAD; 51% versus 26% in those using conventional (Dodd 2002). Standard deviations were not reported within this paper, therefore we were unable to present these data in the analysis. The study authors have been contacted for this information, which (if available) will be included in future updates of the review.

3. Adverse events

Dodd found a higher incidence of reported chest tightness per 1000 days of treatment in the AAD group (0.97) as compared to conventional (0.32) (Dodd 2002). This outcome was not reported by Byrne (Byrne 2003).

4. Respiratory function tests

Byrne found no significant change in FEV1 post-dose with either nebuliser system, raw values were not given (Byrne 2003).

Dodd assessed respiratory function at baseline, day 28 and day 182 in participants taking a bronchodilator before nebulised colistin either as an inhaler or as a nebuliser through a conventional system or through an AAD system (Dodd 2002). An improvement in FEV1 was seen in the AAD group at both time-points and a decrease in FEV1 was seen in the conventional system at both time-points. When the data are entered into the meta-analysis the results are significantly in favour of AAD at day 28, MD -10.50% (95% CI -17.77 to -3.23), but the result at day 182 is not significant, MD -4.20% (95% CI -14.93 to 6.53) (Analysis 3.4).

5. Respiratory exacerbations

Dodd reports assessing this in the 'Methods' section of the full paper and states that there were no significant differences between groups with respect to this, but the original data have not yet been obtained from the authors (Dodd 2002). This outcome was not reported by Byrne (Byrne 2003).

6. Need for additional antibiotic treatment during study period

Only Dodd reports assessing this in the 'Methods' section of the full paper and states that there were no significant differences between groups with respect to this but the original data have not yet been obtained from the authors (Dodd 2002).

8. Patient satisfaction and preference with nebuliser system

Dodd assessed this by questionnaire and found that 109 participants (82%) in the AAD group preferred the nebuliser system they used in the study as compared to 46 participants (37%) of those in the conventional group, RR 0.45 (95% CI 0.35 to 0.57) (Analysis 3.5); although a higher incidence of chest tightness was seen in the AAD group (Dodd 2002). This outcome was not reported by Byrne (Byrne 2003).

Nebuliser systems for delivering dornase alfa

Five studies are included in this intervention (Devadason 2001; Elkins 2006; Fiel 1995; Geller 1998; Shah 1997).

Conventional versus conventional system

Four studies are included in this comparison (Elkins 2006; Fiel 1995; Geller 1998; Shah 1997).

Primary outcomes
1. Treatment time

Three studies assessed this outcome (Elkins 2006; Geller 1998; Shah 1997). Elkins identified no significant difference between the LC Star® and the LC Plus®, MD -2.00 min (95% CI -4.23 to 0.23) (Analysis 4.1). Shah identified a faster nebulisation rate for the Sidestream® (median 4.8 (interquartile range 4.7 to 4.9) minutes) as compared to the Hudson T Updraft® (median 8.4 (interquartile range 8.2 to 10.0) minutes) but did not report any data, suitable to enter in a meta-analysis (Shah 1997). Geller also reported data which could not be entered into the analysis, but the shorter nebulisation time using the Medicaid Durable Sidestream® with a MobilAir® compressor at mean (range) 1.46 minutes (1.30 to 2.00) compared to 9.12 minutes (8.09 to 10.32) using the the Hudson T Updraft® corresponded to the Shah report (Geller 1998).

3. Deposition

Two studies reported on this outcome, but neither provided data suitable to enter into the meta-analysis (Geller 1998; Shah 1997). Geller reported that respirable fraction and percentage delivery were greater for the Medicaid Durable Sidestream® with a MobilAir® compressor while the percentage respirable fraction was greater for the Hudson T Updraft® nebuliser with a DeVilbiss Pulmo-Aide® compressor (Geller 1998). Shah found that the Sidestream® nebuliser produced a higher percentage of respirable particles as compared to the Hudson T Updraft® nebuliser (71% versus 31%); the aerosol output was 33% for the Sidestream® and 16% for the Hudson T Updraft® (Shah 1997).

Secondary outcomes
3. Adverse events

Three studies assessed this outcome (Fiel 1995; Geller 1998; Shah 1997). Available data from the Geller and Shah studies are presented in the graphs and did not show any significant difference in any adverse event: haemoptysis, OR 2.98 (95% CI 0.80 to 11.08) (Analysis 4.2); chest pain, OR 0.72 (95% CI 0.34 to 1.55) (Analysis 4.3); pharyngitis, OR 1.23 (95% CI 0.86 to 1.76) (Analysis 4.4); voice alteration, OR 1.03 (95% CI 0.65 to 1.64) (Analysis 4.5); and cough, OR 1.24 (95%CI 0.88 to 1.74) (Analysis 4.6).

Fiel identified five participants in the Marquest Acorn® group, one participant in Hudson T Updraft® updraft group and one in Pari LC® group who discontinued the study due to adverse events (Fiel 1995). Total adverse events included pharyngitis (15.9% to 21.6% of participants), cough (12.2% to 21.6% of participants), voice alteration (12.9% to 20.1% of participants), dyspnoea (3.8% to 11.9% of participants); however, a further breakdown of these data by treatment group were not provided and neither were any data on adverse events which did not lead to discontinuation (Fiel 1995).

4. Respiratory function tests

Three studies assessed this outcome (Fiel 1995; Geller 1998; Shah 1997), but data were only available for the meta-analysis from two studies (Fiel 1995; Geller 1998). Fiel presented data for FEV1 only in a form that was suitable for the meta-analysis for each of the three nebulisers studied at two time-points (day 8 and day 15) (Fiel 1995). We have presented these data on a single graph (see below).

a. FEV1

Fiel found a similar increase in respiratory function (FEV1, FVC and FEF25-75) at day 8 and day 15 with all three systems (Fiel 1995). At the 1- to 2-week time-point no significant differences between groups were seen: for the Marquest Acorn II® versus the Hudson T updraft®, MD 0.50% (95% CI -3.47 to 4.47); for the Marquest acorn II® versus the Pari LC plus®, MD 0.70% (95% CI -3.27 to 4.67); and for Pari LC plus® versus the Hudson T updraft®, MD -0.20% (95% CI -4.08 to 3.68) (Analysis 4.7).

At the 2- to 3-week time-point there were again no significant differences between groups: for the Marquest Acorn II® versus the Hudson T updraft®, MD 1.10 (95% CI -3.06 to 5.26); for the Marquest acorn II® versus the Pari LC plus®, MD of 1.70% (95% CI -2.46 to 5.86); and for the Pari LC plus® versus the Hudson T updraft®, MD -0.60% (95% CI -4.76 to 3.56) (Analysis 4.7).

Geller assessed respiratory function at day 1 and day 14 and found that respiratory function improved when dornase alfa was administered through either system (Geller 1998) with a non-significant difference between groups, MD -1.80% (95% CI -3.66 to 0.06) (Analysis 4.8).

Shah identified an improvement in FEV1 at day 7, but only reported medians and inter-quartile ranges (IQR); median (IQR) 11% (4% to 25%) for the group using the Hudson T Updraft® nebuliser with Pulmo-Aide® compressor group and 16% (7% to 25%) for the group using the Sidestream® nebuliser with CR50 compressor (Shah 1997).

b. FVC

We were only able to present data from the Geller study (assessed at day 1 and day 14) in the graphs. At day 14 this shows a statistically significant improvement in favour of the Sidestream® group, MD -1.40 (95% CI -2.71 to -0.09) (Analysis 4.9). Fiel reported an increase in respiratory function at day 8 and day 15 with all three systems (Fiel 1995). Raw data were not given for each group, but Fiel stated that average improvements between groups by day 15 were not statistically significant (Fiel 1995).

Shah identified a median (IQR) improvement in FVC at day 7, 10% (5% to 22%) for the Hudson T Updraft® nebuliser with Pulmo-Aide® compressor group and 12% (5% to 20%) for the Sidestream® nebuliser with CR50 compressor group (Shah 1997).

c. FEF25-75

We were only able to present data from the Geller study in the graphs (Geller 1998). This shows a statistically non-significant difference from baseline in FEF25-75 at day 14 between groups (Hudson T Updraft® with Pulmo-Aide®Sidestream® with MobilAir®), MD -1.70% (95% CI -6.98 to 3.58) (Analysis 4.10).

Fiel reported finding a similar increase in respiratory function at day 8 and day 15 with all three systems. Raw data were not given for each group, but Fiel stated that average improvements between the groups for FEF25-75 by day 15 were not statistically significant (Fiel 1995).

Shah identified a median (IQR) improvement in FEF25-75 at day 7, 7% (-4% to 25%) for the Hudson T Updraft® nebuliser with Pulmo-Aide® compressor group and 14% (-5% to 28%) for the Sidestream® nebuliser with CR50 compressor group (Shah 1997).

