James B. Fink

Aerosol Deposition in Neonatal Ventilation

Lung deposition of inhaled drugs in ventilated neonates has been studied in models of questionable relevance. With conventional nebulizers, pulmonary deposition has been limited to 1% of the total dose. The objective of this study was to assess lung delivery of aerosols in a model of neonatal ventilation using a conventional and novel electronic micropump nebulizer. Aerosol deposition studies with 99mTc diethylenetriamine pentaacetate (99mTc-DTPA) were performed in four macaques (2.6 kg) that were ventilated through a 3.0-mm endotracheal tube (with neonatal settings (peak inspiratory pressure 12–14 mbar, positive end-expiratory pressure 2 mbar, I/E ratio 1/2, respiratory rate 40/min), comparing a jet-nebulizer MistyNeb (3-mL charge, 4.8 μm), an electronic micropump nebulizer operating continuously [Aeroneb Professional Nebulizer (APN-C); 0.5-mL charge, 4.6 μm], and another synchronized with inspiration [Aeroneb Professional Nebulizer Synchronized (APN-S); 0.5-mL charge, 2.8 μm]. The amount of radioactivity deposited into lungs and connections and remaining in the nebulizer was measured by a gamma counter. Despite similar amounts of 99mTc-DTPA in the respiratory circuit with all nebulizers, both APN-S and APN-C delivered more drug to the lungs than MistyNeb (14.0, 12.6, and 0.5% in terms of percentage of nebulizer charge, respectively; p = 0.006). Duration of delivery was shorter with APN-C than with the two other nebulizers (2 versus 6 and 10 min for the APN-S and the MistyNeb, respectively; p < 0.001). Electronic micropump nebulizers are more efficient to administer aerosols in an animal model of ventilated neonates. Availability of Aerogens electronic micropump nebulizers offers new opportunities to study clinical efficacy and risks of aerosol therapy in ventilated neonates.

Inhalation Therapy in Patients Receiving Mechanical Ventilation: An Update

Incremental gains in understanding the influence of various factors on aerosol delivery in concert with technological advancements over the past 2 decades have fueled an ever burgeoning literature on aerosol therapy during mechanical ventilation. In-line use of pressurized metered-dose inhalers (pMDIs) and nebulizers is influenced by a host of factors, some of which are unique to ventilator-supported patients. This article reviews the impact of various factors on aerosol delivery with pMDIs and nebulizers, and elucidates the correlation between in-vitro estimates and in-vivo measurement of aerosol deposition in the lung. Aerosolized bronchodilator therapy with pMDIs and nebulizers is commonly employed in intensive care units (ICUs), and bronchodilators are among the most frequently used therapies in mechanically ventilated patients. The use of inhaled bronchodilators is not restricted to mechanically ventilated patients with chronic obstructive pulmonary disease (COPD) and asthma, as they are routinely employed in other ventilator-dependent patients without confirmed airflow obstruction. The efficacy and safety of bronchodilator therapy has generated a great deal of interest in employing other inhaled therapies, such as surfactant, antibiotics, prostacyclins, diuretics, anticoagulants and mucoactive agents, among others, in attempts to improve outcomes in critically ill ICU patients receiving mechanical ventilation.

In vitro comparison of heliox and oxygen in aerosol delivery using pediatric high flow nasal cannula

Drug administration via high flow nasal cannula (HFNC) has been described in pediatrics but the amount of albuterol delivery with an HFNC is not known. The purpose of this study is to quantify aerosol delivery with heliox and oxygen (O2) in a model of pediatric ventilation. A vibrating mesh nebulizer (Aeroneb Solo, Aerogen) was placed on the inspiratory inlet of a heated humidifier and heated wire circuit attached to a pediatric nasal cannula (Optiflow, Fisher & Paykel). Breathing parameters were tidal volume (Vt) 100 ml, respiratory rate (RR) 20/min, and I‐time of 1 sec. Albuterol sulfate (2.5 mg/3 ml) was administered through a pediatric HFNC with O2 (100%) and heliox (80/20% mixture). A total of 12 runs, using O2 and heliox were conducted at 3 and 6 L/min (n = 3). Drug was collected on an absolute filter, eluted and measured using spectrophotometry. The percent inhaled dose (mean ± SD) was similar with heliox and O2 at 3 L/min (11.41 ± 1.54 and 10.65 ± 0.51, respectively; P = 0.465). However at 6 L/min drug deposition was ≥2‐fold greater with heliox (5.42 ± 0.54) than O2 (1.95 ± 0.50; P = 0.01). Using a pediatric model of HFNC, reducing delivered flow from 6 to 3 L/min increased inhaled albuterol delivery ≥2‐fold but eliminated the increase in inhaled drug efficiency associated with heliox. Pediatr. Pulmonol. 2011; 46:795–801.

