Humidification and noninvasive ventilation.
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Humans↗
Biomedical subjects
Gerald C Smaldone
Publications and source records attributed to Gerald C Smaldone.
A randomized trial of inhaled cyclosporine in lung-transplant recipients.
BACKGROUND: Conventional regimens of immunosuppressive drugs often do not prevent chronic rejection after lung transplantation. Topical delivery of cyclosporine in addition to conventional systemic immunosuppression might help prevent acute and chronic rejection events. METHODS: We conducted a single-center, randomized, double-blind, placebo-controlled trial of inhaled cyclosporine initiated within six weeks after transplantation and given in addition to systemic immunosuppression. A total of 58 patients were randomly assigned to inhale either 300 mg of aerosol cyclosporine (28 patients) or aerosol placebo (30 patients) three days a week for the first two years after transplantation. The primary end point was the rate of histologic acute rejection. RESULTS: The rates of acute rejection of grade 2 or higher were similar in the cyclosporine and placebo groups: 0.44 episode (95 percent confidence interval, 0.31 to 0.62) vs. 0.46 episode (95 percent confidence interval, 0.33 to 0.64) per patient per year, respectively (P=0.87 by Poisson regression). Survival was improved with aerosolized cyclosporine, with 3 deaths among patients receiving cyclosporine and 14 deaths among patients receiving placebo (relative risk of death, 0.20; 95 percent confidence interval, 0.06 to 0.70; P=0.01). Chronic rejection-free survival also improved with cyclosporine, as determined by spirometric analysis (10 events in the cyclosporine group and 20 events in the placebo group; relative risk of chronic rejection, 0.38; 95 percent confidence interval, 0.18 to 0.82; P=0.01) and histologic analysis (6 vs. 19 events, respectively; relative risk, 0.27; 95 percent confidence interval, 0.11 to 0.67; P=0.005). The risks of nephrotoxic effects and opportunistic infection were similar for patients in the cyclosporine group and the placebo group. CONCLUSIONS: Inhaled cyclosporine did not improve the rate of acute rejection, but it did improve survival and extend periods of chronic rejection-free survival. (ClinicalTrials.gov number, NCT00268515.).
Acute Disease↗
Steroid effects on mucociliary clearance in outpatient asthma.
Asthma, a chronic inflammatory condition of airways, responds to therapy with anti-inflammatory medications, for example, inhaled (ICS) and/or systemic (SS) corticosteroids. It is associated with impaired clearance of airway secretions. We studied effects of ICS and SS on mucociliary clearance (MC) in outpatient asthma through an in vivo, randomized, placebo-controlled single blind study with patients acting as their own control. Using a gamma camera and radiolabeled aerosol, we measured MC at baseline, after 4 days of nebulized treatment and after 5 days of oral prednisone. MC was expressed as percent of retained activity over time. Spirometry was performed before each MC study. Treatment with nebulized budesonide did not affect MC or forced expiratory volume at 1 sec (FEV1). Treatment with SS was associated with a significant improvement in MC at 24 h (baseline, 41 +/- 6; post-SS, 36 +/- 5; p = 0.04). Post hoc analysis revealed that MC changed only in those patients with significant changes in deposition (specific Central-to-Peripheral ratio C/P--baseline, 1.57 +/- 0.16; post-SS, 1.73 +/- 0.21; n = 6; p = 0.05), suggesting that the changes in MC were not directly related to therapy. In outpatient asthma, MC is unaffected by 4-5 days of anti-inflammatory therapy in spite of significant changes in FEV1.
Administration, Inhalation↗
Advances in aerosols: adult respiratory disease.
Recognition of the importance of breathing pattern in aerosol delivery and deposition has led to the design of devices that allow targeting of deposition to airways and alveoli. Systems incorporating patient feedback provide control of factors affecting deposition, and the control of dose to the lung can now be expected. New devices combined with a medical realization of therapeutic need are beginning to affect the range of drugs now available to the caregiver or in development for the immediate future. The interface between the patient and the device represents a new area of practical research. Facemasks have been shown to be important in terms of drug delivery with different behavior in metered dose inhaler (MDI)/valved holding chambers compared to nebulizers. Recently completed clinical trials have demonstrated the usefulness of therapy targeted to the lungs in reducing systemic toxicity with enhanced efficacy. A prime example is aerosolized cyclosporine, used to prevent rejection in lung transplantation. This agent has recently been shown to reduce mortality in transplant recipients and will lead to a new drug application in the United States. For larger patient populations, the pursuit of therapies to reduce the incidence of ventilator-associated pneumonia (VAP) can affect the outcome of illness in the intubated patient in the Intensive Care Unit (ICU). Patients with idiopathic pulmonary fibrosis (IPF) may benefit from high doses of aerosolized interferon gamma. Patient and caregiver safety are additional factors that will affect future approaches to therapy.
