Paediatric Respiratory Reviews 14 (2013) 98–99

Cochrane Corner

Nebuliser systems for drug delivery in cystic fibrosis

Tracey Daniels 1,*, Nicola Mills 2, Paul Whitaker 3

1 York Adult CF Unit, York Teaching Hospital NHS Foundation Trust, York, UK2 Physiotherapy Department, Glenfield Hospital, Leicester, UK3 Regional Adult CF Unit, Ward 2, Gledhow Wing, St James’ Hospital, Leeds, UK

Contents lists available at SciVerse ScienceDirect

Paediatric Respiratory Reviews

WHY DO WE NEED THIS REVIEW1?

Nebulised medications are used to control the symptoms andprogression of lung disease in people with cystic fibrosis (CF).Studiessuggest that the mean (SD) time taken to complete daily treatmentfor CF is 108 (58) minutes, with nebulised therapy taking up moretime (mean 41mins) than any other type of treatment.2 Burden oftreatment, measured by the Cystic Fibrosis Questionnaire – revised(CFQ-R), is shown to increase with increasing nebulised therapy.2

Developments in nebuliser technology have led to many types ofnebuliser systems being available for use with various medications.No previous systematic review has evaluated these systems in orderto assist clinicians in understanding the impact of using differentsystems with each medication they may wish to prescribe.

The I-Neb adaptive aerosol delivery (AAD) nebuliser system(Picture courtesy of Philips Respironics; Chichester, England).

* Corresponding author.

E-mail address: traceydaniels1@nhs.net (T. Daniels).

1526-0542/$ – see front matter � 2013 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.prrv.2013.03.004

WHAT COMPARISONS DID WE MAKE IN THIS REVIEW?

The aim of this review1 was to evaluate the effectiveness,safety, burden of treatment and adherence to a number ofnebulised medications using different nebuliser systems inpeople with CF. We looked at delivery of the followingmedications:

� tobramycin;� colistin;� dornase alfa;� hypertonic sodium chloride;� other aerosolised medications.

For each medication conventional systems were compared withany other system listed below. We considered conventionalsystems to be an air compressor combined with a jet nebuliser,including open vent jet systems and breath assisted open ventsystems.

Systems for comparison were:

� different types of conventional system;� adaptive aerosol delivery (AAD) nebuliser systems;� AAD incorporating vibrating mesh technology (VMT) nebuliser

systems;� VMT systems;� ultrasonic nebuliser systems.

We searched the Cochrane Cystic Fibrosis and Genetic DisordersGroup’s Trials Register (last search 15th October 2012) and thereference lists of each trial. We approached the manufacturers ofnebuliser systems and nebulised medications for published andunpublished data and approached authors for additional data. Weincluded 20 randomised controlled trials or quasi-randomisedcontrolled trials involving 1936 participants.

T. Daniels et al. / Paediatric Respiratory Reviews 14 (2013) 98–99 99

WHAT DID WE FIND?

We found variability in the delivery of nebulised medication, interms of treatment time and deposition, depending on thenebuliser system used. Our most significant finding was aroundtreatment time. Conventional nebuliser systems, providing higherflows and respirable fractions and smaller particles, reducedtreatment time. Nebulisers using AAD or VMT, reduced treatmenttime to a far greater extent. This finding may be highly significantto clinicians and to people with CF as long treatment times posesignificant challenges in terms of scheduling treatment aroundeducation, work and families.3

Our second main finding was about deposition. Those conven-tional nebuliser systems which provided higher flows andrespirable fractions and smaller particles, increased depositionas compared to the conventional nebuliser systems whichprovided lower flows and respirable fractions and larger particles.Deposition, as a percentage of priming dose, is greater with AAD.The evidence for VMT systems was more variable; deposition wascomparable or greater than conventional systems when measuringsputum levels, but lower when measuring serum levels or usinggamma scintigraphy.

