Inhaled Bronchodilator Therapy in Mechanically Ventilated Patients

RAJIV DHAND and MARTIN J. TOBIN

Division of Pulmonary and Critical Care Medicine, Edward Hines Jr. Veterans Affairs Hospital and Loyola University of Chicago Stritch School of Medicine, Hines, Illinois

	INTRODUCTION

TOP INTRODUCTION CONCLUSION REFERENCES

Therapeutic aerosols are commonly used in mechanically ventilated patients, mainly to deliver bronchodilator drugs. Because ventilator-supported patients often receive several different classes of medications parenterally, the inhaled route of administration is particularly useful as an alternate route for drug delivery. Both nebulizers and metered-dose inhalers (MDIs) can be adapted for use in ventilator circuits. Traditionally, nebulizers have been used to deliver bronchodilators, antibiotics, and surfactant in mechanically ventilated patients, whereas MDIs chiefly have been used to deliver beta-adrenergic and anticholinergic bronchodilators (1). In the past, the combination of an MDI with an elbow adapter was considered to be ineffective (2) due to aerosol impaction in the ventilator circuit and endotracheal tube (3). However, recent studies (4) have clearly established the efficacy of MDIs for delivering bronchodilators in mechanically ventilated patients, with the caveat that the technique needs to be carefully executed. With a better understanding of the many factors influencing aerosol delivery and deposition in mechanically ventilated patients, it is possible to provide a scientific basis for inhaled bronchodilator therapy in these patients.

	FACTORS INFLUENCING LOWER RESPIRATORY TRACT DEPOSITION OF AEROSOL

In mechanically ventilated patients, the efficiency of aerosol delivery to the lower respiratory tract depends on several factors that are not concerns in ambulatory patients (7). Important determinants of aerosol deposition in ventilator-supported patients include the delivery system, particle size, characteristics of the ventilator circuit, ventilator mode, and patient-related factors. The effect of each factor on aerosol delivery is difficult to elucidate because of the large number of variables involved. Therefore, several investigators have conducted in vitro studies to define each variable's influence on aerosol delivery with mechanical ventilators.

In Vitro Deposition Studies

The constraints imposed by the endotracheal tube, ventilator circuit, and configuration of the ventilator breath decrease the efficiency of aerosol deposition in the lower respiratory tract of mechanically ventilated patients compared with ambulatory patients (8). In bench models of mechanical ventilation, the reported efficiency of aerosol delivery to the lower respiratory tract varies from 0 to 42% with nebulizers (9) and from 0.3 to 97.5% with MDIs (9, 13, 14), as shown in Figure 1. Several factors contribute to the wide variability in the results observed by different investigators.

View larger version (13K): [in this window] [in a new window]   Figure 1.   Range of values reported in bench models of mechanical ventilation for the lower respiratory tract delivery of aerosol generated by nebulizers (left panel, open bars) and MDIs (right panel, dark shaded bars); the range is signalled by the upper and lower limits of bars. Depending on the technique of administration, between 0 and 97.5% of the nominal dose was delivered to the lower respiratory tract (9). Delivery was greatest when an MDI was actuated into a catheter (15), since the drug was released directly at the distal end of the endotracheal tube.

Particle size. The proportion of an aerosol's particles in the respirable range (mass median aerodynamic diameter [MMAD] between 1 and 5 µm) is an important determinant of its deposition efficiency in the lower respiratory tract. Nebulizers producing aerosols with MMADs of 1-3 µm are likely to achieve greater deposition in the lower respiratory tract, because larger particles impact on the ventilator circuit and endotracheal tube (10, 17, 18). Similarly, MDI actuation into a chamber spacer placed at a distance from the endotracheal tube decreases impaction losses by reducing the velocity of the aerosol jet (19) and by decreasing the particle size. With evaporation of the propellants as the aerosol travels through air, the MMAD of the aerosol leaving the endotracheal tube is reduced to < 2 µm (13).

Characteristics of the ventilator circuit.

Heat and humidification. Gas delivered to mechanically ventilated patients is invariably heated and humidified to prevent drying the airway mucosa. However, heating and humidification of inhaled gas reduce aerosol deposition by approximately 40% (9, 10, 13, 16), as shown in Figure 2.

