American Journal of Respiratory and Critical Care Medicine

We attempted to resolve the discrepancies in reported data on aerosol deposition from a chlorofluorocarbon (CFC)-propelled metered-dose inhaler (MDI) during mechanical ventilation, obtained by in vivo and in vitro methodologies. Albuterol delivery to the lower respiratory tract was decreased in a humidified versus a dry circuit (16.2 versus 30.4%, respectively; p < 0.01). In 10 mechanically ventilated patients, 4.8% of the nominal dose was exhaled. When the exhaled aerosol was subtracted from the in vitro delivery of 16.2% achieved in a humidified ventilator circuit, the resulting value (16.2 − 4.8 = 11.4%) was similar to in vivo estimates of aerosol deposition. Having reconciled in vitro with in vivo findings, we then evaluated factors influencing aerosol delivery. A lower inspiratory flow rate (40 versus 80 L/min; p < 0.001), a longer duty cycle (0.50 versus 0.25; p < 0.04), and a shorter interval between successive MDI actuations (15 versus 60 s; p < 0.02) increased aerosol delivery, whereas use of a hydrofluoroalkane (HFA)-propelled MDI decreased aerosol delivery compared with the CFC-propelled MDI. A MDI and actuator combination other than that designed by the manufacturer altered aerosol particle size and decreased drug delivery. In conclusion, aerosol delivery in an in vitro model accurately reflects in vivo delivery, providing a means for investigating methods to improve the efficiency of aerosol therapy during mechanical ventilation.

Laboratory investigations have significantly improved our understanding of the complex factors influencing aerosol delivery during mechanical ventilation (1, 2), but the clinical impact of such investigations is limited by the wide discrepancies between the data obtained by in vivo and in vitro testing. Some of these discrepancies are related to differences in delivery systems and techniques of administration (3-13), but when these factors are controlled, aerosol delivery by in vitro methods (3-9) has still resulted in values that are fivefold higher than those reported with in vivo testing (3, 11). Laboratory investigations have been commonly performed under dry conditions, but mechanically ventilated patients typically receive heated and humidified gas. Compared with a dry circuit, several investigators have reported that aerosol delivery is decreased by 40 to 50% in a humidified ventilator circuit (7-9), but the reasons for the reduction in delivery have not been clarified. Moreover, the effect of humidity on delivery of the new hydrofluoroalkane (HFA)-propelled metered-dose inhaler (MDI) formulations has not been investigated; this issue has achieved considerable importance with the planned phase out of chlorofluorocarbon (CFC) formulations because of environmental concerns.

A second factor that may explain the difference between in vivo and in vitro findings is the failure of in vitro testing to account for the proportion of aerosol exhaled by the patient. When a nonintubated, ambulatory patient uses a MDI, ≈ 1% of the nominal dose from the MDI is exhaled (14), but the fraction may be greater in mechanically ventilated patients since their breathing pattern is different. Previous reports using nebulizers in mechanically ventilated patients have found that as much as half of an aerosol that enters the lungs is exhaled (15). However, the proportion of the nominal dose from a MDI that is exhaled by patients receiving mechanical ventilation is not known.

In addition to understanding differences between in vivo and in vitro findings, we applied our in vitro model (9) to identify factors that might enhance the efficiency of aerosol administration during mechanical ventilation. In a previous study, we observed a linear positive correlation between duty cycle (Ti/ Ttot) and aerosol delivery from a MDI (9). This effect is difficult to explain because the time for flume deployment and drug delivery in the circuit is much less (≈ 70 ms) than the inspiratory time (0.5 s or higher). During mechanical ventilation, Ti/ Ttot depends on tidal volume (Vt), inspiratory flow rate, and respiratory frequency. Because a low inspiratory flow rate increases aerosol delivery in nonintubated patients (16), we investigated the relative effect of inspiratory flow rate and Ti/ Ttot on the delivery of aerosol from a MDI during mechanical ventilation.