Administration, Inhalation↗
Variation in pediatric aerosol delivery: importance of facemask.
We have quantified in vitro the influence of the facemask on the amount of drug delivered (e.g., inhaled mass) by jet nebulizer and pressurized metered dose inhaler (pMDI) valved holding chamber (VHC) combinations (non-detergent-coated and detergent-coated). Pediatric breathing patterns were used with a breathing simulator, which was connected to a face onto which each device was positioned. An inhaled mass filter interposed between the simulator and the face captured the aerosolized drug. Budesonide inhalation suspension (0.25 mg) was used with the jet nebulizers and fluticasone propionate (220 microg) pMDI with the VHCs. Maximal drug delivery was measured using constant flow through each device. Breathing pattern effects were assessed for sealed devices (no leaks) and with facemasks (possible leaks at the facemask). Inhaled mass from both nebulizers and pMDI VHCs was affected by breathing pattern, but compared to nebulizers the pMDI VHCs were significantly more variable and sensitive to several factors. The influence of VHC conditioning combined with effects of breathing pattern resulted in the inhaled mass ranging from 0.7 +/- 0.5 to 53.3 +/- 6.2%. Nebulizers were less variable (9.6 +/- 0.7 to 24.3 +/- 3.1%). Detergent coating of VHC markedly increased the inhaled mass and reproducibility of drug delivery (27.2 +/- 1.4 to 53.3 +/- 6.2%) for pMDI VHC combinations, but these effects were lost in the presence of facemasks. Using pediatric patterns of breathing, nebulizer/facemask combinations delivered 4.1 +/- 0.8 to 19.3 +/- 2.3% of the label dose while pMDI and detergent-coated VHC delivered 4.0 +/- 1.6 to 28.6 +/- 2.5%. Facemask seal is a key factor in drug delivery. Leaks around the facemask reduce drug delivery and for pMDI VHCs can negate effects of detergent coating.
Aerosols↗
Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology.
BACKGROUND: The proliferation of inhaler devices has resulted in a confusing number of choices for clinicians who are selecting a delivery device for aerosol therapy. There are advantages and disadvantages associated with each device category. Evidence-based guidelines for the selection of the appropriate aerosol delivery device in specific clinical settings are needed. AIM: (1) To compare the efficacy and adverse effects of treatment using nebulizers vs pressurized metered-dose inhalers (MDIs) with or without a spacer/holding chamber vs dry powder inhalers (DPIs) as delivery systems for beta-agonists, anticholinergic agents, and corticosteroids for several commonly encountered clinical settings and patient populations, and (2) to provide recommendations to clinicians to aid them in selecting a particular aerosol delivery device for their patients. METHODS: A systematic review of pertinent randomized, controlled clinical trials (RCTs) was undertaken using MEDLINE, EmBase, and the Cochrane Library databases. A broad search strategy was chosen, combining terms related to aerosol devices or drugs with the diseases of interest in various patient groups and clinical settings. Only RCTs in which the same drug was administered with different devices were included. RCTs (394 trials) assessing inhaled corticosteroid, beta2-agonist, and anticholinergic agents delivered by an MDI, an MDI with a spacer/holding chamber, a nebulizer, or a DPI were identified for the years 1982 to 2001. A total of 254 outcomes were tabulated. Of the 131 studies that met the eligibility criteria, only 59 (primarily those that tested beta2-agonists) proved to have useable data. RESULTS: None of the pooled metaanalyses showed a significant difference between devices in any efficacy outcome in any patient group for each of the clinical settings that was investigated. The adverse effects that were reported were minimal and were related to the increased drug dose that was delivered. Each of the delivery devices provided similar outcomes in patients using the correct technique for inhalation. CONCLUSIONS: Devices used for the delivery of bronchodilators and steroids can be equally efficacious. When selecting an aerosol delivery device for patients with asthma and COPD, the following should be considered: device/drug availability; clinical setting; patient age and the ability to use the selected device correctly; device use with multiple medications; cost and reimbursement; drug administration time; convenience in both outpatient and inpatient settings; and physician and patient preference.
