Conference Proceedings
December 2002 / Volume 47 / Number 12 / Page 1445
Standardization Issues: In Vitro Assessment of Nebulizer Performance
IntroductionThe delivery of nebulized drugs is poorly controlled and the choice of the most appropriate delivery device is poorly understood, particularly because of off-license prescriptions and a lack of evidence-based medicine. Standardized in vitro methods for measuring nebulizer performance have been adopted in Europe, by the 2001 publication of a European Standard, prEN13544-1. These standardized methods were subsequently incorporated within the European Respiratory Society nebulizer guidelines, which will provide clinicians with useful information to improve nebulizer therapies. Standards for measuring nebulizer performance should be considered in North America and elsewhere. Careful consideration should be given to either adopting the methods embodied in the European Standard or developing the basis for developing that standard further through the International Standards Organization. Either way, confusion among clinicians would be reduced and nebulizer safety and aerosol delivery efficiency increased by standardizing in vitro methods of nebulizer performance assessment.
Standardization Issues
European Nebulizer Standard
Nebulizer Versus Nebulizer System
Measuring Aerosol Output and Aerosol Droplet Size Using the Methods
in the European Standard
Aerosol Output
Aerosol Particle Size
Clinical Relevance of the European Standard in Vitro Methods
European Respiratory Society Guidelines on the Use of Nebulizers
Type Testing Using the European Standard
Characteristics of "Good" and "Bad" Nebulizer Systems
How to Select the Optimal System for a Given Patient Group or Specific Use
Implementation and Use of Standard Operating Practice As a Means
to Improve the Efficacy of Nebulizer Therapy
Standardize the Way Current Nebulizer Systems Are Used
Assess Drug Output from the Current Nebulizer System
Evaluate Alternative Nebulizer Systems
Future Developments in Nebulized Drug Delivery Summary
Introduction
Although delivering nebulized drugs to the lungs has been used for centuries in medical research, and nebulizers and nebulizer drugs have been commercially available throughout the past century, the delivery of nebulized drugs is still poorly controlled and poorly understood by the clinical community.
Prescription drugs delivered orally, intravenously, and via aerosol inhalation from metered-dose inhalers and dry powder inhalers undergo clinical trials to prove the drug's safety and efficacy. This is not the case with the many drugs used for nebulization, which are prescribed off-license and bypass regulatory requirements. Nebulizers are regarded as cheap and convenient plastic devices that readily generate an aerosol (Fig. 1) that will contain whatever drug solutions or suspensions are placed in them for delivery to the respiratory tract. Rarely is the nebulizer delivery device specified on the prescription. Rather, only the drug solution volume and concentration are specified. This leaves open the choice of nebulizer by which to deliver the off-license drug aerosol. The decision of what device to use is often left up to the local doctor or nurse, and sometimes even a hospital clerk, to choose whatever device is either conveniently to hand or has become the hospital's standard nebulizer for that period. The nebulizer is often chosen with little or no objective justification other than the manufacturer's performance claims or, more often, simply the lower cost of a particular nebulizer. The reader should recognize that there is a wide range of performance among nebulizers. If, say, 2 mL of a given drug solution was placed into all available nebulizers, the dose delivered could vary greatly. The lack of regulation and understanding in matching the prescribed drug with the nebulizer implies that the quality, consistency, and control of the delivered dose are poor.
There are 2 main types of nebulizer, jet (or pneumatic) and ultrasonic, which have different operating characteristics (recently reviewed by Hess) and can be described in terms of their overall performance as either constant-output, breath-enhanced, or dosimetric. Each nebulizer brand has specific characteristics that determine its aerosol output, including total rate of aerosol output, rate of aerosol delivered to the patient, dead volume (solution remaining in the nebulizer after nebulization has ceased), and particle size characteristics. Some nebulizers are most efficient at delivering small droplets to the peripheral lung, some nebulizers are better suited to deliver larger particles in the upper airways, and, in my opinion, some nebulizers are not suited to drug aerosol delivery at all. But how is the clinician to know which nebulizer to use for which patient? What criteria can the clinician use to make an informed decision?
Many methods have been described to measure the "performance" of particular nebulizer designs. For instance, measurement of aerosol output using weight loss has been undertaken for decades and is still commonly used. However, weight loss measures both aerosol output and evaporated solvent, and evaporated solvent typically accounts for half of the weight loss over a nebulization period. In some particularly inefficient nebulizers, evaporation can account for more than 75% of the weight loss. Alternatively, total aerosol output can be estimated by measuring the amount of drug solution left in the nebulizer cup. This method can provide a measure of the total drug aerosol emitted and is not confounded by evaporative losses, but it does not reflect the aerosol delivered to the patient, as most nebulizers commonly allow inhalation of only 40-70% of the emitted dose. There is a similar problem with methods that collect all emitted aerosol on a filter, followed by subsequent analysis of the filtered residue. Though all these methods produce data, the results cannot reflect the in vivo situation. This, in my opinion, makes them weak methods on which to base a nebulizer standard, as the results are divorced from the clinical setting.
Measuring aerosol particle size is equally confusing. Cascade impactors, which are commonly used to measure aerosol particle size from metered-dose inhalers and dry powder inhalers, can drastically distort the aerosol size by causing full evaporation of the nebulized aerosol. Laser diffraction (scattered light) size measurement of aerosol droplets cannot take into account droplet evaporation, which is inherent in all constant-output aerosol designs. For both aerosol output and aerosol droplet size many different results are possible from the same nebulizer, depending on the measurement method used.
The relative merits of the various methods to assess in vitro nebulizer performance have been debated in the literature for decades, often by individuals or small groups with greater or lesser amounts of training in aerosol and clinical sciences. From all the different views one common message emerges, namely that the method used should reflect the amount and droplet size of aerosol received by the patient. In other words, the in vitro test should reflect the in vivo dose delivered. However, though that is a commonly held objective, over the past 50 years researchers have not naturally regressed to a commonly accepted nebulizer test method. And because nebulized drugs have escaped regulatory control, no national or international body had been commissioned to examine the science and produce standard methods. Or at least that was the situation until the early 1990s, when the United Kingdom's standards body made the first attempt at standardizing test methods, by publishing a British Standard. Though the British Standard methods had limitations (Table 1) the existence of the published standard became a focal point for debate and progress. In the late 1990s the issue of standardizing in vitro methods to assess nebulizer performance was tackled more comprehensively by the European Standards Organization (Comité Européen de Normalisation or CEN), culminating in the research and development of new nebulizer in vitro test methods published as a European Standard.
The present review summarizes standardization issues inherent in the in vitro measurement of nebulizer performance, describes the scientific and clinical principles underlying the European Standard, introduces the principles underlying the clinical nebulizer guidelines recently published by the European Respiratory Society, and describes how the European Respiratory Society adopted the standard testing methods of the European Standard.