View larger version (18K): [in this window] [in a new window]   Figure 2.   Efficiency of aerosol delivery to the lower respiratory tract in bench models of mechanical ventilation with dry (dark shaded bars) and humidified (light shaded bars) ventilator circuits. The delivery of aerosol to the major airways is reduced by about 40% when the circuit is humidified. Numbers after the authors' names indicate the years of the studies (9, 10, 13, 16). *p < 0.05. **p < 0.01. ***p < 0.001.

Density of the inhaled gas. High inspiratory flow rates produce turbulence, and inhalation of a less dense gas, i.e., helium-oxygen, facilitates the persistence of laminar flows in the airways. Therefore, breathing helium-oxygen may improve aerosol deposition (21). Although the effects of helium-oxygen mixtures on aerosol deposition during mechanical ventilation have not been directly investigated, studies of ambulatory patients with airway obstruction reveal higher aerosol retention when breathing helium-oxygen than when breathing air (21, 22).

Position and method of connecting the aerosol generator in the ventilator circuit. Placing a nebulizer at a distance of 30 cm from the endotracheal tube is more efficient than placing it between the patient Y and the endotracheal tube, because the ventilator tubing acts as a spacer for the aerosol to accumulate in between inspirations (10, 11, 23). Addition of a spacer device between the nebulizer and the endotracheal tube increases aerosol delivery a little more (24). Operating the nebulizer during inspiration is more efficient for aerosol delivery than continuous aerosol generation (23).

Several types of commercially available adapters can be used to connect the MDI canister to the ventilator circuit. These include elbow devices that attach directly to the endotracheal tube, in-line devices placed in the inspiratory limb of the ventilator circuit, and chamber adapters such as cylindrical spacers and reservoir devices (7). Both in vitro and in vivo studies (13, 14, 25, 26) have found that the combination of an MDI and a chamber device results in a four- to six-fold greater delivery of aerosol than MDI actuation into a connector attached directly to the endotracheal tube (Figure 3) or into an in-line device that lacks a chamber (Figure 4). When the elbow adapter was connected to the endotracheal tube, actuation of an MDI out of synchrony with inspiratory airflow achieved negligible aerosol delivery to the lower respiratory tract (13). This observation may explain the lack of therapeutic effect with this type of adapter after administration of very high doses of aerosol from an MDI (2).

View larger version (25K): [in this window] [in a new window]   Figure 3.   Percent aerosol delivery at the distal end of the endotracheal tube with MDI connected to an endotracheal tube (dark shaded bar), an in-line spacer that lacks a chamber (open bar), or a cylindrical chamber placed in the inspiratory limb proximal to the Y connector (light shaded bar). Actuation of the MDI into a cylindrical chamber significantly improved aerosol delivery (p < 0.01). Data from Fuller and co-workers (26) were obtained in mechanically ventilated patients and have been corrected for tissue adsorption of radioactivity (reported values × 1.9), whereas the studies of Rau (14) and Diot (13) and their colleagues were performed in vitro. The number after each author's name indicates the year of the study. *p < 0.01. **p < 0.001.

View larger version (15K): [in this window] [in a new window]   Figure 4.   Pulmonary deposition of aerosol generated by nebulizers (left panel, open bars) and MDIs (right panel, dark shaded bars) with radiolabeled aerosols in vivo. Deposition of aerosol varied from 2.2 to 15.3% with nebulizers and from 3.2 to 10.8% with MDIs. Standard deviations from the mean are shown ( T ). The humidifier was bypassed in the study reported by O'Riordan and colleagues (31), whereas the other studies were conducted in a humidified circuit. The data from Fuller and co-investigators (26) have been corrected for tissue adsorption of radioactivity (reported value × 1.9).

Endotracheal tube size. Aerosol impaction in the endotracheal tube significantly reduces the efficiency of aerosol delivery in mechanically ventilated patients. Aerosol delivery can be improved markedly by attaching a long catheter that extends beyond the endotracheal tube to the nozzle of an MDI (15, 27). However, delivery of very high doses of aerosol directly to a circumscribed area with the catheter system may produce ulceration of the tracheal mucosa (28).