Conventional system versus AAD

Only one study reported on this comparison (Devadason 2001). We report data for two actuations with AAD as compared to conventional as this is as per the manufacturers' recommended use for this medication with this type of nebuliser system.

Primary outcomes
3. Deposition

There was no statistical difference in deposition between treatment groups despite the smaller priming dose for the Halolite® , MD -16.30 µg (95% CI -91.09 to 58.49) (Analysis 5.1). Peripheral deposition was also reported to be significantly better with AAD as compared to conventional (right lung P = 0.015, left lung P = 0.040). No drug was lost to the environment with the Halolite® while 600 mcg were lost to the environment with the Pari LC plus® (Devadason 2001)

Nebuliser systems for delivering other aerosolised medications

Six studies are included in this intervention (Devadason 1997; Kastelik 2002; Köhler 2003; Marshall 1994; Newman 1988; Thomas 1991).

Conventional versus conventional system

Three studies are compared different conventional systems (Devadason 1997; Marshall 1994; Newman 1988). Devadason compared four different conventional nebuliser systems in a cross-over study and we are unable to present these data in the meta-analysis; instead they are presented in the additional tables (Table 1).

Table 1. Comparison of four conventional nebulisers for administering salbutamol (Devadson 1997)
  1. All data are presented as means (standard deviations)

    MA: Marquest Acorn II®
    MA&M: Marquest Acorn II® with miser
    PLC: Pari LC Plus®
    VS: Ventstream®

OutcomeMAMA&MVSPLC
Treatment time (min)10.8 (3.2)10.2 (2.3)11.8 (3.0)10.0 (2.2)
Deposition (%)9.35 (2.74)13.85 (5.45)17.2 (6.83)19.2 (5.78)
Particle size (µm)5.56 (0.21)6.19 (0.13)3.57 (0.07)5.5 (0.17)
Medication remaining (%)54.5 (18.2)55.7 (7.0)56.3 (13.5)57.9 (7.4)
Primary outcomes
1. Treatment time

Only the single-dose four-arm study by Devadason assessed this outcome (Devadason 1997). When administering salbutamol, Devadason found for the Pari LC Plus® to be quickest mean (SD) treatment time of 10.0 (2.2) minutes and the Ventstream® to be slowest at 11.8 (3.0) minutes (Table 1).

3. Deposition

All three studies reported on this outcome (Devadason 1997; Marshall 1994; Newman 1988).

Devadason used filter deposition to assess drug delivery to participants (Devadason 1997). Deposition of salbutamol on the inspiratory filter (indicating nebuliser output) was lower with the conventional jet nebuliser, with or without miser, as compared to the Venturi® type nebulisers. The particle size, mass median aerodynamic diameters (MMAD), generated by the Ventstream® was significantly smaller than that of the other nebulisers and there was no significant difference in the amount of medication left in the chamber of each nebuliser (Table 1).

Marshall measured the proportion of dose of saline with labelled technetium-99m diethylene triamine pentaacetic acid delivered to the participant (Marshall 1994). The volume of aerosol delivered to the participant in the initial dose was significantly greater with Marquest Acorn II® with miser compared with the Marquest Acorn II® alone, MD 5.30% (95% CI 0.29 to 10.31) (Analysis 6.1). The proportion of inhaled aerosol deposited to peripheral regions of the lung was significantly greater with the Marquest Acorn II® with miser than for the Marquest Acorn II® alone, MD 7.50% (95% CI 0.96 to 14.04), but significantly less to the central regions with the Marquest Acorn II® with miser than with Marquest Acorn II® alone, MD -7.50% (95% CI -14.04 to -0.96) (Analysis 6.1).

Newman administered carbenicillin and found that lung deposition was significantly greater with the Turret® nebuliser with Maxi®compressor compared to the Inspiron® nebuliser with Traveller® compressor, MD 9.06 mg (95% CI 7.96 to 10.16) (Analysis 6.2). Peripheral deposition was also significantly greater for the Turret® nebuliser than for the Inspiron® nebuliser, MD 5.08 mg (95% CI 4.40 to 5.76); however, oropharyngeal deposition was significantly lower with the Turret® nebuliser than with the Inspiron® nebuliser, MD -4.62 mg (95% CI -7.77 to -1.47) (Analysis 6.2).

Secondary outcomes
4. Respiratory function tests

Only Marshall reported on this outcome and identified no correlation between baseline respiratory function and deposition with either the Marquest Acorn II® or the Marquest Acorn II® with miser (Marshall 1994).

7. Cost

Only Devadason reported on this outcome and noted that Venturi nebulisers (Ventstream® and Pari LC Plus®) are more costly than standard jet nebulisers (e.g. Acorn®) (Devadason 1997).

Conventional system versus AAD

One identified study assessed the Pari LC Plus® versus the Halolite® AAD system for delivering radio-labelled sodium chloride in a single dose through each nebuliser system (Kastelik 2002). This study included participants with CF and healthy volunteers. Results described within this systematic review are for those participants with CF only.

Primary outcomes
3. Deposition

Kastelik found that lung deposition was higher for the AAD system, median (range) 1.5 (0.7 to 2.1) times higher, although this gave a P value of 0.12. Variation of total dose delivered was lower for the AAD than the conventional system, 22% versus 39% (P = 0.05). The central to peripheral count ratios were higher with the AAD system, but this result was not significant, MD -0.24 (95% CI -0.64 to 0.16) (Analysis 7.1). Homogenity of aerosol deposition was found to be greater with the conventional system than with the AAD system (Kastelik 2002).

Secondary outcomes
4. Respiratory function tests

a. FEV1

Kastelik reported no significant change in FEV1 either via the Pari LC Plus® conventional system or the Halolite® AAD system (Kastelik 2002).

b. FVC

Kastelik reported no significant change in FVC either via the Pari LC Plus® or the Halolite® AAD system (Kastelik 2002).

3. Adverse events

Kastelik did not report any adverse events for either nebuliser system (Kastelik 2002).

Conventional system versus ultrasonic nebuliser

Two identified studies assessed a conventional versus an ultrasonic system; System 22 Acorn® versus Fisoneb® for delivering amiloride (Thomas 1991) and the Parimaster/LC Plus Turbo® versus the Multisonic Compact® with sodium cromoglycate (SCG) (Köhler 2003).

Primary outcomes
1. Treatment time

Treatment time for delivering amiloride was decreased with the ultrasonic nebuliser, range four to five minutes, as compared to a conventional system, range six to seven minutes (Thomas 1991), although this was contradicted by the second study on SCG (Köhler 2003) which found ultrasonic to be comparable to conventional, MD -1.50 min (95% CI -3.47 to 0.47) (Analysis 8.4).

3. Deposition

Thomas reported that total lung deposition of amiloride, as measured by dynamic lung scans, was significantly greater with the ultrasonic nebuliser (Fisoneb®) than with a conventional system (System 22 Acorn®), MD -46.00 µg (95% CI -86.32 to -5.68). This was also true for deposition in the total left lung, MD -22.00 µg (95% CI -40.66 to -3.34), central right lung, MD -8.40 µg (95% CI -15.68 to -1.12) and the upper right lung, MD -6.40 µg (95% CI -11.91 to -0.89) (Analysis 8.1). However, differences were not significant for the total right lung, MD -22.00 µg (95% CI -45.86 to 1.86), peripheral right lung, MD -14.30 µg (95% CI -32.37 to 3.77) and lower right lung, MD -3.30 µg (95% CI -11.77 to 5.17) (Analysis 8.1). Deposition as measured outside of the lungs was greater with an ultrasonic nebuliser: the difference was not significant for the oropharynx, MD -573.00 counts/s (95% CI -1366.52 to 220.52); but was significant in the stomach, MD -586.00 counts/s (95% CI -982.56 to -189.44) (Analysis 8.2). Köhler found the ultrasonic nebuliser system to be comparable to conventional in terms of urinary SCG levels, MD 0.39 mg (95% CI -0.02 to 0.80) (Analysis 8.5) and found significantly more medication left in the chamber as a residual volume for ultrasonic as compared to conventional, MD 0.18 mg (95% CI 0.18 to 0.03) (Analysis 8.6).

Secondary outcomes
3. Adverse events

Thomas stated that no adverse events were reported by the amiloride study participants with either conventional or ultrasonic nebuliser (Thomas 1991).

4. Respiratory function tests

There was no significant change reported in FEV1, FVC or PEF following inhalation of amiloride with either conventional or ultrasonic nebuliser (Thomas 1991): FEV1, MD 0.02 L (95% CI -0.69 to 0.73); FVC, MD -0.21 L (95% CI -1.19 to 0.77); or PEF, MD 5.00 L min-1 (95% CI -80.28 to 90.28) (Analysis 8.3).

