Determinants of Aerosolized Albuterol Delivery to Mechanically Ventilated Infants

laboratory and animal investigations Determinants of Aerosolized Albuterol Delivery to Mechanically Ventilated Infants* Denise M. Coleman, MD/ H. William Kelly, PharmD; and Bennie C. McWilliams, MD

An in vitro lung model and a volume ventilator were used to evaluate the delivery of aerosolized albuterol through an infant ventilator circuit. We compared the following: continuous nebulization (CNA) and intermittent nebulization (INA); various nebulizer gas flows, 5.0, 6.5, and 8.0 Umin; and duty cycle of 33% and 50%. The efficiency and consistency of aerosol delivery by metered-dose inhaler (MDI) with four different spacer devices and by nebulizer positioned at the manifold and at the same position as the MDI were also evaluated. A volume ventilator (Servo 900B) was used with settings selected to reflect those of a moderately to severely ill 4-kg infant. A 3.5-mm endotracheal tube was used in all experiments. A specific type of nebulizer used (Airlife Misty Neb; Baxter; Valencia, Calif) and several spacers were studied (Aerochamber and Aerovent, Diemolding Healthcare Div, Canastota, NY; ACE, Monaghan Medical Corp, Plattsburgh, NY; and an in-line MDI adapter, Instrumentation Industries Inc, Pittsburgh). CNA delivered significantly more aerosol to the lung model (4.8±0.6% of the starting dose) than INA (3.8:±:0.3%; p
Jnfants mechanically ventilated for obstructive lung disease are often treated with aerosolized medica-

*From the Department of Pediatrics (Drs. Coleman, Kelly, and McWilliams) and the College of Pharmacy (Dr. Kelly), University of New Mexico Health Sciences Center School of Medicine, Albuquerque. tcurrently at the Department of Pediatrics, University of Washington, School of Medicine, Seattle. Su_pported by NHLBI grant 4-00651 and by MCH grant 4-32085. Alouterol nebulizin~ so1ution provided by Glaxo Pharmaceuticals. Manuscript receiveaAugust 28; 1995; reVIsion accepted December 19. Reprint requests: H. William Kelly, PharmD, College o{Phar[1WC!J, University ofNew Mexico Health Sciences Center, ZSO:f Marble NE, Albuquerque, NM 87131-1066

tions. The delivery of aerosolized medications to endotracheally intubated and mechanically ventilated adults has been shown to be highly inefficient. 1•2 In addition, aerosol delivery to in vitro pediatric and adult lung models has been shown to be affected by numerous variables, including the mode of ventilation, nebulizer type, volume fill and nebulizer flow, and the presence of humidification in the ventilator circuit. 3-6 Evaluating aerosol delivery to adult subjects is facilitated by the use of radiolabeled compounds; however, this method is limited in infants and children by the ethical considerations of delivering radioactivity. For CHEST/109/6/JUNE, 1996

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Filter

Lung Model FIGURE l. Lung model. Point B is 15 em from the ETT.

this reason, in vitro lung models that simulate mechanically ventilated infants have been developed. 4·7 These mod~ls have been predictive of aerosol delivery in infants. 5·' At our institution, respiratory therapists vary nebulizer flow during mechanical ventilation of infants based on the tidal volume desired and appearance of the aerosol cloud with no standard flow from patient to patient. Varying the driving gas flow has been shovvn to affect nebulizer output8 and delivery in an in vitro neonatal lung model. 4 Studies using adult lung models have shown improved aerosol delivery \vith an increase in duty cycle. 3 Finally, recent evidence suggests that the delivery of aerosols may be more efficient via metered-dose inhalers (MDis) with specially adapted spacer devices than by nebulization in mechanically ventilated adult patients. 2 \Ve used an in vitro infant lung model to evaluate several determinants of aerosol delivery via mechanical ventilation. In a series of studies, we compared the delivery of aerosolized albuterol by continuous nebulization (CNA) and intermittent nebulization (INA), evaluated varying nebulizer flow and duty cycle, and finally compared the delivery efficiency and consistency of MDI with four different spacer devices and the nebulizer. We hypothesized that CNA would deliver a greater amount of albuterol to the lung model than INA owing to the inconsistent aerosol output when the nebulizer reaches sputter point,9 that a higher nebulizer flow would improve delivery by improving nebulizer output, 8 that increasing the duty cycle would increase delivery because of an increased inspiratory time, and that MDI with spacer would be more efficient than nebulizer as in adult studies. 1·2 MATERIALS AND METHODS