Ventilator mode and settings. In ambulatory patients, the characteristics of a breath have an important influence on aerosol deposition. Similarly, in vitro studies with models of mechanical ventilation indicate that synchronization of aerosol generation with inspiratory airflow, a tidal volume greater than 500 ml, and a longer duty cycle (TI / Ttot) are associated with greater aerosol delivery to the lower respiratory tract (10, 11, 13, 16). In the model described by Fink and colleagues (16), albuterol delivery was decreased by up to 23% during controlled mechanical ventilation compared with simulated spontaneous breaths of equivalent tidal volume. In addition, the diluent volume and the duration of treatment influenced nebulizer efficiency (10, 11). Approximately 5% of the nominal dose of albuterol administered by an MDI is exhaled in mechanically ventilated patients (29), whereas < 1% is exhaled by ambulatory patients (30). The mean exhaled fraction (7%) with nebulizers used in mechanically ventilated patients is similar to that with MDIs, but there is considerable variability (coefficient of variation, 74%) between patients (31).

Laboratory bench studies provide considerable quantitative insight into delivery of aerosol to the respiratory tract. However, the results need to be interpreted with caution because the methods employed in various studies are different, and the validity of the results depends on the extent to which the models truly replicate the in vivo situation. The use of a standardized model for in vitro studies of aerosol deposition during mechanical ventilation would greatly facilitate comparisons among the results of various investigators (16). However, in vitro studies cannot predict the site of deposition of aerosol in the respiratory tract, and they do not account for patient-related factors such as airway geometry, type and severity of pulmonary disease, and quantity of exhaled aerosol; thus, findings in bench models require validation with deposition studies conducted in vivo.

In Vivo Deposition Studies

Aerosol deposition in the lower respiratory tract can be estimated by radionuclide studies or by estimating serum levels of the active drug in the aerosol.

Radionuclide studies provide a noninvasive assessment of total and regional aerosol deposition in the lower respiratory tract. The pulmonary deposition of nebulized aerosol (Figure 4) has been variously reported to be 1.22 ± (SD) 0.4% (32), 2.22 ± 0.8% (33), 2.9 ± 0.7% (34), and 15.3 ± 9.5% (31). The variation may be attributed to differences in the type of radiolabel used, types of nebulizers employed, treatment time, humidity in the ventilator circuit, and methods used to calculate the amount of aerosol deposition (10, 31). Fuller and co-workers (26, 32) actuated an MDI containing fenoterol and sodium pertechnetate Tc 99m into a cylindrical chamber placed in the inspiratory limb of a ventilator circuit. About 6% of the dose was deposited in the lower respiratory tract (Figure 4), a value significantly lower than the approximately 24% reported with an MDI and spacer in nonintubated ambulatory patients (35).

Several in vitro model studies of an MDI and spacer revealed that the dose delivered to the lower respiratory tract (9, 13, 14, 16) is approximately five times the pulmonary deposition estimated by in vivo gamma-scintigraphic studies (32). The difference between in vivo and in vitro data may be due to humidification in the ventilator circuit. Also, the quantity of exhaled aerosol is not included in the in vitro measurement. In a bench model, we found that about 16% of the dose from an MDI was delivered to the lower respiratory tract when the ventilator circuit was humidified, and about 30% when it was not (16). In mechanically ventilated patients, we found that up to 5% of the aerosol was exhaled (29). Thus, in vitro studies indicate that about 11% (16 minus 5) of the dose from an MDI is deposited in the lower respiratory tract when using a humidified ventilator circuit, which is more than the approximately 6% found in the in vivo studies of Fuller and colleagues (32). However, Fuller's studies did not account for quenching of radioactivity by the tissues of the chest wall (26). When a correction is made for this factor, deposition in the lower respiratory tract measured in vivo is also approximately 11% (26). Thus, in vitro data obtained with humidified ventilator circuits and in vivo gamma-scintigraphic studies reveal comparable values for aerosol deposition. Moreover, the corrected values for in vivo aerosol deposition in the lower respiratory tract of mechanically ventilated patients using an MDI and spacer are remarkably close to those observed with the optimal use of an MDI without a spacer (10-14%) in ambulatory patients (35).

Unlike nonintubated patients, mechanically ventilated patients cannot receive direct deposition of aerosol in the oropharynx with subsequent enteral absorption. Therefore, estimates of serum levels of drugs administered by an MDI should reflect lower respiratory tract deposition, even though the site of aerosol deposition cannot be determined. Very low serum levels of a drug can be accurately estimated using highly sensitive assays (36). We observed that administration of albuterol with an MDI and spacer produces peak serum levels in mechanically ventilated patients that are similar to those in healthy control subjects (38), although the area under the concentration time curve was lower in the ventilated patients than in the control subjects. These findings, together with the corrected figures from radionuclide studies, have verified the somewhat decreased efficiency of aerosol deposition in the lower respiratory tract of ventilator-supported patients; nevertheless, satisfactory deposition can be obtained when the technique of administration is carefully regulated.