Adrenergic beta-Agonists↗
Assessing new technologies: patient-device interactions and deposition.
As our understanding of aerosol therapy matures, advances in technology afford the potential for solving the major problems in clinical aerosol delivery: control of variability in dosing, and targeting of therapy to different regions of the lung. As "interactive" devices are developed, testing on the bench becomes more sophisticated and demanding. The present review begins with simple in vitro testing techniques and addresses their ability to predict in vivo deposition. Advances in technology are reviewed and control of delivery in vivo is demonstrated.
Administration, Inhalation↗
Facemasks and facial deposition of aerosols.
Passage of aerosol around or through a facemask can result in deposition on the face and in the eyes. The present study quantified facial and eye deposition in a model simulating drug delivery to a young child. Aerosol delivery and facial deposition of radiolabeled saline test aerosols were studied in vitro with filters and a gamma camera. A child's face facsimile, attached to a piston pump, was used to simulate the patient receiving aerosol therapy. A filter placed in the oropharynx of the face facsimile measured aerosol delivery (inhaled mass). Seven commercially available facemasks in combination with three jet nebulizers were studied for aerosol delivery to the "patient" as well as for deposition on the face and in the eyes. Inhaled mass varied from 2.24-5.96% of nebulizer charge (drug placed in the nebulizer). Facial deposition varied from 0.44-2.34% of nebulizer charge, with eye deposition at 0.09-1.78%. All facemasks leaked aerosol, with significant facial and eye deposition approaching in magnitude delivery to the lung. Factors affecting facial and eye deposition include the interactive design characteristics of the facemask and nebulizer, as well as the aerodynamic properties of the aerosol.
Aerosols↗
Regional deposition of aerosolized interferon-gamma in pulmonary tuberculosis.
STUDY OBJECTIVES: Aerosol interferon-gamma (IFN-gamma) is a potential immunomodulator in the treatment of pulmonary tuberculosis (TB). Previous investigations demonstrated conversion of sputum smears in five patients with multidrug-resistant TB after 12 treatments over 1 month, and induction of signaling molecules in 10 of 11 drug-sensitive TB patients using BAL. The objective of the current study was to evaluate particle size and deposition pattern in patients with TB receiving aerosol IFN-gamma treatment. DESIGN: Particle size was determined with a cascade impactor, and deposition of IFN-gamma mixed with (99m)Tc-labeled human serum albumin was assessed using a gamma camera. Local levels of IFN-gamma were measured in BAL using enzyme-linked immunosorbent assays. Study patients/intervention: Fourteen patients with pulmonary TB received IFN-gamma aerosol (500 micro g) for 12 treatments in addition to antimycobacterial therapy with BAL before and after IFN-gamma aerosol treatment. Eight patients with minimal-to-moderate parenchymal involvement underwent deposition studies. Deposited (99m)Tc-labeled IFN-gamma aerosol was partitioned between upper airways and lungs using attenuation correction measurements. (133)Xe equilibrium scanning, (133)Xe washout, and (99m)Tc- macroaggregate injection defined regional lung volume, ventilation, and perfusion. RESULTS: Upper airway deposition was significant often exceeding lung deposition (53.9 +/- 7.09 micro g vs 35.8 +/- 2.73 micro g, respectively [mean +/- SE]). IFN-gamma levels measured in BAL fluid were significantly increased with aerosol treatment (0.83 +/- 0.43 micro g before vs 24.76 +/- 8.71 micro g after, p </= 0.017), and IFN-gamma levels correlated with regional deposition of IFN-gamma aerosol (r = 0.823). Four-quadrant analysis of regional lung deposition best correlated with regional perfusion (r = 0.422, p = 0.013) with penetration of aerosol into areas of obvious radiographic infiltration on chest radiograph. CONCLUSIONS: Aerosol therapy with IFN-gamma in patients with pulmonary TB is widely distributed and results in significant enhancement of IFN-gamma levels in the lower respiratory tract. In patients without lung destruction, IFN-gamma aerosol may be an adjuvant to enhance the local immune response.
Administration, Inhalation↗
Aerosolized antibiotics in mechanically ventilated patients.