An additional factor influencing drug delivery from a MDI is the interval between actuations. Diot and colleagues (8) reported that drug delivery was optimal when actuation of a MDI was synchronized with inspiration and a 60-s interval was interposed between successive actuations; drug delivery decreased when successive actuations were performed without a pause (8). On the surface, this contrasts with our observation that ventilator-supported patients with chronic obstructive pulmonary disease (COPD) display significant bronchodilation after administration of albuterol with a MDI when actuations were synchronized with inspiration but the pause interval between successive doses was 20 to 30 s (17, 18). If the interval between MDI actuations could be reduced without a decrease in the efficiency of drug delivery, the costs of delivering bronchodilators to patients in intensive care units could be minimized and the convenience increased. On the basis of the above considerations, we characterized the pattern of deposition with CFC-propelled MDIs and HFA-propelled MDIs in both dry and humidified ventilator circuits; we determined the proportion of exhaled aerosol in ventilator-supported patients; we compared the influence of changing Ti/Ttot and inspiratory flow rate on aerosol delivery; and we compared drug delivery with 15- versus 60-s intervals between actuations of a MDI during mechanical ventilation.

Studies were conducted employing a tracheobronchial model that allows investigation of aerosol delivery during mechanical ventilation (Figure 1); this is similar to that described in our previous publication (9). The ventilator (900C; Siemens-Elema, Solna, Sweden) provided controlled mechanical ventilation with a Vt of 800 ml, a frequency of 10 breaths/min, and a peak inspiratory flow of 40 L/min delivered with a square-wave configuration. MDI canisters (albuterol or albuterol HFA; Schering, Kenilworth, NJ; manufacturer estimated dose of 90 μg/puff) were warmed to hand temperature, well shaken, and primed using a separate actuator before each experimental run. Each actuation was discharged into a MDI spacer (AeroVent; Monaghan Medical Inc., Plattsburgh, NY) in the inspiratory limb of the ventilator circuit at the onset of inspiration. Successive doses from a MDI were actuated at 15-s intervals, unless otherwise specified. Albuterol was administered from a set of four MDIs, actuated in rotation, with filters placed at four sites in the in vitro model (Figure 1, sites A–D). The quantity of albuterol at each site was collected on a filter with a pore size < 0.3 μm (Respirgard II bacterial/viral Filter, No. 303; Marquest Medical Products, Inc., Englewood, CO). The albuterol deposited on the filter was measured by spectrophotometry (see below). Experiments were performed with inspired gas at ambient temperature (25 to 27° C) with < 10% relative humidity (RH; dry) or heated to 35 ± 1° C with 98 ± 2% RH (Fast-Response Digital Hygrometer/Thermometer; Curtin Matheson, Houston, TX).

In Vivo and In Vitro Determinations of Exhaled Aerosol

To determine the proportion of aerosol exhaled by patients, we administered eight puffs of albuterol into a humidified ventilator circuit (33 to 35° C and > 98% RH). A filter was placed in the expiratory limb of the ventilator circuit to collect aerosol that was exhaled by 10 mechanically ventilated patients with stable COPD receiving bronchodilator therapy as part of their routine management. The aerosol was administered during controlled mechanical ventilation using Vt of 500 to 700 ml, frequency of 10 to 12 breaths/min, and inspiratory flow of 40 to 50 L/min with a square-wave configuration. The experiment was repeated under identical in vitro conditions, but with a filter placed in the expiratory limb of the ventilator circuit (Figure 1, site D) to collect the aerosol that bypassed the model.

Pattern of Aerosol Deposition

To better understand differences in aerosol delivery from HFA- and CFC-propelled MDIs, albuterol deposition was measured at three points: distal to the chamber (site A), distal to the angled connector from the circuit wye before the endotracheal (ET) tube (site B), and distal to the bronchi (site C) (Figure 1). The experiments were repeated to obtain measurements at each site under both dry and humid conditions. The outputs of aerosol from HFA- and CFC-propelled MDIs were compared.

