Reducing electrostatic charge on spacer devices and bronchodilator response

Abstract

Aims

Plastic spacers are widely used with pressurized metered dose inhalers (pMDI). Reducing electrostatic charge by washing spacers with detergent has been shown to greatly improve in vitro and in vivo drug delivery. We assessed whether this finding is associated with an improved bronchodilator response in adult asthmatics.

Methods

Twenty subjects (age 18–65 years) with a known bronchodilator response inhaled in random order salbutamol from a pMDI (Ventolin®) through an untreated new spacer (Volumatic®) and through a detergent washed spacer. Patients received the following doses of salbutamol via pMDI at 20 min intervals: 100 µg, 100 µg, 200 µg, 400 µg, 800 µg. Spirometry, heart rate and blood pressure were checked prior to each dose and 20 min after the last dose.

Results

There were no differences between baseline forced expiratory volume in 1 s (FEV₁) using either spacer (2.61 ± 0.56 and 2.52 ± 0.45 l, untreated and treated with detergent, respectively; mean ±s.d.). The provocation dose required to cause a clinically significant improvement of 10% in FEV₁ (PD10) was significantly lower when the detergent treated spacer was used (1505 ± 1335 and 430 ± 732 µg, untreated and treated, respectively, P < 0.002).

Conclusions

We have demonstrated an improvement in bronchodilator response, in adult asthmatics, after reducing the electrostatic charge in a spacer device by washing it with ordinary household detergent. This finding stresses the importance of an optimal choice of delivery device for asthma medication.

Introduction

Pressurized metered dose inhalers (pMDIs) are widely used with spacer devices in order to avoid difficulties with coordination of actuation and inhalation [1]. Most spacers are made from plastic materials and are therefore nonconducting and hence, can build up electrostatic charge on their surface. Aerosolization and handling of the device induce electrostatic charge on both the inner and outer surface of the spacer. The net effect of these electrostatic charges is attraction of aerosol particles. This will significantly reduce the drug aerosol available for inhalation from plastic spacers by reducing the initial dose available for inhalation and by reducing the aerosol half-life in the spacer. While the half-life may vary depending upon the drug/spacer combination, previous investigators have demonstrated that the half-life of salbutamol is 10 s, compared with 30 s if the static charge is abolished, as electrostatic attraction causes a continuous and rapid disappearance of the aerosol [2–4]. In vitro studies have shown that drug delivery is enhanced by the use of an antistatic lining on a plastic spacer or by using a steel spacer [5, 6]. Washing plastic spacer devices in detergent and allowing them to air dry is an effective, simple and practical method of reducing electrostatic charge in both small volume and large volume plastic spacers [2, 7]. The effect of this method of reducing electrostatic charge has also been shown to be effective in vivo[8]. Piérart et al. reported a mean lung deposition of radiolabelled salbutamol of 45.6% through a detergent-coated, nonelectrostatic spacer compared with 11.5% through a static spacer [8].

Whether the subsequent improvement in drug delivery due to reducing electrostatic charge by detergent coating has a clinically significant effect has not been determined. This study was undertaken to assess whether preparing plastic spacer devices in this manner improved the bronchodilator response of asthmatic patients to salbutamol.

Methods

Patients

Twenty volunteers aged between 18 and 65 years were recruited for the trial. Subjects were eligible if they had bronchodilator responsive airflow limitation, defined as an improvement in FEV₁ from baseline of at least 10% and 200 ml. The study was approved by the Ethics Committee of Royal Perth Hospital and informed consent was obtained.

Study design

Twenty subjects were assessed in a randomized, placebo-controlled, double-blind, crossover trial on two occasions. On one occasion a new, untreated spacer device (Volumatic®, Glaxo-Wellcome, UK) was used. On the other occasion the spacer used was pretreated by immersion in a solution of ordinary household detergent (Farmland®, Coles Supermarkets, Australia) in the dilution recommended by the manufacturer and then allowed to drip dry. Randomization and preparation of the spacer devices was performed by an investigator not involved with data collection.

Subjects were given salbutamol via a 100 µg pMDI (Ventolin®, Glaxo-Wellcome), at 20 min intervals. The doses used in sequence were 100 µg, 100 µg, 200 µg, 400 µg and 800 µg. Each dose was given as a sequence of 100 µg actuations with inhalation from the spacer following each actuation (i.e. 8 separate actuations and inhalations for the 800 µg dose). Heart rate, blood pressure and spirometry (Microlab 3300, Micromedics, UK) were recorded prior to each dose and 20 min after the last dose. Dosing was stopped if patients developed significant side-effects (such as tremor) or if the resting heart rate exceeded 120 beats min⁻¹. If the baseline FEV₁ at the second visit differed from that of the first visit by more than 10% then testing was rescheduled for a later date. After testing in each session was complete the spacers were washed in methanol and the concentration of salbutamol measured to determine the amount of salbutamol deposited within the spacer [2].

