Abstract
Aims
To compare the lung delivery of salbutamol from a commonly used constant output open vent jet nebuliser (Sidestream) with use of both a conventional large volume plastic spacer (Volumatic) and a novel small volume metal spacer (NebuChamber). This was assessed using the early lung absorption profile of salbutamol over the first 20 min after inhalation.
Methods
Twelve healthy volunteers were studied in a randomized single (investigator) blind crossover design. Single 1200 μg nominal doses salbutamol from a CFC-free metered-dose inhaler (12 sequential 100 μg puffs of Airomir) were delivered via the Volumatic and NebuChamber spacers. A single 1200 μg nominal dose of salbutamol was given as a 4ml fill volume from a Sidestream nebuliser with mouthpiece. Mouth rinsing was performed after each drug sequence. Plasma salbutamol was measured at 5, 10, 15 and 20 min after the last dose of each inhalation sequence, with calculation of maximal concentration (Cmax) and average concentration over 20 min (Cav). Systemic β2-responses were measured as plasma potassium, tremor and heart rate.
Results
Both the Volumatic and the NebuChamber spacers produced significantly greater salbutamol concentration than the Sidestream nebuliser. For Cav this amounted to a 7.34-fold difference (95%CI 5.31 to 9.38) between Volumatic vs Sidestream, and a 7.04-fold difference (95%CI 4.91 to 9.17) for NebuChamber vs Sidestream. Similar differences were found for the extrapulmonary β2-responses. There were no significant differences in either salbutamol concentration or extrapulmonary β2-responses between the Volumatic and NebuChamber spacers.
Conclusions
We found that, in vivo, both the Volumatic and the NebuChamber spacers produced seven-fold greater lung delivery of salbutamol than the Sidestream nebuliser when comparing microgram equivalent nominal doses, in terms of the early lung absorption profile.
Keywords: salbutamol, lung delivery, spacer, nebuliser, NebuChamber, Volumatic, Sidestream, Airomir, non-CFC
Introduction
Nebulisers are the widely regarded as the preferred method for the delivery of high doses of salbutamol in acute asthma, and there is also an increasing trend towards the use of regular domiciliary nebulised salbutamol for patients with chronic severe asthma. Nebulisers have achieved a high level of acceptability from patient and clinician alike when used for bronchodilator therapy. It is recognised that patients with severe asthma treated during a hospital stay with a nebuliser often attribute their improvement directly to the nebuliser [1, 2], and the increase in domiciliary nebuliser use is in part fuelled by this same patient perception of enhanced efficacy compared with other inhalation methods.
However, several different options do exist for the delivery of salbutamol in asthma, including the use of a metered-dose inhaler via a spacer device. In fact, from an objective viewpoint the rationale for acute and domiciliary use of nebulisers is questionable. Previous comparisons of salbutamol delivered via nebulisers and spacer devices have in general established that spacers are at least as effective and in some cases more effective than nebulisers in both chronic and acute severe asthma [3, 4].
In vitro studies have shown a wide variation in delivery of respirable dose from nebulisers [5], and it is likely that there are also differences between plastic spacers, particularly small and large volume devices. In addition the performance of plastic spacer devices is affected by several factors such as static charge, inhalation delay and number of puffs per inhalation [6, 7]. The use of metal spacers has been shown to overcome these problems seen with plastic spacers [8, 9].
Following inhalation of salbutamol from a metered dose inhaler most of the dose (60–80%) is delivered to the oropharynx and hence to the gut after swallowing, with a much smaller fraction (10–20%) reaching the lungs. The polarity of salbutamol at salivary pH results in only negligible buccal absorption [10], and the swallowed fraction undergoes extensive first-pass conjugation in the intestinal wall and liver. Since there is no first-pass conjugation in the lung, the initial plasma profile of unchanged salbutamol will reflect the dose delivered to the lung. Gastro-intestinal absorption is markedly delayed compared with lung absorption, and indeed, it has been shown that in the first 30 min after inhalation, gastrointestinal absorption contributes only 0.3% to the overall systemic bioavailability from an inhaled dose [11]. Therefore the relative bioavailability of salbutamol to the lung may be quantified reproducibly by measuring the plasma pharmacokinetic profile over the first 20 min after inhalation, producing an index of lung deposition as we have previously demonstrated [6, 12–14].
