Behr syndrome

Inhaled therapy has been routinely employed for over half a century in ambulatory patients with respiratory disorders. In contrast, many barriers were previously thought to preclude effective aerosol delivery in mechanically ventilated patients. The major barriers were the poor efficiency of aerosol-generating devices in ventilator circuits, inadequate understanding of the factors influencing aerosol delivery during mechanical ventilation, and mechanical ventilators that were not designed to optimize aerosol use. One by one these barriers are falling, and there is a growing potential for employing a variety of inhaled drugs in ventilatorsupported patients.

Aerosol therapy in ventilator-dependent patients is complex. Many factors influence drug deposition in the lung, and the technique of administration needs to be carefully controlled (1-6). In vitro tests played an important role in elucidating the contribution of each of a complex array of factors influencing drug delivery (1-6). There was, however, a wide discrepancy between in vitro and in vivo estimates of aerosol delivery. Some of these discrepancies have been reconciled (7, 8). For example, humidity in the ventilator circuit reduced the efficiency of aerosol delivery by 40% to 50% when compared with dry circuits (1, 5, 7). In this issue of the Journal (pp. 1205-1209), Miller and colleagues (9) correlated in vitro estimates of aerosol delivery with in vivo findings during mechanical ventilation. They tested three different ventilators and two nebulizers. The influence of various variables, such as humidified versus non-humidified circuits, continuous versus breathactuated nebulization, and bias flow versus no bias flow, on aerosol delivery was first determined in a bench model. Significant variation in albuterol delivery under the various conditions of testing was attributed mainly to contributions by humidity and breath-actuated nebulization. These same factors were then assessed in six mechanically ventilated patients receiving inhaled antibiotics (gentamicin, amikacin, and vancomycin). Paired tracheobronchial aspirates were obtained 1 to 2 hours after antibiotic administration. Humidity and breathactuated nebulization were found to account for most of the differences in antibiotic levels. Thus, the findings of in vitro tests correlated well with antibiotic levels in tracheobronchial aspirates from patients. These results (9) further emphasize the need for carefully performed in vitro tests with models that simulate conditions of clinical use. Data from such in vitro studies are very helpful in guiding aerosol therapy during mechanical ventilation.

Depending on the techniques employed, Miller and colleagues (9) found a 20-fold variation in antibiotic concentrations achieved in tracheobronchial aspirates. These findings underscore the need for carefully controlling aerosol delivery techniques, especially when drugs with a narrow safety margin are employed. Although nebulizers have been employed with positive-pressure mechanical ventilation since its inception, aerosol therapy has remained unregulated in mechanically ventilated patients. At present, nebulizers are operated either continuously by an external gas flow or intermittently by inspiratory gas flow from the ventilator. Most nebulizers that are integrated with mechanical ventilators are meant for continuous use. Similarly to previous investigators (10), Miller and colleagues (9) found that continuous nebulization was the least efficient delivery method. Although breath-actuated or intermittent nebulization is preferable, the properties of the aerosol generated and optimal techniques for intermittent nebulization are not well understood. Clearly, more needs to be done to match nebulizer and ventilator operation so that the efficiency of nebulizer systems can be improved and the amount of drug delivered to the patient better controlled.

The data of Miller and colleagues (9) indicate that breathactuated nebulization may have an even greater influence on drug delivery in vivo than is predicted on the basis of bench studies. Thus, breath-actuated nebulization produced about seven times higher antibiotic levels in tracheobronchial aspirates than did continuous nebulization. The bench model would have predicted 3.6-times greater delivery with breath-actuated versus continuous nebulization. Some of these differences in drug delivery may be related to differences in ventilatory parameters between the bench model and parameters used in patients receiving mechanical ventilation. In addition, ventilatory parameters differed between patients, and data for continuous nebulization were obtained in only two patients. While it is difficult to draw any conclusions from the observation by Miller and colleagues (9), it is conceivable that differences in aerosol delivery may be magnified during clinical use of inhalation devices. This issue certainly deserves further study in a larger group of patients.

In addition to improving the efficiency of aerosol delivery, as emphasized by Miller and colleagues (9), precise and consistent dosing is needed if antibiotics (11), surfactant (12), proslaglandins (13), hormones, mucolytics, and other immuno-modulatory peptides (14) are to be employed in ventilator-supported patients. Because the drugs mentioned above are far more expensive than bronchodilator solutions, wastage of drug in a nebulizer needs to be minimized. In addition, successful therapy with some of these agents, for example, surfactant and prostaglandins, requires targeting of aerosols to specific sites within the lung. Miller and colleagues did not find significant differences in the efficiency of aerosol delivery with the type of nebulizer employed (9). Newer generations of nebulizers, however, which have a high efficiency for drug delivery and negligible residual volume, so that they can be employed to aerosolize undiluted drugs, are now available for clinical use (15). Some of these nebulizers are specifically designed for use in ventilator circuits. Compared with conventional jet nebulizers, the high initial cost of these new devices is offset to some extent by the ability to re-use them for extended periods. These new nebulizers have significantly improved the ability to administer a variety of inhaled medications, including suspensions, liposomes, and DNA molecules, in ventilator-supported patients with an efficiency that matches or even exceeds that in ambulatory patients.