Statistical analysis

The means and standard deviations (s.d.) for baseline spirometry and following inhalation of the bronchodilator are reported. The PD10 was calculated for each individual in the following manner. If an increase of 10% from baseline in FEV₁ was not recorded then an arbitrary response of 3200 µg was assigned. An individual was recorded as having a significant bronchodilator response if the response exceeded 10% at a particular dose and at all subsequent doses, with the PD10 recorded as the cumulative bronchodilator dose administered. Paired t-test was used to determine the differences between responses with each spacer. Significance was accepted at the 0.05 level.

Results

There were no differences in any baseline parameters between spacer groups (Table 1). The percentage increase from baseline in FEV₁ for each spacer type is shown in Figure 1. The treated spacer showed a consistently higher clinical response at each dose. There was a significant difference in the provocation dose required to cause a 10% increase in FEV₁ (PD10) (1505 ± 1335 and 430 ± 732 µg, untreated and treated spacers, respectively, P < 0.002) Despite the fact that the study population had a documented history of hyperresponsiveness to bronchodilators, a number of subjects did not exhibit a clinically significant response to inhaled salbutamol, with seven subjects not responding when using the untreated spacer and one subject not responding when using the treated spacer. No differences between spacers were seen in heart rate, blood pressure or FVC in any patient. There was significantly greater salbutamol deposited in the untreated spacers compared to the treated spacers (69.4 µg per 100 µg actuation [s.d. 14.2 µg]vs 39.7 µg[5.2 µg]P < 0.001). Furthermore, the variability of the amount deposited in the untreated spacer per 100 µg actuation was higher when compared to the nonstatic spacers (coefficient of variation 21% vs 13%).

Table 1.

Improvement in FEV₁ following cumulative bronchodilator challenge with salbutamol. Data are expressed as mean ±s.d.

	FEV1 (1)
	Untreated spacer	Treated spacer
Baseline	2.61 ± 0.57	2.52 ± 0.46
100 µg	2.76 ± 0.54	2.83 ± 0.49
200 µg	2.84 ± 0.57	2.97 ± 0.51
400 µg	2.90 ± 0.57	2.99 ± 0.52
800 µg	2.95 ± 0.57	3.02 ± 0.53
1600 µg	2.96 ± 0.40	3.03 ± 0.34

Figure 1.

Percent improvements in FEV₁ from baseline in asthmatic subjects following cumulative bronchodilator challenge. Inhalation of salbutamol was via a static (solid line) or nonstatic (dashed line) spacer. Data are shown as mean values ±s.e.mean.

Discussion

We have demonstrated a significant improvement in bronchodilator response from a salbutamol pMDI when the plastic spacer devices used were washed in ordinary household detergent and allowed to drip dry. This is the first study to show any significant clinical impact of reducing electrostatic charge in spacers. We also confirm the results of previous in vitro and in vivo studies that have demonstrated greater drug delivery through detergent coated, nonelectrostatic spacers.

The effect of avoiding electrostatic charge by detergent coating is dramatic as has been shown in vitro and in vivo studies [2, 7, 8]. Detergent coating of various small and large volume plastic spacers results in an increase of 45–72% in in vitro small particle delivery compared with delivery from new spacers with high charge. Lower flow, delay, and multiple actuations result in decreased delivery from static spacers. These influences of lower flow, delay, and multiple actuations are greatly reduced or even eliminated by detergent coating. In vivo lung deposition of radiolabelled salbutamol has been shown to be 45.6% through a detergent-coated, nonelectrostatic spacer compared with 11.5% through a static spacer when inhaled with a slow, deep inhalation [8]. This four fold increase in drug delivery is much higher than the two fold increase described in an other scintigraphic study [9]. This difference may be most likely explained by different breathing patterns employed in the respective studies, further differences due to the inhaled drug (salbutamol vs glucocorticosteroids) are also possible. Adults can empty a spacer with a fast, deep inhalation in one breath [9], which would reduce the importance of electrostatic charge. However, a fast, deep inhalation leads to a high deposition in the upper airways and to a low deposition in the lungs due to impaction. With a slow, deep inhalation drug deposition in the lungs is enhanced and the clinical efficiency could be expected to be increased [8]. Therefore, we instructed our subjects to inhale slowly through the spacer devices.

The clear improvement in bronchodilator delivery is sufficient alone to recommend patients to prime their spacers. There are various ways of priming a plastic spacer and hence, to reduce electrostatic charge. Priming should coat the inner surface of a spacer with a conducting layer, thereby reducing electrostatic charge. The various priming options should be compared with respect to the stability of the effect during routine use. Repeated use of the pMDI itself primes the plastic to some extent [3]. This priming effect is time dependent, the effect is not immediate but builds up over days. As with other priming procedures, the effect is reversible with ordinary washing. Benzalkonium chloride is effective in neutralizing the electrostatic charge of plastic spacers [3]. Anti static paints have also been used successfully [5]. Potential toxicity from inhaled residues of the chemical used for priming must also be studied. Immersion in household detergents is effective, simple and practical. If detergent is used, it is very important not to rinse the spacer in water or to dry the plastic with a cloth, since this immediately re-charges the spacer, and the spacer should be stored unwrapped [7]. The potential effect on the delivery of other drugs, such as corticosteroids, may be even larger and needs to be assessed, particularly as this is an easy, inexpensive technique and the spacers only need to be treated once per week to maintain the reduction in static electric charge [7].