8. Patient satisfaction and preference with nebuliser system

There was a reported preference for the ultrasonic nebuliser over the conventional system for delivering amiloride due to decreased noise (Thomas 1991). However, the numbers of participants were small (n = 8) and it was not stated how many of the participants preferred the ultrasonic nebuliser.

Discussion

Summary of main results

This systematic review evaluated the effectiveness, safety, burden of treatment and adherence to nebulised therapy using different nebuliser systems. Twenty studies were included of which 16 were available as full text publications. The distribution of these studies across the types of nebuliser systems are described below.

Conventional nebuliser systems

Most of the studies suitable for inclusion assessed one form of conventional nebulisation system versus another conventional system. These studies were: for tobramycin (Clavel 2007; Westerman 2008); for dornase alfa (Elkins 2006; Fiel 1995; Geller 1998; Shah 1997); and for other medications (Devadason 1997; Marshall 1994; Newman 1988). Comparison of conventional nebulisation systems demonstrated differences depending upon type of compressor and upon nebuliser chamber used. Treatment times were reduced with compressors delivering a higher flow rate, for example the CR60® was quicker than the Porta-neb® (Westerman 2008). Treatment times were also reduced with nebulisers which produced a smaller particle size or a higher respirable fraction, or both. For example the Pari LC Star®, which is known to produce smaller particle sizes and a higher respirable fraction, was significantly quicker than the Pari LC Plus® (Elkins 2006); and the Medicaid Durable Sidestream® with a MobilAir® compressor delivering a droplet size of 2.1 µm was quicker than the Hudson T Updraft® nebuliser with a DeVilbiss Pulmo-Aide® compressor producing a droplet size of 4.9 µm (Geller 1998). The Medicaid Durable Sidestream® nebuliser with a CR50® compressor, which had a higher percentage of particles in the respirable range than the Hudson T Updraft® II nebuliser with the Pulmo-Aide® compressor, also had faster nebulisation rates (Shah 1997). One study identified a difference in tobramycin serum levels depending on the type of compressor used with the faster CR60® giving an increased serum level as an indicator of increased lung deposition (Westerman 2008). Increased adverse events of subjective chest tightness were also identified with this compressor as compared to the slower Porta-neb®. Deposition was found to vary with different conventional combinations by two studies, who found increased deposition using a holding chamber (Marshall 1994; Newman 1988), and by Devadason who also identified an improved deposition with a holding chamber, but additionally found a further improvement with use of breath-assisted open-vent systems (Devadason 1997).

AAD systems

We included four studies assessing AAD versus conventional nebuliser systems; all assessed the use of the Halolite® AAD system. Two of these studies assessed the delivery of colistin (Byrne 2003; Dodd 2002); one assessed delivery of dornase alfa (Devadason 2001); and one assessed delivery of radio-labelled saline (Kastelik 2002). Treatment time was reduced with AAD as compared to conventional systems (Byrne 2003). There was a patient preference for AAD and adherence to nebulisers was improved when using AAD (Dodd 2002). Lung deposition as a percentage of loaded dose was higher with AAD (Kastelik 2002, Byrne 2003) and an improvement was seen in respiratory function where bronchodilators were given via an AAD system as compared to a conventional system (Dodd 2002). However, an increased incidence of adverse events in the form of chest tightness was seen with delivery of colistin via AAD as compared to a conventional system (Dodd 2002).

AAD with VMT systems

There were no studies identified which assessed the combined technologies of AAD with VMT. This is a relatively new technology and although deposition, dosing and observational studies exist, no studies identified were RCTs (either parallel or cross-over studies) suitable for inclusion in this review.

VMT systems

Four studies assessing VMT versus conventional systems for delivery of tobramycin were identified; one used the AeroDose 5.5 RP® (Geller 2003) and three used the Pari eFlow rapid® (Griese 2009; Hubert 2009; Lenney 2011 ). Treatment times were reduced with VMT as compared to conventional systems (Geller 2003; Griese 2009; Hubert 2009) although the time difference decreased over time (Hubert 2009) which may represent degradation of the mesh used in VMT systems. Deposition of medication, as measured by sputum levels, was found between to be comparable between VMT and conventional nebulisation or greater with VMT when used over a longer period of time. Where a dose-normalised sputum Cmax was calculated, greater deposition was shown with VMT as compared to conventional nebulisation (Geller 2003). Deposition as measured by serum levels and gamma scintigraphy was, however, less with VMT as compared with a conventional system (Geller 2003; Hubert 2009; Lenney 2011). Sputum levels of the medication are key to the effectiveness of inhaled medications, particularly when inhaling antibiotics. Serum levels of tobramycin may indicate lung deposition as most of the medication found in serum will be as a result of lung absorption; however, this absorption is complex and affected by a number of variables. The results of sputum levels may therefore be more important. Dosing with VMT was well tolerated by participants with similar numbers of adverse events experienced by participants using these nebulisers as by those using conventional systems and no increased evidence of bronchospasm with dosing through VMT systems. There were issues with the reliability of one type of VMT nebuliser system; the AeroDose 5.5 RP® (Geller 2003), but no reliability issues were seen in the other studies (Hubert 2009; Griese 2009; Lenney 2011).

Ultrasonic nebuliser systems

Two identified studies assessed a conventional versus an ultrasonic nebuliser for the delivery of amiloride (Thomas 1991) and SCG (Köhler 2003). These studies demonstrated variable and conflicting results; treatment times were comparable (Köhler 2003) and decreased (Thomas 1991) versus conventional systems; lung deposition was comparable (Köhler 2003) and increased (Thomas 1991) versus conventional systems. There was increased patient preference for the ultrasonic nebuliser system (Thomas 1991).

Overall completeness and applicability of evidence

Four of the included studies were available only in abstract form which limits the data available (Devadason 2001; Dodd 2002; Elkins 2006; Griese 2009). Further information has been requested from a number of authors and we hope that this will enhance the review at a later date. The studies included a range of participants in terms of age and disease severity, therefore we feel that the results are applicable to the general CF population. There was a lack of robust patient-reported outcomes used within the studies (such as quality of life, burden of treatment, etc.) which limited comment on these important measures.

Quality of the evidence

This review included 20 studies involving 1936 participants. It covered a large range of nebuliser systems and medications with only a small number of suitable studies identified for each type of nebuliser system with each medication. There were also gaps where no evidence could be found for a specific medication delivered by a particular nebuliser system, for example conventional versus AAD nebuliser systems for the delivery of tobramycin. Four of the 20 studies identified were in abstract form only (Devadason 2001; Dodd 2002; Elkins 2006; Griese 2009). Abstracts give limited information on methodology and results and the evidence from the abstracts is therefore weaker in general. Further details have been requested from authors in order to strengthen the review.

For all the studies, the generation of allocation sequence was stated as randomised, but in only one of these was the method of randomization described and the study considered to have a low risk of bias (Fiel 1995). The concealment of treatment allocation was unclear in all of the included studies. Only one of the studies was clear that blinding had taken place; although it was unclear whether this was single or double blinding (Byrne 2003). Two other studies stated that the nebuliser was behind a lead shield; however, it was not clear whether this was a safety precaution due to radio-labelling or whether this also provided single or double blinding to the nebuliser system (Kastelik 2002; Newman 1988). Blinding is challenging when testing nebuliser systems as the interface (e.g. mouthpiece) will be noticeably different with different nebuliser systems, the aerosol generated may be noticeably different and the technique for using them correctly will differ. It may therefore be unrealistic to achieve full double blinding of all studies assessing nebuliser systems.

Overall the evidence was consistent and strong around a number of key points:

  1. there is variability in the delivery of nebulised medication depending on the nebuliser system used;

  2. conventional nebuliser systems providing higher flows, smaller particle sizes and higher respirable fractions decrease treatment time and increase deposition as compared to conventional nebuliser systems providing lower flows, larger particle sizes and lower respirable fractions;

  3. newer technologies such as VMT and AAD dramatically reduce treatment time;

  4. AAD systems maintain or improve on lung deposition as compared to conventional systems;

  5. deposition is variable with VMT depending on the measurement method and the VMT system used.

There was weaker evidence around other findings:

  1. there is a patient preference for non-conventional nebuliser systems such as VMT, AAD and ultrasonic nebuliser systems;

  2. adherence to treatment may be improved with the use of AAD nebuliser systems;

  3. ultrasonic nebulisers may be comparable to, or better than, conventional systems in terms of deposition and may be preferred by people with CF;

  4. there is an indication that some nebulisers using VMT may be subject to increased failures or breakdowns.

Potential biases in the review process

There was no obvious bias in the methods used for searching for studies, study selection, data collection or analysis as the authors followed the clear guidance given by The Cochrane Collaboration. However, the authors have requested further data from a number of authors and the lack of this data within the current review may introduce reporting bias.

