Study objectives: The aim of our study was to determine the in vitro delivery of salbutamol from a pressurized metered-dose inhaler (pMDI) containing hydrofluoroalkane (HFA) propellant through various delivery devices to four models of a pediatric lung. Design: To determine the effect of electrostatic charge, delivery of salbutamol was initially assessed with a multistage liquid impinger (MSLI) through an inline nonchamber device (Baxter MDI Adapter) and a small (Aerochamber MV) and a large (Nebuhaler) inline chamber device. Following this, the delivery was assessed to four lung models appropriate for a child of 70 kg, 50 kg, 15 kg, and 4 kg, with the same three reduced static devices inserted directly into a pediatric ventilator circuit.
Measurements and results: Reduction of electrostatic charge improved small particle delivery through holding chambers to the MSLI by 12 to 14%. In the ventilator model, the mean delivery was between 1.9% and 5.4% for the nonchamber device, between 14.3% and 27.2% for the small holding chamber, and between 7.2% and 25.7% for the large holding chamber. Delivery was the least efficient in the 4-kg model compared to the 70-kg, 50-kg, and 15-kg models. Conclusions: Salbutamol from an HFA pMDI is delivered efficiently through inline holding chambers with reduced static in pediatric ventilator settings. A large holding chamber has no advantage over a small holding chamber. In addition, salbutamol delivery is more efficient through a holding chamber than through a nonchamber device. (CHEST 1998; 113:186-91)
Key words: aerosol therapy; electrostatic charge; inhalation devices; mechanical ventilation
Abbreviations: CFC=chlorofluorocarbon; HFA=hydrofluoroalkane; MSLI=multistage liquid impinger; PIP=peak inspiratory pressure, pMDI=pressurized metered-dose inhaler; SVN=small-volume nebulizer; TT=tracheal tube; VT=tidal volume
Bronchodilators for the therapy of reversible airway obstruction are often delivered via inhalation to the lower respiratory tract in both spontaneously breathing and mechanically ventilated patients. The devices usually used for delivery of aerosols to ventilated patients are small-volume nebulizers (SVNs) and pressurized metered-dose inhalers (pMDIs). There is still a controversy about which may be the optimal system for inhalation therapy in ventilated patients in ICUs from the point of view of both economic and therapeutic effectiveness.
Several in vitro and in vivo studies have shown that pMDIs are more efficient in aerosol delivery than SVNs.[2-5] In addition, it was also shown that both SVNs and pMDIs can effectively deliver aerosols in a ventilator model and that aerosol delivery can be significantly improved when a proper technique of administration is followed.[6-8]
To enhance lung deposition of aerosols from pMDIs, several accessory devices have been developed. The accessory devices most commonly used to deliver aerosols from pMDIs into ventilator circuits are inline nonchamber devices and inline holding chambers. The advantage of a holding chamber inserted in the ventilator circuit is that the actuated aerosol cloud is retained within the chamber and hence impaction of the drug within the ventilator circuit is reduced. Holding chamber devices have been shown to be superior to nonchamber devices.[9,10]
Until recently, pMDIs contained chlorofluorocarbon (CFC) propellant, which is damaging to the ozone layer.[9,11] These are now being replaced by pMDIs containing hydrofluoroalkane (HFA) propellant. As the aerosol and delivery characteristics of HFA pMDIs may be different from CFC pMDIs, it is important to test them in in vitro and in vivo studies.
The aim of our study was to compare the in vitro delivery of salbutamol from an HFA pMDI through an inline nonchamber device and a small and a large inline holding chamber inserted in a pediatric ventilator circuit under various ventilator settings.
MATERIALS AND METHODS
In vitro salbutamol delivery was measured through the following devices using a high-performance multistage liquid impinger (MSLI) (Copley; Nottingham, UK): an inline nonchamber device (Rigid 22mm pMDI Adapter; Baxter; Irvine, Calif); a small inline holding chamber (Aerochamber MV; volume 165 mL; Trudell; Ontario, Canada); and a large holding chamber (Nebuhaler; 750 mL; Astra; Lurid, Sweden) modified to function as an inline device for a ventilator circuit. Modification of the large chamber was performed by sealing off air leaks, removing the valve, and inserting the inline nonchamber device in the actuator orifice.
The salbutamol HFA pMDI (20 canisters, Lot 96EO1K of Airomir; 3M Pharmaceuticals; St. Paul, Minn) was actuated 10 times into the study devices and shaken vigorously between actuations. Air was drawn through the study devices that were attached to the MSLI at a continuous flow of 60 L/min. Aerosol droplets were deposited on the device, the glass throat of the MSLI, or one of four stages. The MSLI was calibrated by the manufacturer so that particles [is greater than] 13, 6.8 to 13, 3.1 to 6.8, and [is less than] 3.1 [micro]m were deposited on stage 1, 2, 3, and 4, respectively.
