Aerosolized Bronchodilators in the Intensive Care Unit
Much Ado about Nothing?

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Aerosolized bronchodilators are widely used in hospitalized patients primarily because they are relatively safe and, in patients with bronchospasm, effective. In nonasthmatic patients their efficacy can be difficult to determine, and any pulmonologist can testify that metered dose inhalers (MDIs) and nebulizers are often used in spite of the absence of an obvious clinical response. In the intensive care unit (ICU), many intubated patients with obstructive lung disease have a variable response to bronchodilators. Airway reactivity and resistance potentially can be affected by many factors such as associated infections, changes in lung volume, fluid balance, and use of other drugs (-adrenergic blocking agents, steroids, etc). When compared with other drugs, bronchodilators are not expensive; however, the frequency of treatments, associated personnel requirements for delivery and monitoring, and device costs can be significant. Therefore, it is the economics of bronchodilator therapy that has brought them to the forefront of the aerosol literature, with many claims of efficiency for one device over another.

To my knowledge there is no complete study that adequately compares nebulizers with metered dose inhalers as delivery systems for bronchodilators in mechanically ventilated patients. Many articles have been written on this topic and the subject has been reviewed (1). Such a study would require a thorough understanding of the dose of the drug as well as the clinical and physiologic response; reasonable economic considerations could then be made. For aerosols, this is not easy. In clinical studies deposition of aerosol in the lung is rarely measured and the techniques can be complex. In spontaneously breathing patients, unencumbered by endotracheal tubes and ventilators, a single comparison study using different devices to treat the same patient was carried out by Zainudin and colleagues (2). They actually measured the deposition of drug following inhalation from an MDI, a dry powder inhaler (DPI), and a nebulizer in nine patients with asthma. The MDI resulted in the highest lung deposition (11.2 versus 9.1% [DPI] and 9.9% [nebulizer]). They also found that the nebulizer resulted in more peripheral deposition, but the response (assessed by spirometry) to all devices was similar. Although the efficiencies of these devices varied somewhat, their study suggests that for adult patients with asthma other considerations, such as cost and convenience, will determine which device is actually used in a given patient. In the ICU, the aerosol delivery system includes the ventilator, its tubing, and the endotrachael or tracheostomy tube. Early investigators predicted that these additional factors might prevent adequate delivery of aerosolized drug to intubated patients (3). Fortunately, they do not, except perhaps in neonates (4).

For adult patients in the ICU, the seminal papers include those by Fuller and colleagues and Manthouse and coworkers (5, 6), who performed early studies comparing MDIs with nebulizers in intubated patients. Although often quoted, both contained controversial results that affected conclusions regarding the devices used to deliver the aerosols. The results of Fuller and colleagues favored the MDI in that lung deposition was reported to be greater than that with the nebulizer (5.65 versus 1.22%); however, bronchodilation was equivalent with both devices. Manthouse and coworkers, on the other hand, found that the nebulizer (2.5 mg of albuterol) resulted in more effective bronchodilation than did albuterol via the MDI (up to 100 puffs!). These studies stimulated a flurry of research designed to rectify their differences. While many of their observations were confirmed, both studies were later shown to underestimate the delivery of some aerosols. It is likely that Fuller and colleagues underestimated the actual delivery of drug to the lung via the nebulizer (1, 7), possibly explaining why no difference in bronchodilation between devices was observed. Manthouse and colleagues used a device attached to the MDI that was later shown to prevent the delivery of any aerosol to the lung (8). Once this was recognized subsequent studies confirmed the effectiveness of the MDI plus an appropriate spacer (9, 10). On the basis of these and similar observations made by others, it has become clear that clinical trials of aerosol devices should not be carried out until their ability to deliver aerosols has been adequately demonstrated on the bench. Although bench studies measure only the quantity of aerosolized drug that would be inhaled by a patient, not the actual deposition, they can rectify differences between devices and help investigators design better clinical trials.

Where can we put the article by Guerin and coworkers (11; this issue) in the context of this history? The article has several strengths. The authors have performed bench studies indicating that actual drug delivery to the patients differed, depending on which of two devices was used. Patients inhaled approximately four times more drug from the nebulizer than from the MDI. The study compared the effects of the devices in a randomized cross-over study. Thus, both devices were studied in each patient. They used sophisticated measurements of airway resistance in an attempt to further define "response." They found differences between the response of each device, and they speculated as to the mechanism. They observed that nebulized aerosol may affect parenchymal responses whereas the MDI seemed to affect primarily airways. Their findings clinically parallel the results of Zainudin and coworkers (2), who observed more peripheral deposition after nebulized therapy. They did not measure the actual dose to the lung or the regional distribution of the deposited particles, and, in my opinion, their protocol did not really address the clinical efficacy of either form of therapy: i.e., did patients have a better outcome with one device versus the other?