Effect of Actuator Orifice Size on MDI Output

To better understand the reason for differences in output between CFC- and HFA-propelled MDIs, we measured the actuator orifice in the manufacturer-supplied actuators. We actuated both the CFC- and HFA-propelled MDIs using the actuators supplied with the canister and compared the output with that obtained with the MDI canister and spacer using a 10-stage quartz crystal microbalance, real-time, cascade impactor (PPC-2AS; California Measurements, Sierra Madre, CA). The aerosol produced by a single actuation from a MDI was sampled isokinetically, at a flow rate of 240 ml/min, for 1 to 1.6 s immediately after actuation. The mass of albuterol at each cutoff of particle size was plotted on a log-normal graph, from which the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined (19). The total mass of aerosol depositing in the impactor was also measured.

Effect of Ti/Ttot and Inspiratory Flow

To determine whether inspiratory flow rate or Ti/Ttot had a greater influence on aerosol delivery, eight puffs of albuterol were administered into a dry ventilator circuit with filters placed at the bronchi during controlled mechanical ventilation (Figure 1, site C). The ventilator was set to deliver a Vt of 1,000 ml with a square-wave inspiratory flow of 40 or 80 L/min, and frequency was varied to achieve Ti/Ttot values of 0.50 or 0.25 at each inspiratory flow setting.

Effect of Interval between Actuations

To determine the effect of reducing the time interval between successive actuations on aerosol delivery, four or eight puffs of albuterol (from shaken and primed MDIs) were each administered at the onset of inspiration with 15- or 60-s intervals between successive doses. The tests were performed under humidified conditions with a filter placed immediately distal to the spacer (Figure 1, site A). In addition, the effect on drug output of thoroughly shaking (for ⩾ 10 s) or not shaking the MDI canister between each actuation was determined.

Assay Technique

On completion of each experiment, the filters were labeled, capped, and filled with 5 ml of 0.1 M sodium hydroxide, and the albuterol was eluted by gentle shaking for 24 h. The volume recovered from each filter was recorded and the albuterol concentration was determined at a wavelength of 246 nm using 0.1 M sodium hydroxide as the reference (Beckman Instruments, Fullerton, CA) (19). Individual experiments were repeated three times on different days with single blind analysis.

Data Analysis

All results were expressed as the absolute amount of drug or as the fraction of nominal dose delivered (mean ± SD). The particle size distribution of the emitted dose from the MDI was expressed as MMAD ± GSD. Differences between the delivered amounts of drug and MMAD were analyzed by one-way analysis of variance (ANOVA) with the Newman-Keuls test; p < 0.05 was considered significant.

Determination of Aerosol Exhaled by Patient

The amount of albuterol deposited on a filter placed in the expiratory limb of the ventilator circuit in 10 patients receiving controlled mechanical ventilation is listed in Table 1. The amount of albuterol deposition on a filter in the same location using an in vitro circuit and the same ventilator settings are also listed. The values for aerosol deposition were consistently higher than the values obtained in vitro. In the patients, 8.7 ± 1.2 (SD)% of the aerosol was deposited on the filter placed in the expiratory limb of the circuit, whereas 3.9 ± 0.4% was deposited at the same site in the in vitro lung model (p < 0.001). The difference in the collection of drug in the expiratory limb of the ventilator circuit between in vivo and in vitro conditions (8.7 − 3.9 = 4.8%) represents the aerosol exhaled by the patient.


Patient No.ETT (mm)Vt(L)Rate (b/min)PIF (L/min)Ti/TtotAlbuterol on Expiratory Filter*
Sex In Vivo In Vitro Difference

Definition of abbreviations: ETT = endotracheal tube diameter; PIF = peak inspiratory flow; Ti/Ttot = duty cycle; Vt = tidal volume.

*Expressed as percent of nominal dose.

The difference between in vivo and in vitro values, at similar settings of controlled mechanical ventilaton, is the estimate of the amount of aerosol exhaled by the patient.

Relative Efficiency of CFC- and HFA-propelled MDIs

Aerosol deposition at each of the three sites of the bench model with the CFC formulation are shown in Figure 2. Compared with the dry circuit, a greater proportion of the aerosol exited the spacer when it was actuated into a humidified circuit: 44.8 ± 1.5 and 60.5 ± 1.7 (SD)%, respectively (p < 0.001). In the humidified circuit, however, a greater amount of aerosol was deposited in the ventilator circuit distal to the spacer (31.4 versus 10.2% in the dry circuit; p < 0.0001) and in the endotracheal tube (12.9 versus 4.2%; p < 0.001), such that deposition between the spacer and the bronchial filters was greatly increased (44.3 versus 14.4%; p < 0.0001). As a result, delivery of aerosol to the bronchi was lower in the humidified circuit: 16.2 ± 2.3 versus 30.4 ± 3.1%(p < 0.001).