Lung Model The lung model consisted of a glass gas disperser submerged in a 250-mL stoppered beaker containing the collecting fluid (Fig 1). A 3.5-mm endotracheal tube (ETT) (Portex; Smiths Industries Medical Systems Company; Keene, NH) cmved at a 45° angle was connected to the lung model by way of a Y-connector with one-way 1608

valves of opposite orientation in each am1. The one-way valves ensured that aerosol went in one arm of the Y-piece and down the gas disperser into the collecting fluid. To overcome the resistance that was created by the gas disperser and collecting fluid, the side arm of the beaker was connected to suction at 20 em H20 using an infant water-seal chest drainage unit (Atrium Medical Corporation; Hudson, :"JH). A ventilator (Servo 900B; Siemens; Danzen, Maine) was used with settings selected to simulate a 4-kg infant \Yith moderate to severe pulmonary disease (tidal volume of 55 mL, peak inspiratory pressure of 60 to 64 em H20, positive end-expiratory pressure of 5 em H20, a respiratory rate of 20 breaths per minute, and a duty cycle of 33%). The circuit used was an isothermal custom infant/pediatric respiratory breathing circuit (Baxter; Valencia, Calif), which is corrugated ventilator tubing with a heating wire. The circuit was not heated or humidified during the experiments. Each study was done at ambient temperature and humidity. The relative humidity in Albuquerque is low, generally between 10% and 30%. The nebulizer received flow from a source that was separate from the ventilator. A 0.2-pm low-resistance fllter (Pall Biomedical Inc, Fajardo, Puerto Rico) was placed in the expiratot)' limb at the attachment to the ventilator.

Assay Albuterol was assayed spectrophotometrically and by high-performance liquid chromatography (HPLC). Spectrophotometry was performed at a wavelength of 295 nm with a 5-s averaging time using a spectrophotometer (Uvicon 930; Konitron Instruments; San Diego). The detection limit of the assay was 1 pglmL. A new four- to five-point standard curve was performed for each daily set of samples with the dav-to-dav coefficient of variation (CV) being less than 5%. An HPLC system (Isco model2300; Lincoln, Neb) was used for the HPLC assay with a multiwavelength UV detector set at 278 urn. The mobile phase consisted of 8% acetonitrile in 0.15% phosphoric acid at a flow of 1.7 Umin through a 5-pm Cl8 column. Two 50-pL injections were made of each sample. The peak heights of the absorbance were measured manually. A four-point standard curve was run each day. The CV of the slopes of the standard curves was less than 5%. The limit of detection was 50 nglmL.

Continuous vs Intermittent Nebulization A specific nebulizer (Airlife Misty Neb; Baxter; Valencia, Calif) was used for all studies and was positioned at the manifold (Fig 1). Six nebulizers from four different lots (Y2J349, Y2A342, Y2L19l, and Y3D318) were used and randomly selected for each study day, and the same nebulizer was used each day for both studies. The order of each study, intermittent vs contin:uous, was not randomized; however, the study order did vary based on time convenience. Nebulizer How of 6.5 Umin was used for both continuous and intennittent delivery. This flow was chosen to approximate procedures that are used by the respiratory therapy department at our institution. The collecting fluid used was O.lN sodium hydroxide. The tidal volume delivered to the model lung was measured by a neonatal pulmonary function system (PEDS; Medical Associated Sel'\ices; Hatfield, Pa). The tidal volume was held constant at 55 mL for all studies. This was accomplished by placing a pneumotachometer at the proximal end of the ETT with an empty nebulizer in the system and adjusting the minute ventilation through the ventilator so that the combined nebulizer flow and minute ventilation delivered a volume of 55 mL to the model lung. For the intennittent nebulization studies, the dry nebulizer was replaced with a nebulizer filled with 2 mL of albuterol solution (Glaxo; Research Triangle Park, NC) and 2 mL of 0.9% saline solution for a volume fill of 4 mL. Nebulizers were run to the point of dryness for all studies. A total of 3 nebulizations were performed for each of 6 individual studies so that a total of 30 mg of albuterol was nebulized. To perform the continuous nebulization studies, the model lung LaboratoJY and Animal Investigations

