There has over the past few years been an increasing interest in the use of nebulizers for the delivery of aerosolized drugs, via an endotracheal tube, to the respiratory tracts of patients undergoing intermittent positive pressure ventilation [1-5]. It is controversial whether nebulizing devices or metered dose inhalers provide the most effective vehicle for aerosol preparations in the patient receiving ventilatory support . Indeed the techniques for efficient aerosol delivery in ventilated patients remain poorly understood .
We aimed to devise a simple method for the evaluation of the function of an ultrasonic nebulizer when used in breathing circuits under different ventilatory patterns, prior to use in the intensive care unit. We examined in this experiment, the performance of the DeVilbiss Ultra-Neb 2000 ultrasonic nebulizer, a compact, portable ultrasonic nebulizer designed for general hospital use (DeVilbiss Health Care Worldwide, Somerset, PA, USA) coupled with the Amadeus Ventilator (Hamilton Medical, UK). It was our intention to discover how different levels of positive end-expiratory pressure (PEEP), minute volume, inspiratory flow rate and inspiratory time affected the performance of the nebulizer at different power settings in a simulated mechanical ventilation model. These variables had not been assessed in a previous investigation which assessed the effects of minute volume and flow rate .
A Hamilton 'Amadeus' ventilator, and a DeVilbiss Ultra-Neb 2000 ultrasonic nebulizer were connected via a standard 2-m corrugated tubing and a 2-L Ohmeda reservoir bag through a Y-piece connector. The nebulizer was placed in the inspiratory limb of the circuit, immediately proximal to the Y-piece connector. This position has been reported to produce efficient nebulization in previous studies . All experiments were carried out using air (21% oxygen).
Thirty millilitres of saline 0.9% were placed in a 50 millilitre nebulizer solution cup. As is standard practice when using this nebulizer, all solutions used were at room temperature. After being nebulized for a period of 5 min, the solution remaining in the cup was measured. The remaining volume was subtracted from the original 30 mL to give the volume of solution which had been nebulized. This procedure was repeated at different nebulizer power settings and over a range ventilator settings, involving changes in PEEP, minute volume, inspiratory time and inspiratory flow rate. All the experiments were repeated three times. We obtained three results which differed by no more than 10% (with respect to volume of solution remaining in the nebulizer cup) for each cluster.
The Ultra-Neb 2000 has a dial which enables nebulizer output, which is not marked with any scale to be altered. An arbitrary scale was affixed in which setting '1' was a lower output than setting '2' which in turn was lower than setting '3', 100% of the possible power output of the unit. Experiments involving each setting of the nebulizer were carried out in one block by the same researcher, in order to avoid error in positioning the output control dial.
Four different experiments were carried out using the three separate nebulizer settings. In experiment 1, PEEP was altered (0, 5 and 10 cmH2O) while the other ventilator settings remained constant. These were a tidal volume of 600 mL, a respiratory rate of 12 breaths per minute and an inspiration to expiration (I:E) ratio of 1:2. In experiment 2, inspiratory flow rate was altered from 8.6 L min−1 to 34.3 L min−1 by altering the I:E ratio from 4:1 to 1:4. Because the time per breath was constant, inspiratory time decreased as inspiratory flow rate increased. The minute ventilation was constant with a tidal volume of 600 mL and a respiratory rate of 12 breaths per minute. In experiment 3, minute ventilation was altered from 3.6 L (6 × 0.6 L) to 7.2 L (12× 0.6 L), and the inspiratory flow rate was maintained constant at 10.6 L min−1. The time in inspiration per breath was constant, but the total time in inspiration per minute was doubled with a minute ventilation of 7.2 L, compared with 3.6 L. Finally in experiment 4, the minute ventilation was altered from 3.6 L (6 × 0.6 L) to 7.2 L (12× 0.6 L), but the inspiratory time was kept constant by varying inspiratory flow rate. This resulted in a constant time per min being spent in inspiration (Fig. 1).
Data are presented as mean ± standard deviation. Results were analysed using one-way analysis of variance (ANOVA) and Tukey's intergroup comparison where appropriate on Minitab version 9.2. Statistical significance was accepted at P<0.05.
At a minute ventilation of 7.2 L (12 × 0.6 L), an I:E ratio of 1:2 and with no PEEP the quantity of saline nebulized over 5 min showed a stepwise increase as the nebulizer power was increased. The mean volume of saline with the nebulizer set to '1' was 4.3 ± 0.2 mL, at '2' was 7.2 ± 0.5 mL and at '3' was 10.6 ± 0.7 mL. At all three nebulizer power settings an increase in the amount of PEEP (0, 5 and 10 cmH2O) produced peak airway (Paw) pressures of 28, 30 and 32cmH2O, respectively, and no significant difference in the volume of saline nebulized (P>0.05) (Fig. 2).
Ventilator settings of VT 600 and RR 12 min−1 produced an inspiratory flow rate of 34.3 L min−1 at an I:E ratio of 1:4 and 8.6 L min−1 at an I:E ratio of 4:1. When the nebulizer was set at '1', the increased inspiratory time resulted in no significant difference in mean volume of saline nebulized. This fell from 3.2 ± 0.3 mL to 2.5 ± 0.8 mL (P> 0.05). At setting '2', the increased inspiratory time resulted in an increase in nebulized volume from 6.4 ± 0.7 mL to 11.0 ± 0.6 mL (P < 0.01) (Fig. 3). The difference was greatest with the nebulizer on setting '3'. A ratio of 1:4 produced a mean nebulized volume of 9.1 ± 0.6 mL, while at a ratio of 4:1 this had more than doubled to 18.7 ± 0.2 mL (P < 0.001) (Fig. 3).