Agreements and disagreements with other studies or reviews

We were unable to identify any previous systematic reviews which evaluated the effectiveness, safety, burden of treatment and adherence to nebulised therapy using different nebuliser systems. There are, however, two pieces of guidance identified which relate to nebuliser systems (ERS 2001; Heijerman 2009).

The older ERS guidance details the use of conventional nebuliser systems with little mention of ultrasonic nebulisers and no mention of the newer VMT and AAD technologies (ERS 2001). This guideline was produced using a clear method for identifying and reviewing evidence; the Scottish Intercollegiate Guidelines Network grading system and the Agency for Health Care Policy and Research scoring system. It is focused on the practicalities of using nebuliser nebuliser systems and medications; however, aspects of the findings are in broad agreement with this Cochrane review. The key agreement being that the type of nebuliser system used may radically alter the amount of medication delivered to the lung (ERS 2001).

The European consensus includes a table detailing the grades of recommendation used, but not how the evidence was identified, included or reviewed (Heijerman 2009). It is a more recent guideline and does include ultrasonic nebulisation as well as the newer technologies such as VMT and AAD. The guideline is again broadly in agreement with this Cochrane review on a number of key points. The guideline recognises that there is great variation in the delivery of medication through different nebuliser systems and goes on to state that, "It is therefore possible that the effectiveness of an inhaled drug is dependent on the delivery system". A table within the guideline also points to the variability of medication delivery with conventional nebuliser systems and to lower treatment times and greater fraction of respirable particles available with use of VMT, but does not include any comment about AAD nebuliser systems (Heijerman 2009).

This Cochrane review adds detail to the key points identified in the previous guidelines. It also presents information about AAD performance which has not been included in the past guidance.

Authors' conclusions

Implications for practice

There are differences in treatment time and deposition with different types of conventional nebuliser system with those combinations producing faster flows, smaller particles and higher respirable fractions giving a better outcome in terms of treatment time and deposition. Clinicians need to consider these differences when issuing conventional equipment, particularly if exchanging established equipment for alternatives. The most dramatic results for treatment time are seen with newer technologies such as VMT and AAD. Both types of nebuliser system dramatically reduce treatment time and, as the time taken for nebulisation is a significant part of total CF treatment time and impacts on treatment burden (Sawicki 2009), this is an important finding for clinicians to be aware of and act on.

Deposition, as a percentage of the priming dose, is also dramatically increased with AAD systems and is comparable to conventional as a delivered dose. Deposition for VMT systems is variable depending on the system used and the measurement taken. It is therefore important to monitor any variation in treatment effectiveness when changing the nebuliser system used. Clinicians should be aware, and should educate those using new nebuliser systems, of differences in the priming dose of medication required for some of these new systems as compared to conventional nebuliser systems. Using a priming dose designed for conventional nebulisation in a more efficient nebuliser system may lead to safety issues with an increased delivered dose. This may lead to various effects including increased adverse events such as wheeze, chest tightness and an inability for the person with CF to tolerate nebulised therapy. It may also lead to an increased risk of higher systemic absorption which may be a particular problem when considering the long-term use of aminoglycosides. One of the advantages of using nebuliser systems to deliver these medications is to limit systemic delivery thereby avoiding or delaying possible long-term effects such as hearing loss.

There is an indication that patients prefer AAD and VMT nebuliser systems and there may be increased adherence to medications given through these nebuliser systems. Trials of these nebuliser systems with a focus on patient-reported outcomes are needed to confirm these indications. At present VMT and AAD nebuliser systems appear promising in optimising nebulised therapy for those with CF but, where issued, need to be individually assessed and evaluated carefully.

There are few data about ultrasonic nebuliser systems, therefore clinicians should think carefully about their reasoning for using these systems in preference to other systems which have more data about improved outcomes such as treatment time. There is also information from other sources such as medication summary of product characteristics, which indicate that ultrasonic systems should not be employed with some medications commonly used in people with CF. This may mean that, where ultrasonic nebuliser systems are used, an alternative system may also need to be provided with the cost implications that this brings.

Implications for research

There are still limitations to the evidence base for switching to nebuliser systems utilising new technologies such as VMT and AAD. Further research is needed to comprehensively assess the benefits of these newer nebuliser technologies and particularly for nebuliser systems combining the technologies for which there are no RCTs. There are particularly few data on patient-focused outcomes such as burden of care, quality of life and patient satisfaction with the different nebuliser systems and of the effects of nebuliser systems on adherence. Data have not been identified which demonstrate the superiority of these nebuliser systems with all the medications available as routine maintenance treatment for those people with CF. There are gaps in knowledge about safe and effective dosing levels of some medications in some systems. Further research is needed to define clear and safe dosing regimens for each type of nebuliser system. In view of the great cost differences between nebuliser systems and the variation in the ability of clinicians to provide some of the systems, an economic evaluation of their use is a high priority.

Acknowledgements

We thank Nikki Jahnke and Tracey Remmington from the Cochrane Cystic Fibrosis and Genetic Disorders Group for their editorial support and guidance in completing this review.

Data and analyses

Download statistical data

Comparison 1. Tobramycin - conventional versus conventional
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Bronchoconstriction (nebuliser versus nebuliser)1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
1.1 Single dose1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Bronchoconstriction (compressor versus compressor)1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 Single dose1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Increased cough (nebuliser versus nebuliser)1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 Single dose1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Chest pain (nebuliser versus nebuliser)1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4.1 Single dose1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 FEV1 (% predicted)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Single dose1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Satisfaction with device1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
6.1 Single dose1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Tobramycin - conventional versus conventional, Outcome 1 Bronchoconstriction (nebuliser versus nebuliser).

Analysis 1.2.

Comparison 1 Tobramycin - conventional versus conventional, Outcome 2 Bronchoconstriction (compressor versus compressor).

Analysis 1.3.

Comparison 1 Tobramycin - conventional versus conventional, Outcome 3 Increased cough (nebuliser versus nebuliser).

Analysis 1.4.

Comparison 1 Tobramycin - conventional versus conventional, Outcome 4 Chest pain (nebuliser versus nebuliser).

Analysis 1.5.

Comparison 1 Tobramycin - conventional versus conventional, Outcome 5 FEV1 (% predicted).

Analysis 1.6.

Comparison 1 Tobramycin - conventional versus conventional, Outcome 6 Satisfaction with device.

Comparison 2. Tobramycin - conventional versus VMT
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Treatment time (minutes)3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 Single dose184Mean Difference (IV, Fixed, 95% CI)9.7 [8.15, 11.25]
1.2 Up to 1 week2120Mean Difference (IV, Fixed, 95% CI)11.14 [10.15, 12.12]
1.3 2 to 3 weeks142Mean Difference (IV, Fixed, 95% CI)6.80 [4.31, 9.29]
2 Deposition (serum Cmax)4 Std. Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 Single dose296Std. Mean Difference (IV, Fixed, 95% CI)0.48 [0.06, 0.90]
2.2 Up to 1 week2122Std. Mean Difference (IV, Fixed, 95% CI)0.38 [0.02, 0.74]
2.3 2 to 3 weeks144Std. Mean Difference (IV, Fixed, 95% CI)0.09 [-0.51, 0.68]
3 Deposition (serum AUC)3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 Single dose296Mean Difference (IV, Fixed, 95% CI)1.22 [0.45, 1.98]
3.2 Up to 1 week144Mean Difference (IV, Fixed, 95% CI)1.0 [-0.18, 2.18]
4 Deposition (sputum Cmax)3 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 Single dose184Std. Mean Difference (IV, Random, 95% CI)-1.05 [-1.51, -0.58]
4.2 Up to 1 week2120Std. Mean Difference (IV, Random, 95% CI)-0.15 [-0.51, 0.20]
4.3 2 to 3 weeks142Std. Mean Difference (IV, Random, 95% CI)-0.48 [-1.09, 0.14]
5 Deposition (sputum AUC)2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Single dose1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Up to 1 week1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.3 2 to 3 weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Adherence150Mean Difference (IV, Fixed, 95% CI)0.67 [-1.07, 2.40]
7 Adverse events2 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
7.1 Single dose1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
7.2 2-3 weeks1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8 FEV1: reduction >10%1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
8.1 Single dose1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9 FEV1: reduction >20%1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9.1 Single dose1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Device malfunctions4304Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 1.53]
10.1 Single dose2176Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 1.53]
10.2 2 to 3 weeks150Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10.3 3 to 4 weeks178Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Tobramycin - conventional versus VMT, Outcome 1 Treatment time (minutes).

Analysis 2.2.

Comparison 2 Tobramycin - conventional versus VMT, Outcome 2 Deposition (serum Cmax).

Analysis 2.3.

Comparison 2 Tobramycin - conventional versus VMT, Outcome 3 Deposition (serum AUC).