and ventilator circuit were setup as described above and the minute ventilation adjusted so that the tidal volume was 55 mL. Albuterol was delivered at a rate of 10 mglh for a total of 3 h suing the continuous nebulization set-up previously d escribed. 10 A solution of albuterol and 0.9% saline solution was delivered to the nebulizer via a pump (IVAC; IVAC Corporation; San Diego) at a rate of 16 mVh so that the volume fill remained between 3ancl 4 mL during the 3-h run. Six such studies w ere performed. When each nm was complete, the gas disperser was rinsed with sodium hydroxide solution and the rinse collected in the model lung. The v olume of sodium hydroxide solution in the model lung was then m easured and a 3-mL sample was then assayed spectrophotometrically to determine the amount of albuterol that was delivered to the model lung. Nebulizer Flow

The delivery of albuterol to the model lung was evaluated at different nebulizer flows of 5, 6.5, and 8 Umin. Tidal volume was maintained at 55 mL for all flows using a pneumotachometer as clescJibed above. Six studies at each flow rate were completed by twice nebulizing 4 mL of albuterol solution to the point of d1yness. The six nebulizers that were used w ere numbered and randomly selected for each fl ow. The order of the nebulizer flow studied was also randomized. Albuterol deposition was measured in the various components of the ventilator circuit in 3 of the 6studies at flows of 5 and 8 Umin. This was achieved by 1insing the different components of the circuit (ETT, inspiratory tubing, expiratory tubing, and · nebulizer) with sodium hydroxide and collecting the rinse. The volume of the 1inse was measured a nd recorded. The model lung was rinsed as described above. A lbuterol was assayed spectrophotometrically. In separate studies with the nebulizer flow rate at 5 Umin, the amount of albuterol deposited in the expiratmy Hlter was also measured. This filter ispositioned where the e>.piratory tubing attaches to the ventilator and should there fore collect aerosol greater than 0.2 pm in size that is not deposited in the ventilator circuit or model lung (Fig l ). Duty Cycle

With the nebulizer flow rate at 5 Umin, the delivery of albuterol to the model lung was studied at a d uty cycle (ratio of inspiratory time to total inspiratory and expiratmy time) of 33% and 50%. The nebulizer flow of 5.0 Umin was chosen to maximize clelive1y . The tidal volume remained at 55 mL for all expe1iments. Six studies w ere performed at each duty cycle by nebulizing 4 mL (20 mg) of albuterol solution to the point of cl1yness twice. The model lung and circuit w ere rinsed and assayed spectrophotometrically. MDI With Adapter

The deHve1y efficiency of four diffe rent adapter d evices with an albuterol MDI (Glaxo) was evaluated. For this series of studies, the collecting fluid of the lung model was HPLC grade water and albuterol was assayed by HPLC. We compared the following four adapters: Aerovent (Monaghan Medical Cmporation; Plattsburgh, NY); Aerochamber (Monaghan Medical Co11)0ration); ACE (Diemolding Healthcare Division; Canastota, NY); and an in-line MDI adapter (Instrumentation IndustJies Inc; Pittsburgh), as shown in Figure 2.The adapters or a n ebulizer w ere positioned 15 em from the ETT in the inspiratory limb a t point B, as shown in Figure l. In adclition, a nebulizer was studied at the manifold. For all studies with an MDI plus adapter, 1actuation of albuterol was administered just plior to 4 consecutive breaths 4 times for a total actuated dose of 400 pg (based on the close that exits the canister not the dose that leaves the usual commercial actuator). Thus, the percent clelive1y from each method (nebulizer and MDI canister) is based on the beginning nominal dose in the device. The MDI was

FICUHE 2. Spacers. In order from the top of the figure, the spacers studied w ere the ACE, the Aerochamber, an inline MDI adapter, and the Aerovent. shaken b etween each actuation. Each mode of aerosol delive1y was studied lour separate times in random order. For the experiments with the nebulizer, 5 mg of albuterol mixed with 3 mL of HPLC grade water for a volume fill of 4 mL was nebulized to the point of dryness using a n ebulizer flow rate of 6.5 Umin. All drug delivered distal to the ETT was collected by 1insing the gas disperser with HPLC grade water. The total volume of the lung model was then measured. An aliquot was saved and frozen at -20°C until assayed by HPLC. Statistical Analysis

Sample size for each of the studies (except the spacer studies) was calculated to detect a 50% difference in albuterol deHvery with a=0.05 and ~ =0.2. Single-factor analysis of vmiance (AN OVA) or two-tailed Student's t tests were used to determine statistical significance of results \vith p <0.05 considered significant. When single nebulizers were used as their own controls as in the nebulizer flow studies, paired t test with the Bonferroni correction was used. RESULTS

Table 1 gives the percent delivery of albuterol expressed as the mean± SD of the starting dose for the va1ious expe1iments.