To determine the influence of electrostatic charge on drug delivery, salbutamol delivery was measured through new and detergent-coated devices. Electrostatic charge on the surface of the devices was measured prior to the in vitro test using a modified electrometer and was classified as none (negligible charge, 0 to 1.2 [micro]C/[m.sup.2]), low charge (1.2 to 3.3 [micro]C/[m.sup.2]), and high charge (3.3 to 6.7 [micro]C/[m.sup.2]). All devices were then detergent coated to reduce electrostatic charge. To coat the devices with detergent, they were soaked in diluted (1:250) cationic detergent (Cetrimide 40%; Princess Margaret Hospital Pharmacy; Perth, Australia) for 1 h and drip dried for [is less than] 24 h.
In addition, in vitro salbutamol delivery was measured through the three devices, an inline nonchamber device (Rigid 22-mm pMDI Adapter; Baxter), a small inline holding chamber (Aerochamber MV; Trudell), and a large holding chamber (Nebuhaler; Astra) modified as an inline device for a ventilator circuit inserted in a dry unheated pediatric ventilator circuit (Servo Ventilator 900C; Siemens; Elema, Sweden). Four different models were constructed to mimic appropriate ventilator settings for children weighing (a) 70 kg, (b) 50 kg, (c) 15 kg, and (d) 4 kg. All models used the same ventilator (Servo) and circuit, but tracheal tube (TT) size and the volume/compliance of the test lung were altered to mimic that of children of different sizes (test lung for infants: small volume and low compliance; test lung for older children: large volume and high compliance). Additionally the compliance of the test lung in model b was altered by a constricting "band" to mimic normal and "stiff" lungs. In keeping with standard clinical practice, the ventilator was set on volume control mode for models a, b, and c, and on pressure control mode for model d. Thus models a, b, and c, had a set tidal volume (VT) and resultant peak inspiratory pressure (PIP), whereas model d had a set PIP and resultant VT. Positive end-expiratory pressure was set at 4 cm [H.sub.2]O in all models as was inspiratory time (25%) and pause time (10%). On this type of ventilator, inspiratory flow is not set and is dependent on PIP, inspiratory time, pause time, and lung model compliance. The models used were as follows: (a) TT (Portex; Kent, England) internal diameter 9 mm, VT 750 mL, rate 10 breaths/min, PIP 20 em [H.sub.2]O; (b) TT 7.5 mm, VT 450 mL, breaths/min 10, PIP 20 cm [H.sub.2]0 and 40 cm [H.sub.2]0; (c) TT 5 mm, VT 165 mL, breaths/min 18, PIP 20 cm [H.sub.2]O; and (d) TT 4 mm, VT 40 mL, breaths/min 30, PIP 20 cm [H.sub.2]O, respectively (Fig 1). In addition, in vitro salbutamol delivery through all three devices was measured in a humidified and heated (37 [degrees] C) circuit with ventilator settings for a 70-kg child (model a). All devices were detergent coated to reduce electrostatic charge. They were inserted into the ventilator circuit at the opening of the TT. Salbutamol was collected on an inspiratory filter (Anesthesia Filter, Curity; Kendall; Mansfield, Mass) inserted at the tip of the TT. An identical filter was inserted in the expiratory line. The HFA pMDI was actuated 10 times just prior to initiation of inspiration and shaken vigorously inbetween actuations. Between actuations, a sufficient number of inspiratory and expiratory cycles were allowed, to totally clear the dead space of the delivery device and the ventilator circuit.
[Figure 1 ILLUSTRATION OMITTED]
Each device, throat, TT, inspiratory and expiratory filters, and each of the four stages of the MSLI were washed separately with 45 mL of methanol immediately after the tests. Five milliliters of 0.1 mmol/L NaOH was added to each wash and the volume was made up to 50 mL with methanol. The absorbance (wave length 246 nm) of each sample was measured in duplicate on a spectrophotometer (Hitachi U-2000; San Jose, Calif). The concentration of salbutamol in each sample was obtained by using the absorbance of a standard solution containing a known concentration of salbutamol. The total actuated dose (10 puffs) in the MSLI was determined by adding the amount of drug in the device, the glass throat, and the four stages. The total actuated dose (10 puffs) in the ventilator circuit was determined by adding the amount of drug in the device, the filters, and the TT. The standard curve for salbutamol was linear ([r.sup.2]= 1.00) for concentrations between 0 and 2,100 [micro]g/mL. Each experiment from actuation of the pMDI to the measurements of the drug concentration was repeated four times. Validation of the method, to ensure that no other contents of the pMDI interfere with the speetrophotometrie measurement of salbutamol at the same wave length, was done, using a placebo pMDI containing only the propellant HFA but no salbutamol (Airomir placebo, 3M Pharmaceuticals). All measurements were undertaken under the following atmospheric conditions: mean temperature was 21.7 [degrees] C (range, 21 to 24 [degrees] C) and mean barometric pressure was 760 mm Hg (758 to 766 mm Hg).