Analysis 2.4.

Comparison 2 Tobramycin - conventional versus VMT, Outcome 4 Deposition (sputum Cmax).

Analysis 2.5.

Comparison 2 Tobramycin - conventional versus VMT, Outcome 5 Deposition (sputum AUC).

Analysis 2.6.

Comparison 2 Tobramycin - conventional versus VMT, Outcome 6 Adherence.

Analysis 2.7.

Comparison 2 Tobramycin - conventional versus VMT, Outcome 7 Adverse events.

Analysis 2.8.

Comparison 2 Tobramycin - conventional versus VMT, Outcome 8 FEV1: reduction >10%.

Analysis 2.9.

Comparison 2 Tobramycin - conventional versus VMT, Outcome 9 FEV1: reduction >20%.

Analysis 2.10.

Comparison 2 Tobramycin - conventional versus VMT, Outcome 10 Device malfunctions.

Comparison 3. Colistin - conventional versus AAD
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Treatment time1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Up to 1 week1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Deposition (lung uptake MBq)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Up to 1 week1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Deposition (lung uptake as % of dose used)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 Up to 1 week1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 FEV1 (% change)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 3 - 4 weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Satisfaction with device1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5.1 At 6 months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 Colistin - conventional versus AAD, Outcome 1 Treatment time.

Analysis 3.2.

Comparison 3 Colistin - conventional versus AAD, Outcome 2 Deposition (lung uptake MBq).

Analysis 3.3.

Comparison 3 Colistin - conventional versus AAD, Outcome 3 Deposition (lung uptake as % of dose used).

Analysis 3.4.

Comparison 3 Colistin - conventional versus AAD, Outcome 4 FEV1 (% change).

Analysis 3.5.

Comparison 3 Colistin - conventional versus AAD, Outcome 5 Satisfaction with device.

Comparison 4. Dornase alfa - conventional versus conventional
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Treatment time1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Single dose1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Adverse events: haemoptysis1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 1 to 2 weeks1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Adverse events: chest pain1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 1 to 2 weeks1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Adverse events:pharyngitis2922Odds Ratio (M-H, Fixed, 95% CI)1.23 [0.86, 1.76]
4.1 Up to 1 week1173Odds Ratio (M-H, Fixed, 95% CI)1.54 [0.52, 4.53]
4.2 1 to 2 weeks1749Odds Ratio (M-H, Fixed, 95% CI)1.19 [0.82, 1.75]
5 Adverse events: voice alteration2922Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.65, 1.64]
5.1 Up to 1 week1173Odds Ratio (M-H, Fixed, 95% CI)1.69 [0.39, 7.29]
5.2 1 to 2 weeks1749Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.60, 1.59]
6 Adverse events: cough1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
6.1 1 to 2 weeks1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
7 % Change in FEV1 (multiple nebuliser comparison)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 1 to 2 weeks: MA vs HTU1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7.2 1 to 2 weeks: MA vs PLC1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7.3 1 to 2 weeks: PLC vs HTU1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7.4 2 to 3 weeks: MA vs HTU1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7.5 2 to 3 weeks: MA vs PLC1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7.6 2 to 3 weeks: PLC vs HTU1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 % Change in FEV11 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 1 to 2 weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 FVC1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
9.1 1 to 2 weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10 FEF25-751 Mean Difference (IV, Fixed, 95% CI)Totals not selected
10.1 1 to 2 weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 4.1.

Comparison 4 Dornase alfa - conventional versus conventional, Outcome 1 Treatment time.

Analysis 4.2.

Comparison 4 Dornase alfa - conventional versus conventional, Outcome 2 Adverse events: haemoptysis.

Analysis 4.3.

Comparison 4 Dornase alfa - conventional versus conventional, Outcome 3 Adverse events: chest pain.

Analysis 4.4.

Comparison 4 Dornase alfa - conventional versus conventional, Outcome 4 Adverse events:pharyngitis.

Analysis 4.5.

Comparison 4 Dornase alfa - conventional versus conventional, Outcome 5 Adverse events: voice alteration.

Analysis 4.6.

Comparison 4 Dornase alfa - conventional versus conventional, Outcome 6 Adverse events: cough.

Analysis 4.7.

Comparison 4 Dornase alfa - conventional versus conventional, Outcome 7 % Change in FEV1 (multiple nebuliser comparison).

Analysis 4.8.

Comparison 4 Dornase alfa - conventional versus conventional, Outcome 8 % Change in FEV1.

Analysis 4.9.

Comparison 4 Dornase alfa - conventional versus conventional, Outcome 9 FVC.

Analysis 4.10.

Comparison 4 Dornase alfa - conventional versus conventional, Outcome 10 FEF25-75.

Comparison 5. Dornase alfa - conventional versus AAD
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deposition (sputum) (µg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Single dose1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 5.1.

Comparison 5 Dornase alfa - conventional versus AAD, Outcome 1 Deposition (sputum) (µg).

Comparison 6. Other aerosolised medication - conventional versus conventional
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Radio-labelled saline: deposition (mg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Initial dose1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Peripheral deposition1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 Central deposition1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Carbenicillin: deposition (mg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Lung deposition1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 Peripheral deposition1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.3 Oropharangeal deposition1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 6.1.

Comparison 6 Other aerosolised medication - conventional versus conventional, Outcome 1 Radio-labelled saline: deposition (mg).

Analysis 6.2.

Comparison 6 Other aerosolised medication - conventional versus conventional, Outcome 2 Carbenicillin: deposition (mg).

Comparison 7. Other aerosolised medication - conventional versus AAD
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Sodium chloride: deposition1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Central to peripheral count ratios1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 7.1.

Comparison 7 Other aerosolised medication - conventional versus AAD, Outcome 1 Sodium chloride: deposition.

Comparison 8. Other aerosolised medication - conventional versus ultrasonic
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Amiloride: pulmonary deposition (µg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Total lung1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Left lung1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 Right lung1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.4 Central right lung1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.5 Peripheral right lung1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.6 Upper right lung1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.7 Lower right lung1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Amiloride: extrapulmonary deposition (counts/s)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Oropharynx1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 Stomach1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Amiloride: respiratory function tests1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 FEV1 (L)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 FVC (L)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 PEF (L min-1)1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 SCG: treatment time (min)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5 SCG: deposition measured by urinary levels (mg)120Mean Difference (IV, Fixed, 95% CI)0.39 [-0.02, 0.80]
6 SCG: residual medication in nebuliser (mg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
Analysis 8.1.

Comparison 8 Other aerosolised medication - conventional versus ultrasonic, Outcome 1 Amiloride: pulmonary deposition (µg).

Analysis 8.2.

Comparison 8 Other aerosolised medication - conventional versus ultrasonic, Outcome 2 Amiloride: extrapulmonary deposition (counts/s).

Analysis 8.3.

Comparison 8 Other aerosolised medication - conventional versus ultrasonic, Outcome 3 Amiloride: respiratory function tests.

Analysis 8.4.

Comparison 8 Other aerosolised medication - conventional versus ultrasonic, Outcome 4 SCG: treatment time (min).

Analysis 8.5.

Comparison 8 Other aerosolised medication - conventional versus ultrasonic, Outcome 5 SCG: deposition measured by urinary levels (mg).

Analysis 8.6.

Comparison 8 Other aerosolised medication - conventional versus ultrasonic, Outcome 6 SCG: residual medication in nebuliser (mg).

Contributions of authors

TD drafted the protocol, NM commented on the protocol. TD and PW reviewed and assessed studies identified by the search. TD was lead author on the final review, PW and NM reviewed and commented.

Declarations of interest

TD has completed research utilising one form of nebuliser system but this research is not sponsored by any company. TD also carries out consultancy work for three companies involved in developing, manufacturing and distributing nebuliser systems or medications.

Differences between protocol and review

Within the types of interventions section, AAD nebuliser systems were added as an intervention for comparison. There are two types of AAD nebuliser systems which have been used both clinically and in research. This had been overlooked at protocol stage where only AAD in combination with VMT had been included. An important comparison would be omitted without its inclusion.

Within the protocol we had originally stated that, where evidence existed, we would compare different forms of conventional system (e.g. open-vent jet system or breath-assisted open-vent system) for use with a particular medication as a subgroup. Following the literature search it was apparent that there was sufficient evidence to include different types of conventional system as a comparison and that previous guidance had considered that there may be clinically important differences between conventional systems (ERS 2001; Heijerman 2009).

Within the primary outcome measures section, 'Deposition as measured by radio labelling or serum levels of the studied medication' was expanded to include sputum and urine concentrations. Sputum levels of the studied medications are vital, high sputum levels of medication are required as a way to demonstrate efficacy of the nebuliser system with the specified medication. Serum and urine levels are used in most studies of this type to assess systemic toxicity and therefore to indicate safety; sputum levels should be high while serum or urine levels are relatively low.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Byrne 2003

Methods

Randomised, cross-over study.