Aerosolized antibiotics are potentially useful in intensive care. At State University of New York at Stony Brook we developed a human model of tracheobronchitis in intubated patients. The model provides daily specimens of airway secretions, allowing serial studies of airway inflammation and testing of therapy modes. The presence of local infection is defined by a unique method of quantified sputum collection. Bench models have been developed that illustrate the factors that limit aerosol delivery to intubated patients. With those models clinical trials have defined possible indications for targeted aerosol therapy to patients at risk for deep lung infection. An efficient aerosolized-antibiotics method that delivers the aerosol past the endotracheal tube has been established, and with that method the drug levels in pulmonary secretions exceed by several orders of magnitude the levels expected with intravenous therapy. Potential end points of therapy are being evaluated, including the rate of bacterial resistance and the incidence and definition of deep lung infection.
Administration, Inhalation↗
Aerosol delivery and modern mechanical ventilation: in vitro/in vivo evaluation.
Aerosol delivery via a mechanical ventilator remains unregulated with no standards for drug delivery to intubated patients. Bench models predicting drug delivery have not been validated in vivo. For modern ventilator designs, we chose to identify, on the bench, the most important variables affecting aerosol delivery and to correlate in vitro predictions of aerosol delivery with in vivo end points independent of patient response. Test aerosols of albuterol and antibiotics were compared. Bench measurements of inhaled mass (percentage of nebulizer charge, mean +/- SEM) ranged from 5.7 +/- 0.5% to 37.4 +/- 1.6%, with breath-actuated nebulization and humidity identified as the most important factors determining aerosol delivery. In patients, sputum levels of deposited antibiotics varied from 1.10 to 19.6 microg/ml/mg. Variation in sputum levels correlated with predictions from the in vitro model. Aerosol delivery in ventilated patients can be efficient and reproducible only if defined ventilator parameters are tightly controlled. Key parameters can be determined via in vitro bench testing defining delivery standards for clinical trials of drugs with narrow therapeutic/toxicity ratios.
Administration, Inhalation↗
Lung deposition and pharmacokinetics of cyclosporine after aerosolization in lung transplant patients.
PURPOSE: Aerosolized cyclosporine (aCsA) has proven to be an effective therapy for refractory acute and chronic rejection in lung transplant (LTx) patients. The objective of this study is to evaluate the lung deposition and systemic absorption of aCsA after aerosolized cyclosporine administration in LTx patients in the immediate postoperative period. METHOD: Cyclosporine (CsA) was administered intravenously (1.0 mg/kg) to eight LTx patients, and multiple blood samples were collected over 24 h. At least 24 h later, aCsA (300 mg in propylene glycol) was administered to the same patients using nebulization and multiple blood samples were obtained again. Five patients had an additional inhalational gamma scintigraphy study with aCsA and 99MTc-labeled albumin to measure drug deposition. RESULTS: Peak blood concentrations of CsA after aerosol administration ranged from 119-402 ng/ml, and concentrations at 24 h ranged from 9-48 ng/ml. The rate of decline in drug concentration in blood in the apparent elimination phase was notably slower after administration of aCsA than after IV infusion. Terminal disposition half life (t 1/2 lambda(z)) values ranged from 4.1-9.9 h (mean 6.5 h) following IV administration and from 23.1 to 65.2 h (mean 40.7 h) following pulmonary administration, suggesting that drug absorption occurred throughout the 24-h sampling period following pulmonary administration. Deconvolution analysis indicated biphasic absorption of CsA from the lung in all patients, characterized by rapid initial absorption (absorption half-life 0.73 +/- 0.38 h) over the first 4 to 6 h followed by slower, sustained absorption throughout the remainder of the sampling period (absorption half-life 16.2 +/- 13.2 h). The absolute bioavailability of CsA after aerosol administration ranged from 5.4-11.2% (mean 8.2%) of the dose placed in the nebulizer. The total dose delivered to the lung estimated from scintigraphy ranged from 17.8-39.3 mg, and was in approximate agreement with the amount of drug absorbed, estimated using deconvolution. Essentially all drug deposited in the lungs was systemically absorbed. CONCLUSIONS: This study documents that cyclosporine can be effectively delivered by aerosolization to the lung of transplant patients in the early postoperative period. Part of the cyclosporine deposited in the lung is absorbed rapidly into systemic circulation and a portion is absorbed slowly but completely over a prolonged period.
Administration, Inhalation↗
Lung deposition and respirable mass during wet nebulization.