An increase in the minute ventilation while the I:E ratio was altered to maintain an inspiratory flow rate of 10.6 L min−1, increased time spent in the inspiratory phase per minute in the group with the larger minute volume and led to an increase in the volume of nebulized saline at all nebulizer settings. At the smaller minute volume (3.6 L min−1) nebulizer settings of '1', '2' and '3' gave mean nebulized volumes of 3.2 ± 0.8 mL, 6.7 ± 0.4 mL and 8.2 ± 0.6 mL, respectively. Increasing the minute volume to 7.2 L min−1 resulted in an increase in volume nebulized over all three nebulizer power settings, to 5.5 ± 1.0 mL at setting '1' (P< 0.05), to 9.5 ± 0.2 mL at setting '2' (P< 0.001) and to 15.3 ± 0.7 mL at setting '3' (P< 0.001) (Fig. 4).
An increase in the minute ventilation from 3.6 to 7.2 L min−1 with a constant I:E ratio of 1:2 maintained a constant time in inspiration per minute, albeit with a change in time spent in inspiration per breath. This caused an increase in inspiratory flow from 11.4 to 25.2 L min−1 at the larger minute ventilation. At a minute volume of 3.6 L, nebulizer settings of '1', '2' and '3' gave mean nebulized volumes of 4.9 ± 0.3 mL, 5.9 ± 1.0 mL and 9.0 ± 0.6 mL, respectively. Increasing the minute volume to 7.2 L while maintaining the same inspiratory time did not cause a significant increase in the volume of saline nebulized with volumes of 4.6 ± 0.6 mL at setting '1', 7.5 ± 0.7 mL at setting '2' and 10.0 ± 0.2 mL at setting 3 (Fig. 5).
Delivery of aerosols from a nebulizer, through a breathing circuit and to the site of action, or absorption at alveolar level, is a complicated process. Particle size, gas velocity, the breathing circuit and airway geometry all interact to determine the amount of aerosol that will be deposited in human airways. These characteristics have been studied using lung models of varying degrees of complexity [8,9]. In vivo experiments have shown the situation to be even less predictable than might be expected from these models where there is the added involvement of the endotracheal tube and intrinsic airway disease . This study was limited to assessing the volume of saline delivered from the nebulizer cup and draws no conclusion regarding the amount of saline delivered to the lower airways. Previous studies suggest a correlation between nebulizer retention of aerosol and delivery to lung models . Within these limits, evaluation of the performance of the Ultra-Neb 2000 in a mechanical ventilation model produced several interesting results.
Changes in the breathing system pressure might be expected to affect nebulizer performance. In this study, we were unable to show any difference in nebulizer performance over a PEEP range of 0 to 10 cmH2O and of peak airway pressures of 28-32 cmH2O. This is reassuring for any nebulizer designed to be used in an ITU setting, where mechanical ventilation is often used in association with PEEP. We chose not to investigate levels of PEEP greater than 10 cmH2O as the use of PEEP greater than this is never used in our clinical practice.
As with previous work, at high nebulizer settings an increase in the inspiratory cycle time improves nebulization rate . It appears that the relation between nebulization rate and time spent in the inspiratory phase is complicated by the output of the nebulizer. The effect of increased inspiratory time on increasing nebulized volume is reduced at lower nebulizer settings. Increasing minute ventilation increases nebulized volume only when it is associated with an increase in time spent in the inspiratory phase per minute. If minute ventilation were increased by increasing the inspiratory flow while the time spent in inspiration per minute was kept constant there was no increase in nebulized volume. We can conclude from this that time spent in inspiration per minute, with gas flowing through the nebulizing chamber is the most important and possibly the only important variable affecting the functional output of an ultrasonic nebulizer when used in series in the inspiratory limb of the ventilator during intermittent positive pressure ventilation, and that this effect diminishes at lower nebulizer settings. This reflects that uptake of liquid from the chamber has two components. Firstly, uptake of liquid already nebulized at the start of inspiration, and secondly, uptake of liquid nebulized during inspiration. Increasing time spent in inspiration per minute increases this second component.
Ultrasonic nebulizers may be affected by different patterns of ventilation, and prior assessment may be necessary if they are to provide a reliable method of drug delivery. The method used here for assessing the effects of changing patterns of ventilation is simple to perform and allows for more informed use of an ultrasonic nebulizer as a drug delivery system for use with patients in an ICU. This study revealed that the inspiratory time independently affects the performance of the Ultra-Neb 2000 ultrasonic nebulizer, while minute volume, inspiratory flow and positive end-expiratory pressure do not. If ultrasonic nebulizers are to be studied in detail with ventilated patients, then the effect of alterations in nebulizer power settings combined with ventilator settings should be recognized. If they are to be used in clinical practice clinicians should be aware of the importance of inspiratory time and be aware of varying this indirectly by altering unimportant variables such as inspiratory flow or minute ventilation. It is desirable that in the future there will be an ultrasonic nebulizer with a fixed and measured output for use with intermittent positive pressure ventilation.
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