Future studies of aerosolized therapy should build on our present understanding. It should be clear by now that in the proper hands both MDIs and nebulizers are effective. Past prejudices in favor of one over the other have often been based on erroneous observations and, like many other forms of therapy, a treatment regimen should be tailored to the individual patient. For example, in a responsive intubated patient only a few puffs from an MDI/spacer may be needed for effective bronchodilation (10). In a patient with status, a properly configured nebulizer can provide nearly continuous nebulization and rival 40 puffs from an MDI (8).

Topical therapy to the lungs goes far beyond bronchodilator therapy and simple bronchodilation. What is the clinical effect of these drugs on secretions and clearance? Do they help in weaning or are they reservoirs for infection? From the considerations mentioned above, it is obvious that researchers must be more sophisticated in their approaches to this subject if clinical studies are to be more revealing. Economic issues are not easily generalized and benefit from specific analysis. For example, in our ICU at Stony Brook we tend to use nebulizers for aerosol therapy because they do not require continuous attendance by the therapist. In a critically ill patient with asthma, treatment with an MDI/spacer may require frequent manual coordinated puffs. This practice can be difficult in a busy unit.

New drugs are on the horizon, and the drugs themselves will define the device for delivery. At present only nebulizers can deliver antibiotics. Corticosteroids soon will be available as powders and suspensions that can be delivered by several devices. The dose-response relationship for these aerosols will be more difficult to understand than the model provided by bronchodilators. In many patients, any conventional bronchodilator delivery system probably delivers a lung dose that is on the plateau of the dose-response curve with easily defined toxicity. The advent of more complex therapeutic aerosols with narrow dose-response/toxicity relationships will require a greater understanding of aerosol delivery both by clinical investigators and practicing pulmonary specialists. Fellowship training programs do not formally address aerosol therapy and the major societies have not updated their members with modern symposia. Intensivists are expected to be well versed in many technical areas but board examinations do not include questions about aerosol therapy. How should a delivery system be configured for a particular patient? In my opinion, we have reached the point at which the pulmonologist must be able to critically review the literature on aerosol therapy to design proper treatment protocols for his/her own ICU.

Department of MedicinePulmonary/Critical Care DivisionState University of New York at Stony BrookStony Brook, New York

	References

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1. Dhand, R., and M. J. Tobin. 1997. Pulmonary perspective: inhaled bronchodilator therapy in mechanically ventilated patients. Am. J. Respir. Crit. Care Med. 156: 3-10 [Free Full Text].

2. Zainudin, B. M. Z., M. Biddiscombe, S. E. J. Tolfree, M. Short, and S. G. Spiro. 1990. Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a pressurized metered dose inhaler, as a dry powder, and as a nebulised solution. Thorax 45: 469-473 [Abstract].

3. MacIntyre, N., R. Silver, C. Miller, F. Schuler, and E. Coleman. 1985. Aerosol delivery in intubated, mechanically ventilated patients. Crit. Care Med. 13: 81-84 [Medline].

4. O'Riordan, T. G., L. I. Kleinman, K. Hughes, and G. C. Smaldone. 1994. Predicting aerosol deposition during neonatal ventilation: feasibility of bench testing. Respir. Care 39: 1162-1168 .

5. Fuller, H. D., M. B. Dolovich, G. Posmituck, W. Wong, Pack, and M. T. Newhouse. 1990. Pressurized aerosol versus jet aerosol delivery to mechanically ventilated patients. Am. Rev. Respir. Dis. 141: 440-444 [Medline].

6. Manthous, C. A., J. B. Hall, G. A. Schmidt, and L. D. H. Wood. 1993. Metered dose inhaler versus nebulized albuterol in mechanically ventilated patients. Am. Rev. Respir. Dis. 148: 1567-1570 [Medline].

7. O'Riordan, T. G., M. J. Greco, R. J. Perry, and G. C. Smaldone. 1992. Nebulizer function during mechanical ventilation. Am. Rev. Respir. Dis. 45: 1117-1122 .

8. Diot, P., L. Morra, and G. C. Smaldone. 1995. Albuterol delivery in a model of mechanical ventilation: comparison of MDI and nebulizer efficiency. Am. J. Respir. Crit. Care Med. 152: 1391-1394 [Abstract].

9. Manthous, C. A., W. Chatila, G. A. Schmidt, and J. B. Hall. 1995. Treatment of bronchospasm by metered-dose inhaler albuterol in mechanically ventilated patients. Chest 107: 210-213 [Abstract/Free Full Text].

10. Dhand, R., A. G. Duarte, A. Jubran, J. W. Jenne, J. B. Fink, P. J. Fahey, and M. J. Tobin. 1996. Dose-response to bronchodilator delivered by metered-dose inhaler in ventilator-supported patients. Am. J. Respir. Crit. Care Med. 154: 388-393 [Abstract].

11. Guerin, C., A. Chevre, P. Dessirier, T. Poncet, M.-H. Becquemin, P. F. Dequin, C. Le Guellec, D. Jacques, and G. Fournier. 1999. Inhaled fenoterol-ipratropium bromide in mechanically ventilated patients with chronic obstructive pulmonary disease. 159:1036-1042.