Increased drug deposition in the lower respiratory tract does not necessarily correlate with greater therapeutic efficacy. Several variables related to a patient's airway geometry, severity of disease, presence of mucus, the counter-regulatory effects of inflammation and other drugs, and the degree of airway responsiveness influence the therapeutic response. Therefore, it is essential to corroborate the results of deposition studies with carefully controlled clinical studies.

	EFFICACY OF BRONCHODILATORS IN MECHANICALLY VENTILATED PATIENTS

Selection of Patients

Bronchodilator therapy is commonly used in the intensive care unit (39), although the indications for its use are not well defined. Patients with chronic obstructive pulmonary disease (COPD) demonstrate a significant decrease in airway resistance after administration of bronchodilators (4, 40). Bronchodilators have been successfully used to treat acute bronchial spasm in the operating room (44), and they are widely used in mechanically ventilated patients with severe asthma (47). In addition, a heterogeneous group of mechanically ventilated patients, including some patients without a previous diagnosis of airway obstruction, have shown improvement in their expiratory airflow after bronchodilator administration (48). Although adult respiratory distress syndrome (ARDS) is primarily a disease affecting the alveoli, nebulized metaproterenol sulfate produced a decrease in airway resistance in patients with this disorder (49). The presence of airway reactivity in patients with ARDS is somewhat surprising and emphasizes the need for further studies to establish the indications for bronchodilator therapy in mechanically ventilated patients.

Assessment of the Bronchodilator Response

The assessment of the bronchodilator response can present complex and unique problems in mechanically ventilated patients (7). Because a forced expiratory maneuver is not usually possible, the FVC or FEV₁ cannot be determined for such patients. Therefore, evidence of bronchodilation is commonly determined by showing a reduction in inspiratory airway resistance, calculated by performing rapid airway occlusions at constant flow inflation (50). The airway occlusion produces an immediate drop in airway pressure (Ppeak) to a lower initial pressure (Pinit). The pressure then declines gradually to reach a plateau after 3-5 s (Pplat). The value of Pinit can be extrapolated by extending the slope of the airway pressure tracing backward to the time of airway occlusion (51). By this method, total or maximal inspiratory resistance (Rrs max) can be partitioned into minimal inspiratory resistance (Rrs min), which reflects the "ohmic" resistance of the airways, and an additional effective resistance (Rrs). The Rrs represents two phenomenatime-constant inhomogeneities within the lung ("pendelluft") and the viscoelastic behavior or stress relaxation of the pulmonary tissues (52). Similarly, airway occlusion at end exhalation produces an increase in airway pressure, and its plateau value signifies the level of intrinsic positive end-expiratory pressure (PEEP_i ) (53). From these measurements in a passively ventilated patient, respiratory mechanics can be calculated as follows:

Rrs max = (Ppeak-Pplat)/airflow

Rrs min = (Ppeak-Pinit)/airflow

Rrs = Rrs max-Rrs min

Respiratory system compliance (Crs) = Tidal Volume/(Pplat-PEEP_i ).

Decreases in Rrs max and Rrs min occur after bronchodilator administration in most mechanically ventilated patients with COPD (5, 6, 41, 42, 54). The changes in airway resistance in these studies have been mainly due to a decrease in Rrs min without much apparent effect on Rrs. The decrease in Rrs min with bronchodilator therapy and its rapid onset reflect the relaxant effect of these drugs on the bronchial smooth muscle.

Efficacy of Bronchodilators in Mechanically Ventilated Patients

The efficacy of beta-adrenergic and anticholinergic bronchodilators administered with nebulizers in mechanically ventilated patients with COPD is well established (2, 41, 43, 48, 55). In contrast, the efficacy of aerosol delivery with an MDI in mechanically ventilated patients has had a checkered history. Early studies showed promising results (40, 44). In subsequent studies, different dosages of bronchodilators and different techniques of administration were used to evaluate the efficacy of MDIs in mechanically ventilated patients, leading to variable and often contradictory results (Table 1). Manthous and colleagues (2) reported no benefit from administration of up to 100 puffs of a bronchodilator aerosol with an MDI actuated into an elbow adapter connected to the endotracheal tube. Although such adapters are used frequently (2), no study has shown therapeutic benefit when using an MDI with an elbow adapter. Recent studies, however, have clearly established the efficacy of MDIs combined with a spacer to deliver bronchodilators in mechanically ventilated patients with COPD (4).