Consensus statement: aerosols and delivery devices.

MYRNA B. DOLOVICH, P.Eng., NEIL R. MacINTYRE, F.A.A.R.C, PAULA J. ANDERSON, M.D., CARLOS A. CAMARGO, JR., M.D., Dr.P.H, NANCY CHEW, M.S., R.A.C., CYNTHIA H. COLE, M.D., M.P.H., RAJIV DHAND, M.D., JAMES B. FINK, M.S., R.R.T., F.A.A.R.C., NICHOLAS J. GROSS, M.D., Ph.D., DEAN R. HESS, Ph.D., R.R.T., F.A.A.R.C, ANTHONY J. HICKEY, Ph.D., CHONG S. KIM, Ph.D., TED B. MARTONEN, Ph.D., DAVID J. PIERSON, M.D., F.A.A.R.C, BRUCE K. RUBIN, M.D., and GERALD C. SMALDONE, M.D., Ph.D.

Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial

IntroductionProlonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation.MethodsFifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomized placebo-controlled trial of nebulized heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomization.ResultsNebulized heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point, ventilator-free days amongst survivors at day 28 (22.6 ± 4.0 versus 18.0 ± 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events.ConclusionsNebulized heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings.Trial registrationThe Australian Clinical Trials Registry (ACTR-12608000121369).

Selecting an accessory device with a metered-dose inhaler: variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler.

Accessory devices reduce common problems with metered-dose inhalers (MDIs), namely high oropharyngeal deposition of aerosol and incoordination between actuation and inhalation by the patient. The objective of this study was to systematically compare the performance of various accessory devices in vitro. MDIs were tested alone or in combination with four spacers (Toilet paper roll, Ellipse, Optihaler, Myst Assist) and five holding chambers (Aerochamber, Optichamber, Aerosol Cloud Enhancer, Medispacer, and Inspirease). An Anderson cascade impactor was used to measure aerosol mass median aerodynamic diameter (MMAD) and fine particle dose (MMAD < 4.7 microm). In separate experiments, the influence of asynchronous MDI actuation on drug delivery was determined with a simulated spontaneous breathing model. Compared with the MDI alone, all of the accessory devices reduced aerosol MMAD and increased lung-throat ratio (fine particle dose/throat impaction; p < 0.05 for both parameters). The fine particle dose of albuterol was 40% higher with the Ellipse (p < 0.01), was equivalent with the Toilet Paper Roll, Aerochamber, Optichamber, and Medispacer, and was 33-56% lower with the Optihaler, Myst Assist, Aerosol Cloud Enhancer, and Inspirease (p < 0.03). MDI actuation in synchrony with inspiration produced highest drug delivery; when MDI actuation occurred 1-sec before inspiration or during exhalation, decrease in drug delivery with holding chambers (10-40% reduction) was less than that with spacers (40-90% reduction). Accessory device selection is complicated by variability in performance between devices, and in the performance of each device in different clinical settings. In vitro characterization of a MDI and accessory device could guide appropriate device selection in various clinical settings.

Inhalation therapy during mechanical ventilation

An increasing number of pharmacologic agents, including bronchodilators, prostaglandin, proteins, surfactant, mucolytics, and antibiotics are administered to mechanically ventilated patients by the inhalation route. To achieve a therapeutic effect, adequate amounts of an inhaled agent must be delivered to the desired site of action. The delivery of inhaled drugs to the lower respiratory tract of mechanically ventilated patients is complicated by deposition of the aerosol particles in the ventilator circuit and endotracheal tube, and the factors governing pulmonary deposition in mechanically ventilated patients are different from those in ambulatory patients. Meticulous adherence to several steps in the technique of aerosol administration is necessary for successful aerosol therapy in mechanically ventilated patients. With a proper technique of administration, an increasing number of inhaled drugs may be administered safely, conveniently, and effectively to mechanically ventilated patients.

An inhaled matrix metalloprotease inhibitor prevents cigarette smoke-induced emphysema in the mouse.