Statistical analysis was carried out using analysis of variance (StatView 512+; Abacus Concepts Inc; Berkeley, Calif) with a significance level of 95% (p [is less than] 0.05).
Measurements of electrostatic charge and drug delivery using the MSLI are shown in Table 1. The electrostatic charge on the new devices ranged from low to high. Reducing electrostatic charge by coating the devices with cationic detergent significantly increased the delivery of small particles ([is less than] 3.1 [micro]m) from the inline holding chambers (p [is less than] 0.001). Electrostatic charge did not affect delivery through the nonchamber device. Delivery of small particles ([is less than] 3.1 [micro]m) is increased by 12% from the small holding chamber (Aeroehamber MV) and by 14% from the large holding chamber (Nebuhaler). Delivery of small particles ([is less than] 3.1 [micro]m) was significantly higher from the small holding chamber (Aerochamber MV) device compared to the inline nonehamber device (Baxter MDI Adapter) (p [is less than] 0.001). However, delivery of small particles ([is less than] 3.1 [micro]m) was less from the small holding chamber (Aeroehamber MV) compared to the large holding chamber (Nebuhaler) (p [is less than] 0.001).
(*) Mean (SD) in vitro delivery of salbutamol from HFA pMDI through different inline devices under static and reduced static conditions measured using an MSLI with cutoffs of particles >13, 6.8 to 13, 3.1 to 6.8, and <3.1 [micro]m for stage 1, 2, 3, and 4, respectively, expressed as percentage of the total actuated dose.
Drug deposition for the four lung models using the pediatric ventilator circuit is shown in Table 2. Drug deposition on the inspiratory filter as a proportion of drug delivery to the patient was between 1.9% and 5.4% through the inline nonchamber device (Baxter MDI Adapter) and was significantly less than through the two inline holding chambers (Aeroehamber MV and Nebuhaler) (p [is less than] 0.001). Drug deposition on the inspiratory filter was between 14.3% and 26.0% through the small holding chamber (Aerochamber MV) and was significantly higher than through the large holding chamber (Nebuhaler) for ventilator settings appropriate for a child of 50 kg (b), 15 kg (c), and 4 kg (d) (p [is less than] 0.001). However, there was no significant difference for a child of 70 kg (a). The amount of salbutamol through the small holding chamber (Aerochamber MV) deposited on the inspiratory filter was significantly higher (p [is less than] 0.001) in ventilator settings appropriate for a child of 70 kg (a) and 50 kg (b) than in ventilator settings for a child of 15 kg (c) and 4 kg (d), whereas drug deposition on the expiratory filter was significantly lower (p [is less than] 0.001). Drug deposition on the inspiratory filter was between 7.2% and 25.6% for the large inline holding chamber (Nebuhaler) and decreased with lower VTs from the ventilator setting for a child of 70 kg (a) to the ventilator setting for a child of 4 kg (d) (Fig 2). A change in the compliance of the lung model while maintaining the same ventilator setting appropriate for a child of 50 kg (b) did not alter drug delivery through the small holding chamber (Aerochamber MV). However, humidification of the ventilator circuit for a child of 70 kg resulted in a significant (p [is less than] 0.001) decrease of salbutamol deposition on the inspiratory filter by 24% for the large and 18% for the small inline holding chambers (Table 2).
[Figure 2 ILLUSTRATION OMITTED]
(*) Mean (SD) in vitro delivery of salbutamol from HFA pMDI through an inline nonchamber device and two inline holding chambers in pediatric ventilator circuit under different ventilator settings appropriate for a child of 70 kg (a), 50 kg (b), 15 kg (c), and 4 kg (d) with and without humidification, expressed as percentage of the total actuated dose.
The mean (range) of total dose (10 puffs) of salbutamol from HFA pMDIs was 1,040 [micro]g (890 to 1,180 [micro]g).