Dose Response to Bronchodilator Administration in Mechanically Ventilated Patients

Few investigators have examined the dose response to bronchodilators in mechanically ventilated patients (2, 4, 6, 41). In seven patients with COPD receiving intravenous aminophylline, Bernasconi and colleagues found significant decreases in airway resistance with cumulative doses of 0.4, 0.8, and 1.6 mg of fenoterol administered with a nebulizer; however, the response to the higher doses was no greater than that observed with the initial dose (41). Manthous and co-workers (2) administered incremental doses of 2.5, 5.0, and 7.5 mg of albuterol by a nebulizer in 10 patients with airway obstruction. They found a significant decrease in airway resistance with the 2.5 mg dose, a tendency toward a greater effect with a cumulative dose of 7.5 mg, but no further improvement with the cumulative dose of 15 mg (2). In the same study, up to 100 puffs (10 mg) of albuterol administered with an MDI and elbow adapter did not produce any bronchodilator effect (2). Subsequently, these investigators studied the administration of 5, 10, and 15 puffs of albuterol using an MDI and cylindrical spacer (4). Cumulative doses of 15 and 30 puffs of albuterol produced a significant bronchodilator effect, and the effect was similar with either dose; the fall in airway resistance with 5 puffs was not significantly different from baseline values. In mechanically ventilated patients with COPD, we administered 4, 8, and 16 puffs of albuterol with an MDI and cylindrical spacer (6). A significant decrease in airway resistance was observed after administration of 4 puffs, with no additional effect after cumulative doses of 12 and 28 puffs (Figure 5). In a separate group of patients with COPD, the bronchodilator effect of a single dose of 4 puffs of albuterol was sustained for at least 60 min (6). In summary, when the technique of administration was carefully executed, most stable mechanically ventilated patients with COPD achieved near-maximal bronchodilation after receiving 4 puffs of albuterol. Patients with acute exacerbations of asthma or COPD may require higher doses of inhaled bronchodilators, but further studies are needed to establish a dosing schedule in such patients.

View larger version (17K): [in this window] [in a new window]   Figure 5.   Effect of albuterol on minimal inspiratory resistance (Rrs min) in 12 stable mechanically ventilated patients with COPD. Significant decreases in Rrs min occurred within 5 min of administration of 4 puffs of albuterol. The addition of 8 and 16 puffs (cumulative doses of 12 and 28 puffs, respectively) did not achieve a significantly greater effect than that with 4 puffs (p > 0.05). Bars represent SE. **p < 0.001. (Modified from Dhand and colleagues [6]. Reproduced with permission).

Choice of Inhaled Bronchodilator

Both inhaled beta-adrenergic (2, 4, 48, 55) and anticholinergic bronchodilators (40, 42) are effective in mechanically ventilated patients. Among the sympathomimetic drugs, inhaled isoproterenol hydrochloride (44, 45), isoetharine mesylate (46), metaproterenol sulfate (48), fenoterol (41), and albuterol (2, 4, 42, 55) all produce significant bronchodilation. A combination of fenoterol and ipratropium bromide was more effective than ipratropium alone in ventilator-supported patients with COPD (54).