Single centre.
Initial washout of 7 days, order of 7-day intervention was randomised with 7-day washout.

Participants

15 participants with CF. All had chronic PsA requiring daily nebulised colistin.

Mean age 14.1 years (range 7 - 23 years).
Mean (SD) FEV1 56.5 (18.9)%.

Interventions

1 mu colistin in 2 ml NaCl 0.9% and 1 ml sterile water primed with 60 MBq Tc99m-DTPA through:

1. HaloLite nebuliser (AAD);

2. Pari LC plus® and Pariboy® compressor (conventional).

7 days of intervention followed by 7-day washout period and then alternative nebuliser system.

Outcomes

Lung deposition (radio-labelled colistin)

Time to nebulise

Respiratory function pre- and post-nebuliser

Colistion levels in sputum at 1 and 4 hours

PsA load in sputum at 1 and 4 hours

Residual drug volume in nebuliser

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as a randomised study; however, method of generation of allocation sequence was not stated.
Allocation concealment (selection bias)Unclear riskDid not report whether allocation was concealed.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipant was shielded from nebuliser system, but unclear whether researcher or those analysing data (or both) were blinded to nebuliser system.
Incomplete outcome data (attrition bias)
All outcomes
Low riskWithdrawals clearly stated with numbers, point of withdrawal and reason. 14 completed radionucleotide outcomes, 13 completed microbiology outcomes (1 too ill to complete, 1 declined to complete).
Selective reporting (reporting bias)Unclear riskAll outcomes identified in methods were reported on in results, however paper stated there was no significant change in FEV1 post-dose with either nebuliser system and did not give actual data.
Other biasLow riskCross-over a suitable design. No carry-over effect (week washout). Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Clavel 2007

Methods

Randomised, cross-over pilot study.

Single centre.

Participants

10 participants.

Aged under 6 years.

Clinically stable disease.

Interventions

Tobramycin 300 mg in 5 ml via:

1. Pari LC plus® with Turboboy® (conventional);

2. atomiser box plus a form of jet nebuliser (conventional).

Outcomes

Urinary tobramycin concentrations (over 6 hours post-dose).

Delivery time.

NotesSingle dose given with each nebuliser system at least 1 week apart and within 1 month.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of allocation not stated.
Allocation concealment (selection bias)Unclear riskDid not report whether allocation was concealed.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Low riskWithdrawals clearly stated with numbers, point of withdrawal and reason. 16 potential participants: 2 individuals declined; 4 individuals lived too far away to attend study.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasHigh risk

Difficult participant group for both consistent administration of nebuliser and for full urine collection.

Cross-over a suitable design. No carry-over effect (single dose with week washout). Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Devadason 1997

Methods

Randomised, cross-over study.

Single centre.

Participants18 people with CF.
Aged 3 - 16 years.
Interventions

Single dose salbutamol 2.5 mg/2.5 ml via:

1. Marquest Acorn II® nebuliser (conventional);

2. Marquest Acorn II® with Miser system (conventional);

3. Ventstream® (conventional);

4. Pari LC plus® (conventional).

All with 6 L/min air flow from hospital compressed air supply.

Outcomes

Drug output measured by inspiratory filter deposition.

Particle size distribution.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of allocation not described.
Allocation concealment (selection bias)Unclear riskDid not report on allocation concealment.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Low riskWithdrawals clearly stated with numbers, point of withdrawal and reason. Only missing data for respiratory function in those children who could not perform reliable spirometry. Spirometry not an outcome measure, only for baseline characteristics.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasUnclear riskCross-over a suitable design but possibility for carry over effect (same day, unclear about time between doses). Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Devadason 2001

Methods

Randomised, cross-over study.

Single centre.

Participants

15 children with CF.

Aged 3 - 16 years.

Interventions

Single dose dornase alfa labelled with Technetium-99m:

1. 2.5 mg/2.5 ml via Pari LC plus® with compressor (conventional);

2. 1.25 mg/1.25 ml via HaloLite (AAD).

Outcomes

Lung deposition.

Drug lost to environment.

NotesAbstract only.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as randomised cross-over study; however, not stated how the randomisation was achieved.
Allocation concealment (selection bias)Unclear riskDid not report on whether allocation was concealed.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo data appears to have been excluded; however, in abstract form only and more information needed.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasUnclear riskUnclear whether cross-over a suitable design. Unclear about carry-over effect as no details about washout. Both period data not available. Methods of statistical analysis not adequately described. Unclear whether results were comparable to a parallel group design.

Dodd 2002

Methods

Randomised, parallel study.

Multicentre (USA, Australia, Canada and Europe).

Participants

259 participants with CF.

Median age 17 years.

Median FEV1 56%.

Interventions

Randomised to usual maintenance treatment (dornase alfa or nebulised antibiotic (or both)) for 182 days via:

1. HaloLlite system (AAD);

2. conventional high efficiency nebuliser.

Outcomes

FEV1.

Days of antibiotic use.

Exacerbation frequency.

Time to first exacerbation.

Adherence to nebuliser system.

Adherence to prescribed regimen

Safety

Device acceptability

Notes

Randomised within 7 days of exacerbation requiring oral or IV antibiotics.

This study was available as a series of eight abstracts. This made data difficult to extract and data limited. Need original author data.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method of randomisation described.
Allocation concealment (selection bias)Unclear riskDid not report on whether allocation was concealed.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place
Incomplete outcome data (attrition bias)
All outcomes
High risk259 participants entered the study, there is no information regarding the numbers that completed.
Selective reporting (reporting bias)High riskNot all outcomes listed were fully reported. A statement was given that, 'there was no statistically significant difference ...for secondary outcome variables'. Require further information as in abstract form only.
Other biasLow riskNo evidence of other bias.

Eisenberg 1997

Methods

Randomised cross-over.

Multicentre (10 tertiary centres in the USA).

Participants

68 participants with CF.

Age 21.5 years (range 10.6 - 40.9).

Mean FEV 1 60% (range 24% - 102%).

Interventions

Single dose of tobramycin 300mg/5mls in random order via:

1. Sidestream with Pulmoaide (conventional);

2. Pari LC Plus with Pulmoaide (conventional).

Single dose of tobramycin 600mg/30mls via:

Ultraneb 99/100 (ultrasonic).

Outcomes

Sputum tobramycin levels.

Serum tobramycin levels.

Respiratory function pre- and post-dose.

Adverse events.

Administration time/ number of breaths to administer

NotesPriming dose of tobramycin for use with the Ultraneb 99/100 was variable as a complete dose was defined as 200 inhalations. If the initial priming dose was insufficient to achieve 200 inhalations then further tobramycin was added in 15 ml amounts.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method of randomisation described.
Allocation concealment (selection bias)Unclear riskDid not report on whether allocation was concealed.
Blinding (performance bias and detection bias)
All outcomes
High riskNo blinding, open-label study.
Incomplete outcome data (attrition bias)
All outcomes
Low riskWithdrawals clearly stated with numbers, point of withdrawal and reason. Data is presented for 60 patients out of the original 68 enrolled.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasLow riskCross-over a suitable design. No carry over effect (minimum 48-hour washout). Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Elkins 2006

MethodsRandomised, cross-over study.
Participants

10 people with CF, age not stated although study carried out at an adult CF unit.

Stable lung disease.

Interventions

Single dose 2.5 mg dornase alfa via:

1. Pari LC star® nebuliser with compressor (conventional);

2. Pari LC plus® with compressor (conventional).

OutcomesNebulisation time.
NotesAbstract only.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of randomisation not described.
Allocation concealment (selection bias)Unclear riskNo allocation concealment described.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk10 participants were studied. No details of individual outcomes or incomplete data.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasUnclear riskUnclear if cross-over a suitable design. No information regarding washout or carry-over effect. Both period data were available. Methods of statistical analysis limited information. Unable to ascertain if results were comparable to a parallel group design.

Fiel 1995

Methods

Open-label, randomised, parallel study.

Multicentre (26 clinical sites in the USA).

Participants

397 participants with CF.

Over 5 years of age.

FVC 40% - 70% predicted.

Oxygen saturation >90% room air.

Interventions

Dornase alfa for 15 days via:

1. Marquest Acorn II® with De Vilbiss PulmoAide® compressor;

2. Hudson T Updraft®;

3. Pari LC Plus® with Pariboy® compressor.

Outcomes

FEV1 (at baseline, 8 days & 15 days).

FVC (at baseline, 8 days & 15 days).

Adverse events.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Permuted block design.