Continuous vs Intermittent Nebulization A minimum of 6 experiments for each method of nebulization were performed so that for CNA n=6 and CHEST I 109 I 6 I JUNE, 1996

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Table 1-Albuterol Delivery Is Expressed as the Mean Percent Delivery±SD of the Starting Dose of Albuterol Parameter Studied Nebulization Continuous (n=6) Intermittent (n= 7) Nebulizer flow, Umin 5.0 (n=6) 6.5 (n=6) 8.0 (n=6) Duty cycle 33% (n=6) 50% (n=6) Nebulizer position ETI (n=4) Manifold (n=4) MDI with Aerochamber (n=4) Aerovent (n=4) Adapter (n=4) ACE (n=4)

Mean% Delivery±SD

cv,!

p Value

4.8±0.6 3.8±0.3

<0.01

4.8±1.3 3.7±1.1 2.7±1.1

<0.03* <0.0031 <0.0151

4.6±1.1 5.6±1.2

Not significant

0+-----------------+---------------~

5.0LPM

5.1±3.9 4.0±3.7

76.2 93.7

11.9±1.4 6.8±4.2 6.4±2.8 14.5±9.7

11.9 61.7 42.9 66.6

*p value for the difference between 5.0 and 6.5 Umin, Bonferroni correction. fp value for the difference between 6.5 and 8.0 Umin, Bonferroni correction. lp value for the difference between 5.0 and 8.0 Umin, Bonferroni correction. lev=coefficient of variation.

for INA n= 7. Delivery by CNA (mean of 4.8±0.6% of the starting dose) was greater than by INA (mean of 3.9±0.3% of the starting dose) (p<0.01). This represented an actual delivery for CNA ranging from 1.8 to 1.2 mg and for INA ranging from 1.4 to 1.1 mg. Nebulizer Flow

As nebulizer flow increased, the delivery to the lung model significantly decreased in a decremental fashion (Fig 3). The mean percent delivery at 5 Umin was 4.8±1.3% (range of 6.7 to 2.7%; 2.7 to 1.1 mg). Increasing the flow to 6.5 Umin significantly decreased the mean percent delivery to 3. 7 ± 1.1% (range, 2.1 to 4.9%); 0.84 to 2.0 mg; p<0.03). Increasing the flow to 8.0 Umin caused a further significant decrease in the mean percent delivery to 2.7±1.1% (range, 1.0 to 3.8%; 0.4 to 1.5 mg; p<0.003). The difference in delivery between 5.0 and 8.0 Umin was also signifiTable 2-Albuterol Deposition Within the Circuit With Delivery Expressed as the Mean Percent Delivery±SD of the Starting Dose of Albuterol Site

5.0 Umin

8.0 Umin

Lung (n=6) ETI (n=3) Expiratory tubing (n=3) Inspiratory tubing (n=3) Nebulizer (n=3)

4.8±1.3 0.7±0.03 3.9±0.9 34.7±0.7 30.4±6.0

2.7±1.1 0.4±0.16 3.8±0.7 43.7±4.9 25.3±4.1

1610

p < 0.015'

&.SLPM

8.0LPM

FIGURE 3. Mean percent delivery at the various flows studied. Each line represents an individual nebulizer studied. Asterisk=twotailed, paired t test, Bonferroni.