Mechanically ventilated patients present a unique opportunity to exploit the inhaled route for drug delivery. Progress has recently been made in several key areas, especially in understanding the various factors that influence aerosol delivery and deposition in ventilator-supported patients and development of new technologies for aerosol generation. Keeping these promising developments in view, it appears that aerosol therapy in the mechanically ventilated patient is now ready for prime time.

References

1. O'Riordan TG, Greco MJ, Perry RJ, Smaldone GC. Nebulizer function during mechanical ventilation. Am Rev Respir Dis 1992;145:1117-1122.

2. O'Doherty MJ, Thomas SHL, Page CJ, Treacher DF, Nunan TO. Delivery of a nebulized aerosol to a lung model during mechanical ventilation: effect of ventilator settings and nebulizer type, position, and volume of fill. Am Rev Respir Dis 1992;146:383-388.

3. O'Riordan TG, Palmer LB, Smaldone GC. Aerosol deposition in mechanically ventilated patients: optimizing nebulizer delivery. Am Rev Respir Dis 1994;149:214-219.

4. Diot P, Morra L, Smaldone GC. Albuterol delivery in a model of mechanical ventilation: comparison of metered-dose inhaler and nebulizer efficiency. Am J Respir Crit Care Med 1995;152:1391-1394.

5. Fink JB, Dhand R, Duarte AG, Jenne JW, Tobin MJ. Deposition of aerosol from metered-dose inhaler during mechanical ventilation: an in vitro model. Am J Respir Crit Care Med 1996;154:382-387.

6. Dhand R, Tobin MJ. Inhaled bronchodilator therapy in mechanically ventilated patients. Am J Respir Crit Care Med 1997;156:3-10.

7. Fink JB, Dhand R, Grychowski J, Fahey PJ, Tobin MJ. Reconciling in vitro and in vivo measurements of aerosol delivery from a metereddose inhaler during mechanical ventilation and defining efficiencyenhancing factors. Am J Respir Crit Care Med 1999;159:63-68.

8. Hess DR, Dillman C, Kacmarek RM. In-vitro evaluation of aerosol bronchodilator delivery during mechanical ventilation: pressure-control versus volume control ventilation. Intensive Care Med 2003;29:1145-1150.

9. Miller DD, Amin MM, Palmer LB, Shah AR, Smaldone GC. Aerosol delivery and modern mechanical ventilation: an in vitrolin vivo evaluation. Am J Respir Crit Care Med 2003;168:1205-1209.

10. Hughes JM, Saez J. Effects of nebulizer mode and position in a mechanical ventilator circuit on dose efficiency. Respir Care 1987;32:1131-1135.

11. Palmer LB, Smaldone GC, Simon SR, O'Riordan TG, Cuccia A. Aerosolized antibiotics in mechanically-ventilated patients: delivery and response. Crit Care Med 1998;26:31-39.

12. Anzueto A, Baughman RP, Guntupalli K, Weg JG, Wiedemann HP, Raventos AA, Lemaire F, Long W, Zaccardelli DS, Pattishall EN. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. N Engl J Med 1996;334:1417-1422.

13. Olschewski H, Simonneau G, Galie N, Higgenbottam T, Nallie R, Rubin LJ, Nikkho S, Speich R, Hoeper MM, Behr J, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-329.

14. Rubin BK. Experimental macromolecular aerosol therapy. Respir Care 2000;45:684-694.

15. Dhand R. Nebulizers that use a vibrating mesh or plate with multiple apertures to generate aerosol. Respir Care 2002;47:1406-1416.

Conflict of Interest Statement: R.D. has participated as a speaker for GlaxoSmithKline ($3,500 in 2003) and Boehringer Ingelheim ($5,000 in 2003), attended a meeting sponsored by Seprachor, Inc. ($2,500 in 2002) and Aerogen ($3,000 in 2001), and has research grants from Seprachor ($38,000) and Omron, Inc. ($140,000).

Acknowledgment: The author thanks Jim Fink and Ryan Grueber for their helpful suggestions.

RAJIV DHAND, M.D. Division of Pulmonary, Critical Care, and Environmental Medicine

University of Missouri-Columbia and Harry S. Truman VA Hospital

Columbia, Missouri

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