Participants were randomized to one of two groups and randomization was stratified within each centre according to severity of illness at enrolment (FVC either less than 70% or 70% and over) by means of a stratified block design, but there is no description of how the sequence for the block design was generated (e.g. computer-generated, random number tables etc),

Allocation concealment (selection bias)Unclear riskNo concealment described.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Withdrawals clearly stated with numbers, point of withdrawal and reason.

5 participants dropped out due to increased cough and/or respiratory exacerbation:

3 in Group 1;

1 in group 2;

1 in group 3.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasLow riskNo other bias identified.

Geller 1998

Methods

Randomised, open-label, parallel study.

Multicentre.

Participants

749 people with CF.

Age >5 years.

Mild lung disease (FVC >70% predicted).

Interventions

Dornase alfa 2.5 mg twice daily for 2 weeks via:

1. Medicaid Durable Sidestream® with a MobilAir® compressor (conventional);

2. Hudson T Updraft® nebuliser with Devilbiss PulmoAide® compressor (conventional).

Outcomes

Respiratory function (FEV1, FVC and FEF25-75) at 1 and 14 days.

Adverse events.

Serum levels of dornase alfa at baseline and within 4 hours of the final dose.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskReported as randomised study; however, method of randomisation not described.
Allocation concealment (selection bias)Unclear riskNo concealment described.
Blinding (performance bias and detection bias)
All outcomes
High riskNo blinding, open-label study.
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analysis.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasLow riskNo other bias identified.

Geller 2003

MethodsOpen-label, randomised, cross-over study.
Single dose then 1 week washout.
Participants

53 participants with CF.

Age >12 years.

FEV1 >40%.

Able to expectorate >2 g sputum in 24 hours.

Interventions

Tobramycin 300 mg, total volume 5 ml via Pari LC plus® with PulmoAide® compressor.

Then 2 out of 3 of the following:

30 mg, 60 mg or 90 mg tobramycin (60 mg/ml) mixed with normal saline, total volume 0.5 ml via Aerodose 5.5 RP®.

Outcomes

FEV1 (pre and 30 minutes following dose).

Sputum concentration of tobramycin (pre, 10 min, 1, 2, 4 & 8 hours).

Serum levels of tobramycin (pre, 10 min, 1, 2, 4 & 8 hours).

Nebulisation time.

Urinary tobramycin concentration (pre, 0 to 8hours, 8 to 24 hours)

Adverse events

NotesAlthough presented as randomised, no information re randomisation of these doses.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo methods of randomisation were described.
Allocation concealment (selection bias)Unclear riskNo allocation concealment was described.
Blinding (performance bias and detection bias)
All outcomes
High riskNo blinding, open-label study.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Intention-to-treat analysis. Withdrawals clearly stated with numbers, point of withdrawal and reason: 56 screened, 53 met criteria and were randomised, 52 received minimum of 1 dose of medication, 1 dropped out before commencing study due to respiratory exacerbation.

49 completed study, 2 dropped out with respiratory exacerbation and 1 dropped out with potential drug reaction.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasLow riskCross-over a suitable design. No carry-over effect (week washout). Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Griese 2009

Methods

Randomized, parallel group study.

Multicentre.

Participants78 people with CF; 42 children (8 - 17 yrs) and 36 adults (18 - 42 yrs).
Interventions

1. TOBI® (300 mg/5 ml delivered by PARI LC PLUS®;

2. Tobramycin PARI (150 mg/1.5 ml, delivered by an investigational eFlow®).

given twice daily for 28 days.

Outcomes

Sputum concentration of tobramycin at 7 days of use.

Serum levels of tobramycin at 7 days of use.

Adverse events.

Nebulisation time.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethods of randomisation not described.
Allocation concealment (selection bias)Unclear riskNo reported concealment.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo data reported missing.
Selective reporting (reporting bias)High riskData presented is too limited to be certain. Some outcomes reported in results that weren't identified in methods.
Other biasLow riskNo other bias identified.

Hubert 2009

MethodsRandomised, cross-over study.
Participants

25 adults with CF.

Age 19 to 44 years.

Chronic colonisation with PsA.

Interventions

Tobramycin 300 mg twice a day for 15 days via:

1. Pari LC plus® with compressor (conventional);

2. Pari eFlow rapid® (vibrating mesh).

Outcomes

Adherence (measured by returned ampoules)

Nebulisation time.

Sputum tobramycin level.

Serum tobramycin level.

Adverse events.

FEV1.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskReported as randomised study; however, methods not described.
Allocation concealment (selection bias)Unclear riskNot described in abstract.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo premature discontinuations reported.
Selective reporting (reporting bias)Low riskNo evidence of selected reporting. All outcomes identified in methods were reported on in results.
Other biasLow riskCross-over a suitable design. No carry-over effect (week washout). Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Kastelik 2002

Methods

Randomised cross-over study.

Single dose with 7-day washout period.

Participants

Six adults with CF.

Age 19 - 42 years.

Mean (SD) FEV1 63.2 (20.2)% predicted.

Interventions

Single dose 3 ml normal saline labelled with 150 MBq Technetium-99m diethylene triamine pentaacetic acid on 2 occasions via:

1. Pari LC plus® with compressor (conventional);

2. HaloLite® (AAD).

Outcomes

Nebulisation time.

Dose delivered.

Lung deposition.

Gastrointestinal and oropharyngeal deposition.

Adverse events.

Respiratory function (FEV1 and FVC).

NotesThis study also assessed 16 healthy volunteers (data not presented in this Cochrane review).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethods of randomisation not described.
Allocation concealment (selection bias)Unclear riskNo reported allocation concealment.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskBody of nebuliser covered by lead shield but not clear whether patient and staff were aware of which nebuliser being used.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data reported.
Selective reporting (reporting bias)Unclear riskAll outcomes identified in methods were reported on in results however for respiratory function tests stated there were no significant changes and did not provide any data
Other biasLow riskCross-over a suitable design. No carry-over effect (week washout). Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Köhler 2003

MethodsRandomised, cross-over study.
Participants10 people with CF (age 9 to 21 years).
Interventions

Single dose 20 mg sodium cromoglycate and beta agonist with each of the following:

1. ultrasonic nebuliser;

2. jet nebuliser.

Outcomes

Excreted sodium cromoglycate in urine up to 12 hours post-dose

Treatment time

Residual volume of medication in nebuliser

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethods of randomisation not described.
Allocation concealment (selection bias)High riskPatients alternately assigned to the test groups a or b.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData reported for all 10 participants.
Selective reporting (reporting bias)Unclear riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasLow riskCross-over a suitable design. No carry-over effect (2-day washout). Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Lenney 2011

Methods

Single-dose, open-label, two-way randomised cross-over study.

Multicentre.

Participants

13 participants aged 18 - 65 years.

7 with CF with chronic PsA infection and FEV1 equal to or above 25% predicted.

6 healthy volunteers with FEV1 equal to or over 80% predicted and BMI within ± 25% of ideal.

Note: only data from participants with CF was included in this review.

Interventions

A single dose of 300 mg/5ml tobramycin for inhalation with 99mTc DTPA via:

1. Pari eFlow rapid® nebuliser;

2. Pari LC plus® nebuliser.

Randomly assigned with a minimum washout of 72 hours.

Outcomes

Lung deposition

Oropharangeal and abdominal deposition

Serum tobramycin levels

Respiratory function

Adverse events

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskPaper states that participants were randomly assigned 1:1, but methods of randomisation not described.
Allocation concealment (selection bias)Unclear riskNo reported concealment.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Low riskWithdrawals accounted for and all who received at least one dose were included in the intention-to-treat analysis.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasLow riskCross-over a suitable design. No carry-over effect (minimum 72-hour washout). Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Marshall 1994

MethodsRandomised cross-over study.
Participants

12 people with CF (6 male, 6 female).

Age: mean 12.7 (range 10 to 16).

FEV1 >40%.

No respiratory exacerbation within last 2 weeks.

Interventions

4 ml solution of saline with labelled Tc99m-DTPA via:

1. Marquest Acorn II® nebuliser and mouthpiece (conventional);

2. Marquest Acorn II® nebuliser attached to a miser system 22 aerosol conservation device (conventional).

OutcomesLung deposition using radio-labelling.
NotesCorrelated lung deposition with baseline respiratory function.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethods of randomisation not described.
Allocation concealment (selection bias)Unclear riskNo reported concealment.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo data reported missing.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasLow riskCross-over a suitable design. No carry-over effect (week washout). Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Newman 1988

MethodsRandomised cross-over study.
Participants

7 adults with CF.

Age 22 to 48 years.

On regular aerosolised antibiotics.

FEV1 16%-57% predicted.