cantly different (p<0.015). There was a stepwise decrease in the time it took to reach the point of dryness with increasing nebulizer flow. At 5 Umin, the time to the point of dryness for a 20-mg albuterol nebulizer run (half the total dose) ranged from 18 to 34 min. The time decreased to a range of 17 to 23 min for a flow of 6.5 Umin and further decreased with a flow of 8.0 Umin to 12 to 20 min. The deposition of albuterol within the system was quantitated at the extremes of the flows studied (n=3). Table 2 describes the mean percent of the starting dose of 40 mg of albuterol that was recovered from each component. In two separate studies, the amount of albuterol in the expiratory filter was also quantitated and found to be 9.8% and 9.6%. Figure 3 illustrates the considerable individual variability in delivery among the nebulizers at the different flows studied. The nebulizers were numbered 1 through 6 and randomly selected at each flow studied. Nebulizers 4 and 6 were never selected. Nebulizers 1 and 3 were each selected twice. There was a notable amount of intranebulizer and intemebulizer variability. The intranebulizer variability is illustrated by the finding that at a flow of 5 Umin, nebulizer 3 delivered 5.4% during 1 run and on a separate day 2.7% during a different run with all experimental variables held constant. The intemebulizer variability is demonstrated by the range of deliveries found using the same flow of 5 Umin during different runs on separate days (2.7 to 6.6%). Duty Cycle

The mean delivery of nebulized albuterol was compared at duty cycles of 33% and at 50%. The mean deliveries of 4.6±1.1% and 5.6±1.2%, respectively, were not significantly different. Laboratory and Animal Investigations

MDI With Adapter The mean delivery via MDI with the four spacers studied and via nebulizer at the two positions is listed in Table l. The CV for each method of delivery was calculated and is also shown in Table l. The Aerochamber and ACE were significantly more efficient at aerosol delivery than the nebulizer in either position (p<0.025, ANOVA); however, all modes of delivery except the Aerochamber demonstrated a marked degree of variability. The actual dose delivered was greater with the nebulizer based on the starting doses used with nebulizers vs MDI (58 pg maximum delivery for the spacers and 260 pg for the maximum delivery of the nebulizer). The ACE delivered a significantly greater percent of the starting dose than either the Aerovent or the inline adapter (p<0.025, AN OVA) while none of the other comparisons were significantly different. DISCUSSION

As with previous studies, we have shown that aerosol delivery is dependent on mode of delivery and operating conditions. 3.4 The brand of nebulizer, type of ventilator (ie, volume or pressure limited), changes in nebulizer flow and ventilator settings, the presence of humidity in the ventilator circuit, and the nebulization of a solution vs a suspension have all been shown to alter aerosol delivery to in vitro pediatric and infant lung models. 4-6•11 We elected not to humidifY the circuit, as humidification has been shown to decrease delivery, and humidification is stopped during nebulization in our institution. 2·3 \Ve did not evaluate the effect of heating the circuit, although the circuits are routinely heated at our institution. With comparable conditions, we found similar delivery results as Benson et al4 who used a lung model with a fluid collection system. We chose a fluid collection system over a filter collection system in our model lung in an attempt to avoid decreased airflow through a filter with increasing resistance as wet aerosol is deposited. The use of our in vitro lung model has several limitations, including no true exhalation (all aerosol delivered past the tip of the ETT was trapped in the collection fluid), a limited range of compliance for the tidal volumes used, and the lack of lower airway anatomy that affects aerosol deposition patterns. 12 The lack of true exhalation is currently shared by all in vitro models, including filter collection systems, yet these have been shown to provide accurate assessments (though not precise) of in vivo delivery. 5 ·7,1 3 The advantage of in vitro models includes low cost and the capability to manipulate variables without concerns for patient well-being. We did not assess the amount of albuterol delivered that was contained in particles in the "respirable range"