Inhalation therapy with bronchodilators to mechanically ventilated patients is usually performed using SVNs or pMDIs containing CFC propellant. Recent studies have shown that CFC pMDIs are an effective alternative to SVNs for aerosol therapy to the mechanically ventilated patient.[2-4] However, because of its harmful effect on the ozone layer, the use of CFC pMDIs will be discontinued. Thus, CFC-free products, such as HFA pMDIs, have been introduced for inhalation therapy. The performance of salbutamol HFA pMDIs in drug delivery is different from CFC pMDIs in some situations. However, another study has shown that salbutamol HFA pMDIs did not perform differently from salbutamol CFC pMDIs in drug delivery through spacer devices. We have shown in our study that salbutamol from an HFA pMDI is delivered efficiently in an in vitro model of a pediatric ventilator circuit. Our results with a maximal deposition of 26.0% of salbutamol from an HFA pMDI on the inspiratory filter are comparable to another study measuring albuterol delivery from a CFC pMDI in an adult ventilator circuit model with a maximal deposition of 25.1%.
The technique of administration and the devices used for administration of CFC pMDIs play a major role in the efficacy of aerosol delivery. We have shown in the present study the importance of the choice of device for HFA pMDI administration. We showed in a previous study that electrostatic charge on the surface of a plastic spacer device is the most important factor influencing salbutamol delivery from a CFC pMDI. We also found in that study that the shape and the volume of the spacer device play a major role in delivery of salbutamol CFC pMDI. In the present study, we have shown that the delivery of salbutamol from an HFA pMDI through a plastic holding chamber is also dependent on electrostatic surface charge, and hence, is increased when the holding chambers are coated with ionic detergent to reduce static.
In the MSLI model, salbutamol delivery from the HFA pMDI was higher through the large-volume holding chamber than the small. One might therefore expect that a large holding chamber may be superior to a small holding chamber in delivery of salbutamol from an HFA pMDI in a pediatric ventilator circuit. However, we have shown that a large chamber has no advantage over a small chamber in this setting. This might be explained by the low VTs used in pediatric ventilator settings and the clearance of a holding chamber, inserted between the Y-ventilator connector and the TT in a ventilator circuit, in both the inspiratory and expiratory phase. Thus, a large inline chamber might not be totally cleared in inspiration but will be cleared in both inspiration and expiration, hence, wasting drug during the expiratory phase. We have shown that inline holding chambers are only efficiently cleared in inspiration when the VT exceeds the volume of the inline holding chamber. This problem may be overcome by inserting the spacer in the inspiratory limb of the ventilator circuit. We have also shown that a small chamber is more efficient in pediatric ventilator settings where low VTs are used. A change in the compliance of the lung model while maintaining the same ventilator settings did not alter drug delivery. In addition, we found that salbutamol delivery is less efficient through a nonehamber device than through a holding chamber.
A change in the compliance of the lung model did not alter salbutamol delivery. However, salbutamol delivery through the holding chambers was reduced by 18% through the small chamber and by g4% through the large chamber in a heated and humidified ventilator circuit compared to a dry ventilator circuit. Humidification may lead to hygroscopic growth of the aerosols and increased impaction of aerosols on the chamber surface, and hence, decreased delivery of salbutamol to the inspiratory filter.
Our in vitro study with measurements of drug deposited on a filter gives only an idea about the dose most likely reaching the lungs in a clinical setting. The distribution of the aerosol and the clinical response remain unknown. However, the importance of the in vitro assessment of different devices, under different conditions, proceeding in vivo studies, is shown by the results of three previous studies. One study, using a suboptimal delivery device (pMDI adapter), did not show a clinical response of bronchodilators administered by CFC pMDI, whereas the other two studies, using a delivery device (inline holding chamber), shown in vitro to be optimal, found a significant clinical response.[19,20]
In conclusion, we have shown that salbutamol from an HFA pMDI is efficiently delivered through inline holding chambers with reduced static in pediatric ventilator circuits and that a large holding chamber has no advantage over a small holding chamber. However, delivery through a nonehamber device was distinctly inefficient.
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(*) From the Perth Medical Aerosol Research Group, Departments of Respiratory Medicine (Drs. Wildhaber, Dore, Devadason, and LeSouef) and Intensive Care (Dr. Hayden), Princess Margeret Hospital for Children, Subiaco, Western, Australia. Manuscript received January 6, 1997; revision accepted June 25, 1997.
Reprint requests: Johannes Wildhaber, MD, Department of. Respiratory Medicine, Princess Margeret Hospital for Children, Roberts Road, Subiaco 6008, WA, Australia; e-mail: hannesw@ cyllene.uwa.edu.au
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