The pattern of aerosol deposition with the HFA-propelled MDI (Figure 3) was similar to that with the CFC formulation. Compared with the dry circuit, the humidified circuit resulted in a greater proportion of aerosol exiting the spacer (42.8 ± 1.2 versus 31.4 ± 2.2%; p < 0.001), a greater amount of aerosol depositing in the ventilator circuit (30.5 versus 9.4%; p < 0.001), and less aerosol delivery to the bronchi (12.3 ± 0.8 versus 22.0 ± 1.7%, respectively; p < 0.001). Under both dry and humidified conditions, delivery of the HFA formulation to the bronchi was ≈ 24% less than that with the CFC formulation (p < 0.01 in both instances).

The orifice of the actuator for the CFC-propelled MDI supplied by the manufacturer (0.021 inch) is larger than that for the HFA actuator (0.011 inch). The results of actuating the CFC- and HFA-propelled MDIs using the CFC actuator, the HFA actuator, and the spacer adapter are shown in Table 2. When the actuator supplied by the manufacturer was employed, the aerosol particle distribution and total output were similar for the CFC- and HFA-propelled MDIs. When the MDI canister was placed in the actuator designed for the other formulation, the MMAD of both formulations was altered and drug output reduced (p < 0.001). Likewise, when the HFA-propelled MDI was actuated in the spacer chamber, MMAD was increased and total output was decreased. The orifice of the spacer chamber (0.023 inch) was similar to that of the CFC actuator, but more than twice the diameter of the orifice of the HFA actuator. The use of the HFA-propelled MDI with the spacer resulted in decreased drug output and an aerosol with a higher MMAD (Table 2).


MDI CombinationTotal Mass(g/m3 )*
CanisterActuatorMMAD ± GSD
CFCCFC2.51 ± 2.83.5
CFCHFA1.32 ± 3.1 1.7
CFCSpacer2.12 ± 1.92.1
HFAHFA2.16 ± 2.34.4
HFACFC4.59 ± 4.2 1.2
HFASpacer3.53 ± 3.1, 1.1,

Definition of abbreviations: CFC = chlorofluorocarbon-propelled MDI; HFA = hydrofluoroalkane-propelled MDI; GSD = geometric standard deviation; MMAD = mass median aerodynamic diameter; Spacer = actuator device for use of MDI with ventilator circuit.

*Total mass of aerosol deposited within the cascade impactor.

p < 0.001 compared with the MMAD or total mass from the manufacturer-provided MDI and actuator combination.

p < 0.0001 compared with CFC-MDI actuated in the spacer.

Effect of Ti/Ttot versus Inspiratory Flow

Albuterol delivery to the bronchi was greater with a Ti/Ttot of 0.50 than of 0.25 at inspiratory flows of 40 L/min (27.4 ± 0.4 versus 24.1 ± 0.7%, respectively; p < 0.002) and 80 L/min (10.2 ± 0.1 versus 9.4 ± 0.0%, respectively; p < 0.04). For both values of Ti/Ttot, albuterol delivery with an inspiratory flow of 40 L/min (25.8 ± 0.6%) was more than twice the delivery at 80 L/min (9.8 ± 0.1%), demonstrating the relatively greater effect of inspiratory flow over Ti/Ttot on aerosol delivery (p < 0.0001).

Effect of Interval between Actuations and Shaking of Canister

With four puffs, no difference in MDI output was found when successive doses were actuated at intervals of 15 versus 60 s. With eight puffs, more drug was delivered with a 15-s interval (47.5 ± 5.7%) than with a 60-s interval (41.7 ± 6.5%; p < 0.02). With four puffs, MDI output was higher when the canister was not shaken between actuations (52.6 ± 3.0%) than when it was shaken (46.2 ± 3.3%; p < 0.0003).