Comparison of Metered-Dose Inhalers and Nebulizers

For ambulatory patients, nebulizers and MDIs are equally effective in treating airway obstruction. In a model of mechanical ventilation, nebulizers and MDIs delivered an equivalent mass of aerosol beyond the endotracheal tube (13), and in mechanically ventilated patients similar therapeutic effects were achieved with each device (55). However, several problems exist with the use of nebulizers. Contamination of nebulizers can lead to aerosolization of bacteria (56), and grossly negligent practices by respiratory therapy staff have led to epidemics of nosocomial pneumonia (57). Moreover, use of nebulizers requires adjustment of tidal volume and inspiratory flow to compensate for the nebulizer flow. While this is inconsequential in most adults, instances of hypoventilation have resulted in patients who are unable to trigger the ventilator during assisted modes of mechanical ventilation (58). Another shortcoming of nebulizers is the considerable variation in the efficiency of different commercial brands as well as among various batches of the same brand (59). In contrast, MDIs are easy to administer, involve less personnel time, and provide a reliable dose of the drug. Moreover, when MDIs are used with a collapsible cylindrical spacer it is not necessary to disconnect the ventilator circuit for each treatment, thereby reducing the risk of ventilator-associated pneumonia. Using MDIs instead of nebulizers results in substantial cost savings (60). Bowton and co-workers reported that more than two thirds of the respiratory treatments in their 700-bed hospital were administered to patients admitted to the intensive care units (61). They found that substituting MDIs for nebulizers could decrease potential patient costs of aerosol therapy in their hospital by $300,000 annually (61).

Aerosol Therapy in Mechanically Ventilated Neonates and Infants

In contrast to ventilation for adults, pressure-limited, time- cycled modes of mechanical ventilation are widely used in neonates and infants. Several investigators have reported that the small diameter of the endotracheal tubes and ventilator tubing and the low tidal volumes used for ventilating neonates and infants decrease aerosol delivery to the respiratory tract (17, 20, 62). Only one group of investigators has reported on the deposition of radiolabeled aerosols in mechanically ventilated infants with bronchopulmonary dysplasia (63). They found the lung deposition to be as low as 0.98 ± 0.2% and 0.22 ± 0.1% with an MDI and spacer or a jet nebulizer, respectively (63). Even such low levels of drug deposition are adequate when considered in terms of the body weight of the patient (mg of drug deposited per kg body weight). Inhaled beta-adrenergic and anticholinergic drugs (64) are effective in ventilator-supported neonates and infants with acute, subacute, and chronic lung disease. The use of inhaled corticosteroids has also been advocated in infants with bronchopulmonary dysplasia (67, 68).

	DRUG TOXICITY

Higher doses of beta-agonists delivered by an MDI can cause adverse effects because of the systemic absorption of the drug or propellants. The potential for hypokalemia and atrial and ventricular arrhythmias must be borne in mind when high doses of beta-agonists are given to critically ill patients (69- 71). Manthous and colleagues (2) observed sinus tachycardia or supraventricular ectopy following a cumulative dose of 7.5 mg of albuterol administered by a nebulizer in four of ten patients, and most of the remaining patients developed premature atrial and ventricular contractions with a cumulative dose of 15 mg (2). Although most investigators have reported no adverse effects following administration of albuterol with an MDI (2, 4, 5, 32, 42), we observed a dose-dependent increase in heart rate, which became significant after a cumulative dose of 28 puffs (6). Similarly, no significant arrhythmias or other serious cardiovascular side effects were observed in ambulatory patients in an emergency department who were treated for acute asthma with up to 16 puffs each of albuterol or fenoterol administered with an MDI attached to a holding chamber and facemask (72). Continuous nebulization of beta-adrenergic bronchodilators has been shown to be effective and safe in nonintubated children (73) and adults (74) with acute severe asthma. To our knowledge, the efficacy and safety of continuous nebulization of bronchodilator aerosols have not been evaluated in mechanically ventilated patients. A few anecdotal reports have described cardiac toxicity due to chlorofluorocarbons (CFCs), which are used as propellants in an MDI (75). Adverse cardiac effects are unlikely to occur with the doses recommended in clinical practice, particularly if there is a short interval between successive doses, because CFCs have a short half life (< 40 s) in blood of healthy volunteers (76). However, with a catheter connected to an MDI nozzle, a substantial portion of the total mass output is delivered directly on to the tracheobronchial mucosa. Because CFCs constitute most of the total mass output of an MDI (e.g., each puff of an albuterol MDI containing 100 µg of albuterol has a total mass output of 85 mg), systemic concentrations of CFCs could reach toxic levels with this delivery system. With a catheter system, significant quantities of oleic acid, a surfactant used in some MDI formulations, are also delivered to the respiratory tract; this may produce necrotizing inflammation and ulceration of the mucosa, as shown in mechanically ventilated rabbits (28).