Other findings were that the newer technologies, AAD and VMT,are safe when used with an appropriate priming dose, which maybe different to the priming dose for conventional systems. There isalso an indication that adherence is maintained or improved withthese newer systems. People with CF may prefer those conven-tional nebuliser systems which provide higher flows, respirablefractions and smaller particles. They may also prefer ultrasonic,AAD or VMT systems. However, some nebuliser systems using VMTmay be subject to increased failures.

There were a small number of participants (total 18) in thestudies assessing ultrasonic systems and the results conflicted. Onestudy indicated deposition and treatment times were comparableto conventional systems, while the other found total lungdeposition greater and treatment times reduced for ultrasonicsystems as compared to the conventional systems.

WHAT DO THE GUIDELINES SAY?

Two pieces of guidance relate to nebuliser systems; theEuropean Respiratory Society (ERS) Guidelines4 and the EuropeanCystic Fibrosis Society (ECFS) consensus document.5 The older ERSguidance (2001) is focused on the practicalities of using conven-tional systems. Aspects of the guidance are in broad agreementwith this review. The key agreement being that the type ofnebuliser system used may alter the amount of medicationdelivered to the lung.4

The later ECFS consensus document (2009) includes ultrasonic,VMT and AAD as well as conventional systems. It is again broadly inagreement with this review on a number of key points. It

recognises variation in the delivery of medication throughdifferent nebuliser systems and states that, ‘‘It is therefore possiblethat the effectiveness of an inhaled drug is dependent on thedelivery system’’. It identifies the variability of medication deliverywith conventional nebuliser systems and also quicker treatmenttimes and greater fraction of respirable particles available with useof VMT, but does not include detailed comment about AADsystems.5

In addition to this Cochrane review1 enhancing the findings ofprevious guidelines, it also provides information about AADperformance which has not been included in previous guidelines.

WHAT FURTHER RESEARCH IS NEEDED?

There is a need for long-term randomised controlled trials ofnebuliser systems to determine patient-focused outcomes (such asquality of life and burden of care) and clinical outcomes (such ashospitalisations and need for antibiotics). There are also gaps inknowledge about safe and effective dosing levels of somemedications in some systems. In view of the great cost differencesbetween nebuliser systems and variation in the ability of cliniciansto provide some of the systems, an economic evaluation of theiruse is a high priority.

THE TAKE HOME MESSAGES

Clinicians should be aware of variability in performance ofdifferent nebuliser systems when used with different medications.The authors suggest that clinicians should look carefully at theavailable dosing data for the medication they wish to prescribethrough the nebuliser system that they will be providing.

Technologies such as AAD and VMT have advantages overconventional systems in terms of treatment time, patientpreference and adherence and can have advantages in deposition.As nebulised therapy has been shown to contribute greatly to dailytreatment times and to burden of treatment, these technologiesshould be considered for use whenever possible.

References

1. Daniels T, Mills N, Whitaker P. Nebuliser devices for drug delivery in cysticfibrosis. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.:CD007639. http://dx.doi.org/10.1002/14651858.CD007639. pub2.

2. Sawicki GS, Sellers DE, Robinson WM. High treatment burden in adults withCystic Fibrosis: challenges to disease self-management. J Cyst Fibros 2009;8:91–6.

3. Dodd ME, Webb AK. Understanding non-compliance with treatment in adultswith Cystic Fibrosis. J R Soc Med 2000;93(suppl38):2–8.

4. European Respiratory Society Task Force. European Respiratory Society Guide-lines on the use of nebulizers. European Respiratory Journal 2001;18:228–42.

5. Heijerman H, Westerman E, Conway S, Touw D, Doring G, for the consensusworking group. Inhaled medication and inhalation devices for lung disease inpatients with cystic fibrosis: A European consensus. Journal of Cystic Fibrosis2009;8(5):295–315.

In collaboration with the Cochrane CF and Genetic Disorders Group’ http://cfgd.cochrane.org/.