Because many factors influence the delivery of aerosols to mechanically ventilated patients, reliable in vitro methods are needed to determine the contribution of each individual factor to the overall efficiency of aerosol administration. For the first time, we have shown that when the effects of humidity in the ventilator circuit and the aerosol exhaled by a patient are taken into account, aerosol delivery to the bronchi of an in vitro model replicates findings reported with in vivo methods. We also identified a number of factors that can influence the efficiency and convenience of aerosol administration in ventilator-supported patients.

When applying the results of bench studies to clinical practice, the large discrepancy between reported values for in vivo and in vitro aerosol deposition using similar devices and techniques of administration, ≈ 6 and 30%, respectively (3, 4, 8, 11), has posed a significant problem. Compared with a deposition of > 30% in an in vitro model under dry conditions, deposition of only ≈ 16% has been reported under similar conditions in a humidified circuit (8, 9). We found that the amount of aerosol exhaled by the patient, which cannot be measured in an in vitro model, is another factor that contributes to the discrepancy between in vivo and in vitro measurements of aerosol deposition. Within a narrow range of ventilator settings, we found that patients exhaled ≈ 4.8% of the nominal dose (range, 2.9 to 6.3%); this value may be an underestimate because of our inability to measure the amount of aerosol that deposits on the endotracheal tube during exhalation. Subtraction of this estimate of exhaled aerosol from the measured in vitro delivery of a drug in a humidified circuit provides a more accurate estimate of aerosol deposition in a mechanically ventilated tracheobronchial model (16.2 − 4.8 = 11.4%). The resulting value is remarkably similar to the calculated deposition of radiolabeled aerosol in mechanically ventilated patients after adjusting for tissue adsorption of radioactivity (viz., 10.8%) (13). These findings support the relevance of our in vitro model for predicting changes in aerosol delivery to the lower respiratory tract in mechanically ventilated patients.

Several investigators have reported that aerosol delivery is decreased when a ventilator circuit is humidified (7-9). The reduction in aerosol delivery is unlikely to be due to hygroscopic growth of the aerosol particles since the particles emerging from a MDI are coated with hydrophobic surfactants and propellants. In a nasopharyngeal model, Kim and colleagues (20) found that addition of humidity (⩽ 25 mg H2O/L) did not increase the MMAD of aerosol produced by a MDI. Unlike their model, however, ventilator circuits in clinical use typically have a higher absolute humidity (> 39 mg H2O/L), which might influence the rate of propellant evaporation. In addition, the formation of water condensate on the aerosol particles may increase their mass, increasing both impaction and rainout of aerosol in the ventilator circuit. Compared with dry conditions, the percent of nominal dose of drug from a MDI that exits from the spacer chamber into a heated and humidified ventilator circuit is larger (Figures 2 and 3), with a greater amount of drug being lost en route to the bronchi. In a preliminary investigation, we found that the MMAD from a CFC-propelled MDI leaving a spacer chamber was larger in a humidified than in a dry ventilator circuit (1.6 versus 1.3 μm; p < 0.05) (21); this suggests that the increased drug mass is contained in larger particles leaving the adapter, and, consequently, has greater risk of inertial impaction in the ventilator circuit. Although use of a dry ventilator circuit should make it possible to deliver more drug to the bronchi, the potential adverse effects of cold, dry air on the airway during bronchodilator administration have not been evaluated. Moreover, switching off a humidifier during aerosol administration achieves little clinical advantage, and we have observed significant bronchodilation after as few as four puffs of albuterol from a MDI delivered to patients via a humidified ventilator circuit (18).