	GUIDELINES FOR INHALED THERAPY

Both nebulizers and MDIs are effective in delivering aerosols to the lower respiratory tract of mechanically ventilated patients when careful attention is given to the technique of administration. Subtle differences in the administration method can markedly decrease aerosol deposition in the lower respiratory tract (10, 13, 16). Our strategy for bronchodilator therapy in mechanically ventilated patients with an MDI is shown in Table 2. We employed controlled mechanical ventilation (CMV) in our research studies in which the response to bronchodilator therapy was being carefully measured (5, 6), because spontaneous breathing efforts can lead to errors in the measurement of airway resistance (77). However, CMV is not a prerequisite for aerosol administration. Indeed, bench studies suggest that aerosol delivery during mechanical ventilation is improved when the aerosol is administered in synchrony with a spontaneous breath (16). Therefore, routine bronchodilator therapy can be given successfully with assisted modes of ventilation if aerosol delivery is synchronized with inspiratory airflow. Based on the recommendation for the use of MDIs in ambulatory patients, some investigators have used a postinspiratory breath hold after aerosol administration with an MDI (42, 55), but the influence of this maneuver on bronchodilator response in mechanically ventilated patients has not been evaluated. Although humidification of the circuit reduces aerosol deposition by about 40% (16), we do not recommend bypassing the humidifier because it requires disconnecting the ventilator circuit, and several minutes would be added to each bronchodilator treatment while waiting for the circuit to dry. Furthermore, even with a humidified circuit a significant effect is observed with as few as 4 puffs of a bronchodilator aerosol when MDI technique is carefully executed (6).

The method employed for administering an aerosol with a nebulizer should be close to the optimal operating characteristics of the device. The optimal fill volume, gas flow rate, and nebulization time vary considerably between nebulizers (10). At the same time, the employed ventilator strategy should not compromise the patient's respiratory mechanics. For example, increasing the duty cycle enhances aerosol deposition but it can worsen dynamic hyperinflation in patients with airflow limitation. A modification of the method recommended by Hess for the use of nebulizers in mechanically ventilated patients is shown in Table 3 (1). Some investigators (10, 31) suggest that the humidifier be bypassed during aerosol administration because of the associated decrease in aerosol deposition. However, administration of dry gas for the period of nebulization is likely to be detrimental to the airway mucosa. For routine bronchodilator treatment, we recommend using nebulizers with a humidified ventilator circuit and adjusting the dose accordingly. During nebulizer use, additional gas flow is required to generate aerosol, and appropriate ventilator adjustments in the minute volume and alarm systems must be made to avoid unexpected hypoventilation during assisted ventilation. Most modern ventilators provide inspiratory flow for a nebulizer and compensate for the additional volume and airflow in the circuit. However, the inspiratory flow provided by different ventilators is variable, and its adequacy for aerosol generation with a particular brand of nebulizer device must be checked before use.

	CONCLUSION

TOP INTRODUCTION CONCLUSION REFERENCES

The administration of inhaled drugs to mechanically ventilated patients is complicated by deposition of the aerosol particles in the ventilator circuit and endotracheal tube. Thus, aerosol deposition in the lower respiratory tract of mechanically ventilated patients is lower than that in ambulatory patients. Delivery of aerosols to mechanically ventilated patients requires attention to several variables, including the type of nebulizer used, actuation of an MDI into an in-line chamber spacer, timing of actuation, ventilator mode, tidal volume, circuit humidification, and duty cycle. With proper technique, we have shown that 4 puffs (0.4 mg) of albuterol with an MDI and spacer produce significant bronchodilation in most patients with COPD, and additive bronchodilation with higher doses is minimal (6). The bronchodilator effect obtained with 4 puffs of albuterol from an MDI is comparable to that obtained with 6 to 12 times the same dose given by a nebulizer and is likely to be far more cost-effective. In mechanically ventilated patients, MDIs offer several advantages over nebulizers for routine bronchodilator therapy.

	Footnotes

Correspondence and requests for reprints should be addressed to Rajiv Dhand, M.D., Division of Pulmonary and Critical Care Medicine, 111N, Edward Hines Jr. Veterans Affairs Hospital, Hines, IL 60141.

(Received in original form October 8, 1996 and in revised form January 27, 1997).

Acknowledgments: The authors thank James B. Fink, M.S., R.R.T., and Marilyn Smith for their help with the illustrations.

	References

TOP INTRODUCTION CONCLUSION REFERENCES

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