The purpose of the study was therefore to evaluate the delivery of salbutamol from a conventional large volume plastic spacer (Volumatic), compared with a novel small volume metal spacer (NebuChamber). These two spacers were also compared with a nebuliser (Sidestream), which has been shown to be an efficient example of a constant output open vent jet nebuliser [5]. We have therefore evaluated the pharmacokinetic profile for the first 20 min after inhalation, in order to assess the relative lung delivery of salbutamol.
Methods
Twelve healthy volunteers mean (s.d.) age 22.0 years (1.41), FEV1 102.0% (7.4) predicted, were studied in a randomized single (investigator) blind crossover design. Single 1200 μg nominal doses salbutamol from a CFC-free metered-dose inhaler [Airomir, 3M Healthcare Ltd, Loughborough, UK] (12 sequential 100 μg puffs) were delivered via a Volumatic large volume plastic spacer (750 ml) (Allen & Hanbury’s, Uxbridge, Middlesex, UK) and a NebuChamber small volume metal spacer (250 ml) (Astra Draco, Lund, Sweden). Although the Volumatic and Nebuchamber spacers are not designed for use with the Airomir mouthpiece, it was possible to achieve a good fit by moulding of the pliable plastic mouthpiece with the orifice of each spacer device. Inhalation from the spacers was performed using single puffs with no delay between inhalation and actuation, with a slow inspiratory breath from residual volume to total lung capacity.
A single 1200 μg nominal dose of salbutamol was given via a Sidestream constant output open vent jet nebuliser with mouthpiece (Medic-Aid, Pagham, Sussex, UK) driven by compressed air at 8 l min−1. Each dose of salbutamol was given in a total fill volume of 4 ml made up with saline and nebulised to residual volume (associated with spluttering) over a period of up to 10 min. Mouth rinsing was performed after each inhalation sequence in order to further obviate gastrointestinal absorption. The spacers were washed in warm water and left to drip dry prior to each individual study visit.
The subjects were studied on 3 days each separated by 1 week. They were carefully instructed in inhalation technique as described by the manufacturers product insert. Plasma salbutamol was measured at 5, 10, 15 and 20 min after the end of each inhalation sequence with time zero corresponding to the last dose. Systemic β2-responses were measured as plasma potassium, tremor and heart rate taken at baseline and 20 min (all measurements made with the subject supine after inhalation in the sitting position). The study was approved by the Tayside committee for medical research ethics and informed consent was obtained from all subjects.
Measurements
Finger tremor was measured with an accelerometer transducer (Entran, Ealing, UK) [15]. Heart rate was measured from standard lead II of an electrocardiogram monitor. Plasma potassium was assayed by flame photometry using an IL943 analyser (Instrumentation Laboratory Ltd, Warrington, UK). The intra-assay and interassay values for analytical imprecision were 0.41% and 1.04% respectively.
Plasma salbutamol was assayed by high performance liquid chromatography (h.p.l.c.), the extraction process using silica adsorption with chromatography followed by reverse phase ion pair h.p.l.c. and electrochemical detection. The analytical imprecision for plasma salbutamol (at 5 ng ml−1) was 7.8% (intra-assay) and 6.7% (interassay). The h.p.l.c. detection limit for salbutamol was 0.02 ng ml−1.
Statistical analysis
The results were analysed by using the ‘Statgraphics’ statistical software package (STSC Software Publishing Group, Rockville, USA). Salbutamol concentrations were calculated as maximal (Cmax) and average over 0–20 min (Cav). For all parameters, comparisons were made by multifactorial analysis of variance (MANOVA) and Bonferroni's multiple-range testing was used to establish where the differences were significant. A probability value of P < 0.05 (two-tailed) was considered as being of significance.