Inadequately regulated proteolytic activity is responsible for the chronic lung tissue degeneration and irreversible loss of pulmonary function that define emphysema. In this study, we show that an inhaled broad-spectrum matrix metalloprotease inhibitor, ilomastat, can provide protection against the development of emphysema in cigarette smoke-treated mice. Control animals were exposed to daily cigarette smoke for 6 months. As has been reported previously, cigarette smoke was seen to increase significantly the recruitment of macrophages into the lungs of these animals, leading to concomitant alveolar airspace enlargement and emphysema. In animals treated daily with nebulized ilomastat for 6 months, lung macrophage levels were greatly reduced, and neutrophil accumulation was also inhibited. Corresponding reductions in airspace enlargement of up to 96% were observed. These striking observations suggest that delivery of ilomastat directly into the lungs of smoke-treated mice can not only inhibit lung tissue damage mediated by metalloproteases, but may also reduce that component of tissue degeneration mediated by excess neutrophil-derived products. Our data also suggest that the matrix metalloprotease inhibitors may represent a class of drugs that, when delivered by inhalation, could be used practically to treat cigarette smoking-related chronic obstructive pulmonary disease by modifying the course of the disease.

An In Vitro Evaluation of Aerosol Delivery Through Tracheostomy and Endotracheal Tubes Using Different Interfaces

BACKGROUND: Previous research reporting factors influencing aerosol delivery in intubated patients has been largely focused on the endotracheal tube (ETT) during mechanical ventilation, with little comparative analysis of effect of types of artificial airways and their interfaces on aerosol delivery during spontaneous breathing. The purpose of this study was to compare aerosol delivery via tracheostomy tube (TT) and ETT, using interfaces such as T-piece, tracheostomy collar, and manual resuscitation bag. METHODS: A teaching manikin was intubated with either an ETT (8.0 mm inner diameter) and TT (8 mm inner diameter). Both bronchi were connected to a collecting filter, attached to a sinusoidal pump simulating the breathing pattern of a spontaneously breathing adult (tidal volume 450 mL, respiratory rate 20 breaths/min, inspiratory-expiratory ratio 1:2). Albuterol sulfate (2.5 mg/3 mL) was nebulized through a jet nebulizer, using each airway and interface as appropriate (n = 3). Drug on the filter was eluted and analyzed with spectrophotometry, and expressed as mean percent of loaded dose delivered. Descriptive statistics, the Student t test, and one-way analysis of variance were applied. RESULTS: A greater percentage of nominal dose was delivered via TT than ETT with both T-piece (13.79 ± 2.59% vs 9.05 ± 0.70%) and manual resuscitation bag (45.75 ± 1.8% vs 27.23 ± 8.98%, P = .038 and P = .025, respectively). Use of manual resuscitation bag with both TT and ETT increased lung dose more than 3-fold. Inhaled dose with tracheostomy collar was (6.92 ± 0.81%) less than T-piece with TT (P = .01). CONCLUSION: In this adult model of spontaneous ventilation, aerosol therapy through ETT was less efficient than TT, while the manual resuscitation bag was more efficient than T-piece or tracheostomy collar.

Factors affecting bronchodilator delivery in mechanically ventilated adults

BACKGROUND Bronchodilators are increasingly being used in patients undergoing mechanical ventilation. There are multiple factors that affect bronchodilator delivery during mechanical ventilation. These factors can be classified into three categories: ventilator-related factors, circuit-related factors and device-related factors. AIMS The purpose of this paper is to review in depth each of the factors affecting bronchodilator delivery during mechanical ventilation. SEARCH STRATEGIES A literature search was undertaken using several databases including Cochrane, Pubmed, Medline, Cinahl and Science Direct. The literature search, although limited to the English language, covered materials from 1985 to May 2009. CONCLUSION Aerosolized bronchodilator delivery to mechanically ventilated patients is complex as a result of the multiple factors that affect the amount of aerosol deposited in the lower respiratory tract. When these factors are not carefully controlled and the optimum technique for aerosol delivery is not utilized, a greater proportion of the aerosol will deposit in the ventilator circuits and artificial airways decreasing the available dose to the patient. Attention to these factors and optimizing aerosol delivery techniques will help to reach therapeutic endpoints of bronchodilator therapy in patients receiving ventilatory support. RELEVANCE TO CLINICAL PRACTICE Bronchodilator delivery during mechanical ventilation is factor and technique dependent. A clear understanding of the factors affecting aerosol drug delivery during mechanical ventilation is very important in optimizing the efficiency of bronchodilator delivery in mechanically ventilated adults. Through the recommendations made in this paper, clinicians will be able to optimize both their technique and the therapeutic outcomes of aerosol drug delivery in patients receiving ventilator support.