The patterns of deposition with the HFA- and CFC-propelled MDIs were similar, in that humidity increased the amount of drug exiting the spacer adapter (by 36.3 and 35.0%, respectively) and decreased deposition to the bronchi (by 44.1 and 46.7%, respectively). However, the drug delivered to the bronchi with the HFA-propelled MDI was consistently less (≈ 24%) than with the CFC formulation. The orifice of the actuator employed by manufacturers of the HFA formulation is smaller than that of the CFC formulation, with the intent of providing comparable dosages on a puff-per-puff basis. When either MDI canister was used with an actuator orifice that was larger or smaller than that designed by the manufacturer for use with a particular formulation, the characteristics of the aerosol were altered and the drug available to the patient was reduced. When used with a variety of aerosol formulations, MDI accessory devices with an internal actuator other than that provided by the manufacturer result in variable particle size characteristics and aerosol output (22). Therefore, a MDI should not be combined with an accessory device other than that supplied by the manufacturer, unless the efficiency of the MDI and actuator combination is established by in vitro testing before clinical use. The results of in vitro testing should help in guiding clinicians in the selection of MDI accessory devices that achieve a drug output comparable to that of the MDI when used with the manufacturer-supplied actuator. To achieve efficient aerosol delivery, the HFA-propelled MDIs will require the use of chamber adapters with smaller actuator orifices.

Drug delivery was influenced by Ti/Ttot, but to a smaller extent than that effected by a proportional change in inspiratory flow rate. As previously observed in nonintubated patients (17), aerosol delivery was increased with use of a low inspiratory flow during mechanical ventilation. Patients with severe airway obstruction are often mechanically ventilated with high inspiratory flows to shorten the inspiratory time. This method of ventilation is intended to allow additional time for exhalation through obstructed airways and reduce dynamic hyperinflation (23). However, our results show that a high inspiratory flow decreases aerosol delivery. Accordingly, a low inspiratory flow and a Ti/Ttot ⩾ 0.30 should be employed, if possible, during the time that a MDI is being administered to a ventilator-supported patient.

The interval allotted between successive actuations from a MDI is a major determinant of the overall time required for the delivery of aerosol therapy during mechanical ventilation. Diot and colleagues (8) reported that successive actuations of a MDI without an intervening pause reduced drug delivery when compared with the manufacturer-recommended interval of 60 s. We found no difference in delivered dose when the interval between successive actuations was only 15 versus 60 s— a conclusion also supported by the findings of Shalansky and coworkers (24). These findings are consistent with our previous observations of a significant response to albuterol from a MDI actuated at 20- to 30-s intervals in ventilator-supported patients with COPD (17, 18). Consequently, the time required to deliver an effective dose of four puffs in a stable ventilator-supported patient need not exceed 2 min. The routine clinical application of these findings could substantially reduce the time spent by clinicians in the administration of bronchodilators, and thereby decrease the cost of bronchodilator therapy in an intensive care unit.

Aerosol output was reduced by the removal of the MDI canister from the spacer chamber for shaking between each actuation. When a MDI canister is returned to the spacer adapter, the nozzle stem may not be seated properly in the actuator until sufficient pressure is applied to actuate the MDI; actuation of a canister with a partially seated stem may reduce aerosol output. The shaking of a MDI canister before actuation is intended to agitate any ingredients that have settled over time, such that the metering chamber, which fills during each actuation, will receive a homogenous mix of ingredients. Our results suggest that multiple actuations within a few minutes of thoroughly shaking the MDI canister provide greater drug output than the removal of a canister from the adapter to shake between actuations.

In summary, we have demonstrated that when the influence of humidity in a ventilator circuit and the aerosol exhaled by the patient are taken into account, the delivery of aerosol from a MDI in our in vitro mechanically ventilated tracheobronchial model is similar to that reported with in vivo methodology. Aerosol delivery was less with use of a HFA-propelled MDI than with a CFC-propelled MDI, under both humidified and dry conditions. The use of a HFA-propelled MDI in an actuator designed for the use of a CFC-propelled MDI, or with a spacer designed for another formulation, increased MMAD and reduced total mass of drug output. Aerosol delivery was increased with lower inspiratory flow rate, a longer Ti/Ttot, and a shorter interval between successive MDI actuations. In conclusion, in vitro estimates of aerosol delivery can accurately reflect in vivo delivery, and offer a viable means for the investigation of methods to improve the efficiency of aerosol therapy in patients receiving mechanical ventilation.

Supported in part by VA Research Service.

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Correspondence and requests for reprints should be addressed to James B. Fink, M.S., R.R.T., Division of Pulmonary and Critical Care Medicine, 111 N, Hines VA Hospital, Hines, IL 60141.


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