Results
Both the Volumatic and the NebuChamber spacers produced significantly greater salbutamol Cmax and Cav than the Sidestream nebuliser, as shown in Figure 1 and Table 1. This amounted to a 7.34-fold difference (95%CI 5.31 to 9.38) between Volumatic and Sidestream in Cav, and a 6.25-fold difference (95%CI 3.99 to 8.50) for Cmax. Comparing NebuChamber and Sidestream there was a 7.04-fold difference (95%CI 4.91 to 9.17) for Cav and a 5.92-fold difference (95%CI 4.04 to 7.81) for Cmax. There were no significant differences in Cmax or Cav between the Volumatic and NebuChamber spacers. Similar differences were found for the extrapulmonary β2-responses of tremor, heart rate and potassium (Table 1).
Figure 1.
Values are shown for mean plasma salbutamol concentration (0–20min) after inhalation of salbutamol. The average for all time points is also shown with s.e.mean. Asterisks denote a significant difference between either Volumatic (•) or NebuChamber (○) spacers compared with Sidestream (▵) nebuliser P < 0.001.
Table 1.
Mean values for plasma salbutamol concentration as maximum (Cmax) and average 0–20min (Cav), and for increase in tremor and heart rate, and decrease in plasma potassium. 95% CI for difference between either Volumatic and the NebuChamber spacers compared with the Sidestream nebuliser are also shown. Asterisk denotes a significant difference (P < 0.001) for comparison between Volumatic or NebuChamber spacers vs Sidestream nebuliser.
Discussion
Our study revealed that both the large volume plastic spacer and the small volume metal spacer produced seven-fold greater delivery of salbutamol compared with an open vent jet nebuliser when using microgram equivalent nominal doses. This is explained by the inefficient delivery from constant output jet nebulisers in terms the wastage during exhalation along with the residual volume after the end of nebulisation. We also found that there were no significant differences between the two spacer devices. Previous studies comparing salbutamol delivery in acute asthma have shown that a six-fold lower nominal dose from a spacer (Aerochamber small volume or Inspirease large volume), produces an equivalent bronchodilator response compared to an updraft type constant output jet nebuliser [16, 17]. This would be in keeping with the seven-fold greater delivery of salbutamol between spacer and nebuliser in the present study.
There are currently little data available on the NebuChamber which has recently become available in Europe. Due to its metal construction it has antistatic properties and has been shown to improve the in vitro delivery of budesonide [8, 9]. We have previously studied the NebuChamber used with non-CFC salbutamol in healthy volunteers, in which the NebuChamber produced approximately two-fold greater lung delivery than salbutmaol dry powder from a Turbuhaler [12]. Using the same pharmacokinetic methodology it has been shown that washing a plastic Volumatic spacer was an effective way of reducing static, whilst delay and multiple actuations reduced delivery of salbutamol [6]. Hence, in the current study we were comparing a large volume plastic spacer in optimal condition with the antistatic small volume metal spacer, perhaps explaining the similarity in performance between these devices.
It is important to highlight that our results were found using a CFC-free metered dose inhaler which was not designed to be used with either of the spacer devices, although it proved possible to achieve a good fit by moulding the plastic mouthpiece in the spacer orifice. Obviously there are many possible variables with inhaler deposition studies and these include the type metered dose inhaler used via the spacer device [13], the inhalation technique and the condition of the spacer prior to each study day [6], for example whether it is primed or pre-washed. As in the near future only CFC-free MDIs will be available we felt it was important to use this for our study, and we chose an efficient conventional open vent jet nebuliser to compare with the two spacers. Although essentially our results are valid only for the devices we have used, it is interesting to note the similar results previously obtained in spacer vs nebuliser comparisons using bronchodilator responses. It would seem logical to extend this pharmacokinetic model to asthmatic patients which would allow a direct comparison of salbutamol pharmacokinetics with bronchodilator responses.
Acknowledgments
There was no commercial pharmaceutical sponsorship involved in this study.
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