Interventions

1 g carbenicillin powder and 4 ml Tc99m-DTPA solution labelled with 185 MBq technetium-99m via:

1. Turret® nebuliser with Maxi® Mark 1 compressor with tidal breathing (conventional);

2. Inspiron® mini-neb nebuliser with Traveller® compressor with tidal breathing (conventional);

3. Turret® nebuliser with Maxi® Mark 1 compressor with combination of tidal and deep breathing (conventional).

Outcomes

Lung deposition

Oropharangeal deposition

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo methods of randomisation described.
Allocation concealment (selection bias)Unclear riskDid not report whether allocation was concealed.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskBody of nebuliser covered by lead shield but not clear whether patient and staff were aware of which nebuliser being used.
Incomplete outcome data (attrition bias)
All outcomes
Low riskWithdrawals clearly stated with numbers, point of withdrawal and reason: 1 participant withdrew and data obtained prior to withdrawal accounted for.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasUnclear riskCross-over a suitable design. No information regarding wash out or carry-over effect. Both period data were available. Methods of statistical analysis were described and correct. Unable to ascertain if results were comparable to a parallel group design.

Shah 1997

Methods

Parallel design, randomised, open-label study.

Multicentre (3 UK centres).

Participants

173 people with CF.

> 5 years of age.

FVC >40%.

Oxygen saturations >90% room air.

Interventions

Dornase alfa 2.5 mg once daily for 7 days via:

1. Sidestream® nebuliser with CR50® compressor, 86 participants (conventional);

2. Hudson T Updraft® II nebuliser with PulmoAide® compressor, 87 participants (conventional).

Outcomes

FEV1

FVC

FEF25-75

Adverse events

NotesIn vivo particle size study also assessed as subgroup.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo methods of randomisation described.
Allocation concealment (selection bias)Unclear riskDid not report whether allocation was concealed.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described in paper.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. Withdrawals clearly stated with numbers, point of withdrawal and reason:
Other biasLow riskNo other bias identified.

Thomas 1991

MethodsRandomised, cross-over study.
Participants8 adults with CF (6 male, 2 female).
Interventions

Amiloride 1 mg with 99mTc HSA 37 MBq in total volume of 3 ml via:

1. System 22 Acorn® with CR60® compressor (conventional);

2. Fisoneb® (ultrasonic).

Outcomes

Pulmonary amiloride deposition

Oropharangeal and gastrointestinal deposition of amiloride

FEV1, FVC and PEF

Adverse events

Patient preference

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo methods of randomisation described.
Allocation concealment (selection bias)Unclear riskDid not report whether allocation was concealed.
Blinding (performance bias and detection bias)
All outcomes
High riskNo evidence that blinding took place.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasUnclear riskCross-over a suitable design. No information regarding wash out or carry-over effect. Both period data were available. Methods of statistical analysis were described and correct. Unable to ascertain if results were comparable to a parallel group design.

Westerman 2008

  1. a

    AAD: adaptive aerosol delivery
    AUC: area under the curve
    BMI: body mass index
    CF: cystic fibrosis
    Cmax: maximal plasma concentration
    FEF25-75: forced expiratory flow from 25% to 75% of vital capacity
    FEV1: forced expiratory volume at one second
    FVC: forced vital capacity
    HSA: human serum albumin
    IV: intravenous
    MBq: megabecquerel
    NaCl: sodium chloride
    PEF: peak expiratory flow
    PsA: Pseudomonas aeruginosa
    SD: standard deviation
    Tc99m-DTPA: technetium-99m diethylene triamine penta-acetic acid

MethodsOpen, randomised, single-dose, cross-over study
Participants10 adults (>18 years) with CF.
Interventions

Tobramycin 300 mg via Pari LC plus® with:

1. CR60® compressor;

2. Portaneb® compressor.

Outcomes

Participant experience (questionnaire)

Nebulisation time

Tobramycin serum concentration

Pharmacokinetics (Cmax)

Pulmonary deposition (AUC0-6)

Respiratory function

Medication osmolality (ampoule and residual in nebuliser)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethods not described.
Allocation concealment (selection bias)Unclear riskDid not report whether allocation was concealed.
Blinding (performance bias and detection bias)
All outcomes
High riskOpen trial therefore no blinding to medication or compressor.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData provided for all 10 patients.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting. All outcomes identified in methods were reported on in results.
Other biasLow riskCross-over a suitable design. Both period data were available. Methods of statistical analysis were described and correct. Results were comparable to a parallel group design.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Conway 1993Compared nebulised to inhaled treatment (not part of remit of review).
Crowther Labiris 1999Compared nebulised to inhaled treatment (not part of remit of review).
Dolovich 2005Compared particle size not nebuliser systems.
Faroux 2000Compared conventional with and without positive pressure not separate nebuliser systems.
Hung 1995Compared nebulised to inhaled treatment (not part of remit of review).
Johnson 2006In vitro study - did not include relevant patient groups.
Kovaleva 2001Compared nebulised to inhaled treatment (not part of remit of review).
Laube 2000Compared particle size not nebuliser systems.
Mallol 1996Not comparing nebuliser systems.
Mallol 1997Compared fill volume not nebuliser systems.
Militz 2008Contacted authors - unable to provide sufficient information about methodology and results.
Moss 2005Comparing dose not nebuliser systems.
Mulrennan 2004Not a randomised controlled study.
Podolec 2001Unable to contact authors, therefore not able to obtain sufficient data.
Potter 2008In vitro study - did not include relevant patient groups.
Vanlaethem 2008Not comparing nebuliser systems.

Characteristics of studies awaiting assessment [ordered by study ID]

Denk 2009

MethodsUnclear.
Participants16 males aged 10 - 34 years with CF currently or recently using inhaled tobramycin for PsA infection.
Interventions1. 150 mg/1.5 mL of a new tobramycin nebuliser solution mixed with the radiolabel 99mTc-DTPA using a investigational eFlow®;
2. TOBI® (300 mg/5 ml) mixed with the radiolabel 99mTc-DTPA using a Pari LC plus® nebuliser.
Outcomes

Lung deposition

Nebulisation time

NotesNeed further information about methodology and results. Authors contacted. No response, written again and emailed.

Govoni 2012

MethodsUnclear. States "randomized, open label, multicentre, two-period, crossover trial" but only available as an abstract so no information about how participants randomised, etc.
Participants27 people with CF aged 18 years, with chronic PsA. infection and FEV1 equal to or more than 30% predicted.
Note: 25 completed study (no information regarding reason for non-completion and dealing with data regarding this).
Interventions

Twice-daily tobramycin 300 mg/4 ml for 28-days delivered by:

1. Pari eFlow rapid®;

2. Pari LC plus®.

Separated by a 4-week washout.

OutcomesBlood and sputum levels at day 1 and day 28
Time for nebulisation
Notes

Awaiting full publication or further data before classification.

Pharmaceutical publication (Cheisi).

Haeussermann 2006

MethodsRandomised, cross-over study.
Participants16 people with CF.
Interventions

Inhaled 2x per day, 1 day of each:

  • tobramycin 300 mg/5 ml via Pari LC plus®;

  • tobramycin 160 mg/4 ml via Pari LC star® with AKITA®.

Outcomes

Gamma-scintigraphy

FEV1

Serum levels of tobramycin 1 hour post-inhalation

NotesAbstracts only, therefore difficult to assess methods and bias. Washout unclear as study 3 days in total. Authors contacted by letter and by email with no response.

McCormack 2011

  1. a

    CF: cystic fibrosis
    FEV1: forced expiratory volume at one second
    MU: mega unit
    PsA: Pseudomonas aeruginosa
    SD: standard deviation
    TBM: tidal breathing mode
    Tc99m-DTPA: technetium-99m diethylene triamine penta-acetic acid
    TIM: target inhalation mode

MethodsRandomised controlled study, parallel design. Duration 8 - 10 weeks.
Participants

20 children (14 male) with CF age range 5–16 years.

10 patients (7 male) were randomised to TIM and 10 (7 male) continued on TBM.

Clinically stable - all patients with PsA infection who were established on long-term (>3 months) antibiotic therapy through the I-nebTM using standard TBM of inhalation.

All patients completed the study.

Interventions

System to administer a commercial preparation of colistin (Promixin®, Profile Pharma Ltd., Chichester, UK) with a standard treatment dose being 1 MU diluted in 2 ml normal saline (1 ml being used for each of 2 daily treatments). In some patients, a once-daily dose of 1 MU colistin in 1 ml normal saline was prescribed

Baseline period (4-6 weeks) using TBM with AAD system, then randomised to continue TBM or switch to TIM (8-10 weeks) with AAD system.

Patients were prescribed 1–3 treatments a day.

OutcomesPrimary outcome measure: average time for each treatment episode (calculated from data download)
Secondary outcome measures: treatment adherence (calculated as a percentage of expected treatments), patient preference (questionnaire), pulmonary function, adverse events and withdrawals
NotesConsider post hoc change to include AAD versus AAD system.

Ancillary