as other studies have done.·5·7.1 3 However, Loffert et al 14 found 35% of the output of the Misty Neb to be in the respirable range under similar operating conditions. In a previous study by investigators at our institution utilizing a similar heated wire neonatal ventilator circuitry and ETT and multistage liquid impinger, it was shown that 95% of the particles escaping the ETT were in the respirable range (<6.4 pm) as the larger particles rained out in the system. 5 While the marker drug in that study was cromolyn, like albuterol it is a solution and current evidence suggests that solutions, though not suspensions, behave identically when nebulized.'· ll Thus, we would expect a similar proportion of the albuterol delivered to our lung model to be in the respirable range. Studies comparing in vivo delivery with in vitro delivery appear to confirm this assumption. 5 ·7•13 CNA delivered significantly more albuterol to the model lung than INA. With CNA, the nebulizer never reached the sputter point as occurred with INA. Malone et al9 have shown that significant delivery of aerosolized albuterol does not occur past the sputter point. The total difference in delivery was most likely due to the cumulative effect of reaching sputter point three times for each INA study. In all studies, we found variability in the performance of the nebulizers. With the CNA studies, even though the albuterol solution was delivered to the nebulizer at the same rate and nebulizer flow was held constant for all experiments, occasionally the nebulizers would begin to run dry or overflow. When this occurred, we adjusted the drip to compensate for the nebulizer variability in output efficiency, thus preventing the inadvertent occurrence of reaching sputter point or overflow. Also, the setup can be somewhat cumbersome in comparison to INA. The placement of the nebulizer at the manifold not only makes it easier to keep the nebulizer upright but also positions the nebulizer so that it is out of the way of nurses and respiratory therapists. With the development of large-volume nebulizers, some of the problems of CNA may be overcome; however, each device has individual optimal operating characteristics, and data from CNA with small-volume nebulizers should not be extrapolated to large-volume nebulizers. Studies of the delivery efficiency and reproducibility of large-volume nebulizers will need to be done to determine the optimal operating conditions for these new devices. In contrast to Benson et al, 4 we found a stepwise decrease in aerosol delivery to our lung model with increasing nebulizer flow. We expected to show an increased delivery at the higher flow as previous studies have shown increased nebulizer output with increasing flow. 8 In an attempt to explain these results, we determined the deposition of albuterol within the CHEST/109/6/JUNE, 1996

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ventilator circuit. There was increased deposition of albuterol in the inspiratory limb of the ventilator circuit and less albuterol recovered from the nebulizer with increasing nebulizer flow. The amount of albuterol recovered from the ETT at the upper and lower nebulizer flows studied was minimal and equivalent. It would seem that although the increased flow might improve nebulizer output, it also increased impaction in the T -connector that attaches the nebulizer to the inspiratory circuit. These data point out that we cannot extrapolate information from study to study. At all of the nebulizer flows studied, we found intranebulizer and intemebulizer variability in delivery of albuterol to the model lung. For example, one nebulizer (labeled neb 3) under the same conditions with a nebulizer flow of 5 Umin delivered 5.4% of the starting dose during 1 run on 1 day and 2.7% during a different run on a separate day. As the order of the studies with each nebulizer was randomized, the variation due to flow rate could not have been due to the order of each study. We make the argument that dosing should be titrated to effect based on this variability of delivery. Some of the intemebulizer vmiability may have been due to the use of differing lots of the nebulizer. 14J 5 We found no significant difference in albuterol delivery with increasing duty cycle. The hypothesis was that increasing duty cycle would lead to improved delivery because a greater percentage of time would be spent in inspiration. In an in vivo setting, an increase in duty cycle could theoretically allow for more sedimentation of aerosol particles within the airways. Our findings were in contrast to O'Riordan and coinvestigators3 who found marked changes in aerosol delivery to a model lung with manipulation of the duty cycle. Comparisons to their study should be made cautiously as the lung model used in their studies consisted of a filter collecting system and adult ventilator tubing; in addition, different types of nebulizers were used, and the nebulizers were positioned12 em from the Y-piece in the inspiratory limb. The lack of a significant difference in our study may be a function of our model lung design and/or the brand of nebulizer used. Studies employing adult ventilatory circuits and settings have shown improved delivery efficiency ·with the use of MDis with specially designed adapters.l· 2 We compared four different adapter devices to a nebulizer positioned at the manifold and at the same position the adapters were placed. Similar to the other studies, we found that overall the spacers were generally more efficient in delivery than the nebulizer at either position studied. The total dose of albuterol delivered was greater with the less efficient method of using a nebulizer as the starting dose was higher (5 mg with the nebulizer and 400 pg with the spacers and MDI). However, all of the adapter devices did not 1612