For metered dose inhalers (MDIs), high-flow cascade impaction with a United States Pharmacopia (USP) throat provides a useful prediction of in vivo lung and oropharyngeal aerosol deposition. Particles expected to deposit in the lung are included in the "fine particle fraction" measured on the bench. Comparable in vitro standards are not available for nebulizers. The present study compared aerosol deposition in an in vitro model using low-flow cascade impaction with deposition in vivo in human subjects. A low-flow (1 Lmin), 10-stage cascade impactor measured aerodynamic distributions of aerosolized interferon-gamma (IFN-gamma) from two nebulizers (Misty-Neb and AeroEclipse). (99m)Technetium diethylene triaminepenta-acetic acid ((99m)Tc-DTPA) was used as the radiolabel. Two bench conditions were specified: no breathing (standing cloud) and simulated ventilation with a piston pump (tidal volume 750 mL frequency 25 per minute and duty cycle 0.5). Mass median aerodynamic diameter (MMAD) for both nebulizers was affected by ventilation (Misty-Neb vs. AeroEclipse: 5.2 vs. 4.6 microm for standing cloud and 3.1 vs. 2.2 microm during ventilation). In three subjects, measured values of oropharyngeal deposition averaged 68.1 +/- 0.08% for Misty-Neb and 30.9 +/- 0.03% for AeroEclipse. In vivo deposition patterns compared to aerosol distributions from both nebulizers indicated that, for wet nebulization, penetration of aerosol beyond the upper airways (fine particle fraction) will occur only for aerosol particles below 2.5 microm. This assessment requires that the bench aerosol distribution be measured under conditions of clinical use (i.e., during tidal breathing).
Administration, Inhalation↗
Effect of tubing deposition, breathing pattern, and temperature on aerosol mass distribution measured by cascade impactor.
Aerosols produced by nebulizers are often characterized on the bench using cascade impactors. We studied the effects of connecting tubing, breathing pattern, and temperature on mass-weighted aerodynamic particle size aerosol distributions (APSD) measured by cascade impaction. Our experimental setup consisted of a piston ventilator, low-flow (1.0 L/min) cascade impactor, two commercially available nebulizers that produced large and small particles, and two "T"-shaped tubes called "Tconnector(cascade)" and "Tconnector(nebulizer)" placed above the impactor and the nebulizer, respectively. Radiolabeled normal saline was nebulized using an airtank at 50 PSIG; APSD, mass balance, and Tconnector(cascade) deposition were measured with a gamma camera and radioisotope calibrator. Flow through the circuit was defined by the air tank (standing cloud, 10 L/min) with or without a piston pump, which superimposed a sinusoidal flow on the flow from the air tank (tidal volume and frequency of breathing). Experiments were performed at room temperature and in a cooled environment. With increasing tidal volume and frequency, smaller particles entered the cascade impactor (decreasing MMAD; e.g., Misty-Neb, 4.2 +/- 0.9 microm at lowest ventilation and 2.7 +/- 0.1 microm at highest, p = 0.042). These effects were reduced in magnitude for the nebulizer that produced smaller particles (AeroTech II, MMAD 1.8 +/- 0.1 to 1.3 +/- 0.1 microm; p = 0.0044). Deposition on Tconnector(cascade) increased with ventilation but was independent of cascade impactor flow. Imaging of the Tconnector(cascade) revealed a pattern of deposition unaffected by cascade impactor flow. These measurements suggest that changes in MMAD with ventilation were not artifacts of tubing deposition in the Tconnector(cascade). At lower temperatures, APSD distributions were more polydisperse. Our data suggest that, during patient inhalation, changes in particle distribution occur that are related to conditions in the tubing and may reduce the diameters of particles entering the patient. This effect is more significant for nebulizers producing large particles. Changes in ambient temperature did not affect these observations.
Administration, Inhalation↗
Smart nebulizers.
Physicians are familiar with conventional nebulizers, which deliver aerosols in a relatively uncontrolled manner. As aerosol medications evolve beyond bronchodilators, the need for control of dose variability, the possibility of overdose, and the need for efficient delivery have provoked the industry to redesign aerosol delivery systems. The need to target aerosol delivery to specific lung regions has focused efforts to coordinate aerosol delivery with defined breathing maneuvers. This review summarizes the major factors affecting aerosol deposition, discusses how those factors are guiding new designs for aerosol delivery systems, and describes some examples of the improved precision and efficiency of those systems.
Administration, Inhalation↗