produce significantly greater delivery. The larger-volumed devices (ACE and Aerochamber, Fig 2) produced significantly greater delivery than the nebulizer. All modes of delivery were found to have a great deal of variability except for the Aerochamber. Our results reinforce the problem with trying to extrapolate delivery data from one device to another. The difference in delivery and variability also supports the need to titrate dosing to desired clinical effect as long as side effects are not seen. Clinically, it may be more important to use a device that provides the greater consistency rather than the greatest mean delivery, thereby reducing significant intradevice variability as a cause of response variability. One could reasonably expect that the intradevice variability might be increased in the normal clinical use outside of the laboratory where all conditions are kept consistent. If a patient fails to respond to treatment with an aerosolized medication while being mechanically ventilated, it may be that little or no drug has reached the patient's airways. This may be due to drug not leaving the spacer or being lost in the circuit before it reaches the airways. Unlike O'Riordan et al, 13 we made no attempt to first find the optimal nebulizer conditions for delivery prior to comparing the nebulizer with MDI plus adapters. They were able to produce 15 to 20% delivery via a nebulizer which exceeds the delivery that we found with MDI and adaptersP Interdevice variability has been reported previously, 3·8.1US but our finding of a significant intradevice and particularly intranebulizer variability is equally disconcerting. Although the disposable nebulizers used in our study are not meant for repeated use, many patients and hospitals may use them repeatedly. In conclusion, we have shovm that aerosol delivery depends on the mode of delivery and the operating conditions but that both nebulizers and MDis with adapters are capable of delivering clinically significant amounts of albuterol to the airways. We have demonstrated improved delivery with CN A vs IN A, improved delivery and decreased deposition in the inspiratory circuit with lowering nebulizer flow, no significant difference in delivery with varying the duty cycle, and a higher delivery efficiency vvith MDI and adapters as compared with nebulizer delivery. The clinical significance of the differences in delivery is best illustrated by the seemingly small difference between INA and CNA (Table 1). However, this represents a 300-pg difference in total drug delivery to the lung, the equivalent of 30 inhalations or more from an MDI in a spontaneously breathing adult with excellent inhaler technique. This is an amount that clearly can produce a clinically significant physiologic effect. Thus, although differences appear to be small, they can easily be clinically significant. Remembering that under the Laboratory and Animal Investigations

usual conditions (spontaneously breathing adults), that nebulizers deliver only 5 to 10% of the nominal dose, a difference of 1% represents as much as 10 to 20% of usual expected delivery. ACKNOWLEDGMENTS: The authors thank Judy Rauc_Y-, PhD, for the assay development, and Barbara Ortega, RTI, for her technical support.

REFERENCES

1 Macintyre NR, Silver RM, Miller CW, et a!. Aerosol delivery in intubated, mechanically ventilated patients. Crit Care Med 1985; 13:81-4 2 Fuller HD, Dolovich MB, Posmituck G, eta!. Pressurized aerosol versus jet aerosol delivery to mechanically ventilated patients. Am Rev Respir Dis 1990; 141:440-44 3 O'Riordan TG, Greco MJ, Perry RJ, et a!. Nebulizer function during mechanical ventilation. Am Rev Respir Dis 1992; 145: 1117-22 4 Benson JM, Gal P, Kandrotas RJ, eta!. The impact of changing ventilator parameters on availability of nebulized drugs in an in vitro neonatal lung system. DICP Ann Pharmacother 1991; 25:272-75

5 Watterberg KL, Clark AR, Kelly HW, et a!. Delivery of aerosolized medication to intubated babies. Pediatr Pulmonol 1991; 10:136-41 6 Garner SS, Wiest DB, Bradley JW. Albuterol delivery by metered-dose inhaler with a pediatric mechanical ventilatory circuit model. Pharmacotherapy 1994; 14:210-14 7 Grigg J, Arnon S, Jones T, et a!. Delivery of therapeutic aerosols to intubated babies. Arch Dis Child 1992; 67:25-30 8 Clay MM, Pavia D, Newman SP, eta!. Factors influencing the size distribution ofaerosols from jetnebulisers. Thorax 1983; 38:755-59 9 Malone RA, Hollie MC, Glynn-Barnhart A, eta!. Optimal duration of nebulized albuterol therapy. Chest 1993; 104:1114-18 10 MurphyS, Kelly HW. Management of acute asthma. Pediatrician 1991; 18:287-300 11 Cameron D, Clay M, Silverman M. Evaluation of nebulizers for use in neonatal ventilator circuits. Crit Care Med 1990; 18:866-70 12 Aerosol consensus statement. Chest 1991; 100:1106-09 13 O'Riordan TG, Palmer LB, Smaldone GC. Aerosol deposition in mechanically ventilated patients: optimizing nebulizer delivery. Am J Respir Crit Care Med 1994; 149:214-19 14 Loffert DT, Ikle D, Nelson HS. A comparison of commercial jet nebulizers. Chest 1994; 106:1788-93 15 Alvine GF, Rodgers P, Fitzsimmons KM, et a!. Disposable jet nebulizers: how reliable are they. Chest 1992; 101:316-19

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