What the pulmonary specialist should know about the new inhalation therapies.

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patient's inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.

Experimental and theoretical screening of nanoscale oxide reactivity with LiBH4.

Experimentation, thermodynamic modeling, and atomic modeling were combined to screen the reactivity of SiO2, Al2O3, and ZrO2 nanoscale oxides with LiBH4. Equilibrium thermodynamic modeling showed that the reactions of oxides with LiBH4 could lead to formation of stable Li-bearing oxide and metal boride phases. Experimentation was conducted to evaluate the discharge/recharge reaction products of nanoscale oxide-LiBH4 mixtures. Thermal gravimetric analyses-mass spectroscopy and x-ray diffraction revealed significant SiO2 destabilization of LiBH4 dehydrogenation, resulting in the formation of lithium silicate and boric acid. A smaller amount of lithium metaborate and boric acid was formed with Al2O3. No destabilization products were observed with ZrO2. Density functional theory atomic modeling predicted much stronger LiBH4 interfacial adsorption on the SiO2 and Al2O3 surfaces than on the ZrO2 surface, which was consistent with the experimental findings. Following dehydrogenation, interfacial Li atoms were predicted to strongly adsorb on the oxide surfaces effectively competing with LiH formation. The interfacial Li interactions with Al2O3 and ZrO2 were equal in strength in the fully hydrided and dehydrided states, so that their predicted net effect on LiBH4 dehydrogenation was insignificant. Zirconia was selected for nanoframework development based on the combined observations of compatibility and weaker associative interactions with LiBH4.

Simplified assessment of fine aerosol distribution in human airways.

We characterized homogeneity of bronchopulmonary distribution of a 0.9% saline aerosol with a mass median aerodynamic diameter (MMAD) of 1.12 micron (sigma g = 2.04) labeled with [99mTc]sulfur colloid in nine normal subjects and nine patients with asthma. Aerosol distribution was quantified from frequency distribution histograms generated from Anger camera scans. Skew (a measure of histogram asymmetry) and kurtosis (a measure of histogram range) were significantly elevated (p less than 0.05) in the asthma patients with 0.68 +/- 0.30 and 2.62 +/- 0.81, respectively, compared with 0.39 +/- 0.12 and 1.89 +/- 0.18, respectively, in the normal subjects. Skew and kurtosis were significantly correlated with baseline forced expiratory volume in 1 sec (FEV1, an index of airway obstruction) with rs = -0.4799 (p less than 0.05) and -0.5929 (p less than 0.01), respectively. Skew and kurtosis were also significantly correlated with mucociliary clearance after approximately 90 min (an index of large, central airway deposition) with rs = 0.6801 and 0.6373, respectively (p less than 0.01). This simplified method of analysis does not require additional study days or procedures and facilitates the detection of airflow obstruction in asthma.

Regional deposition of inhaled fog droplets: preliminary observations.

The regional deposition of a monodisperse 10-micron mass median aerodynamic diameter fog was studied in four healthy adult male nonsmokers. The fog was radiolabeled with technetium-99m sulfur colloid to enable detection by an Anger camera of deposited activity in the following regions of the respiratory tract: oropharynx, larynx, trachea, and intrapulmonary airways. Intrapulmonary deposition was further analyzed by computer with inner, intermediate, and outer zones, and within apical, intermediate and basal zones of the right lung. The radiolabeled aerosol was inhaled by mouth through a face-mask with the nasal airway occluded. Respiratory frequency, tidal volume, and jaw position were controlled and were commensurate with the oral component of oronasal breathing during moderate exercise. Deposition in the larynx, trachea, and intrapulmonary airways was a function of the scrubbing efficiency of the oropharynx, which differed substantially among subjects, and ranged from 72 to 99%. The density of the aerosol deposit in the larynx probably exceeded that of any of the subdivisions of the tracheobronchial tree and lung. Within the lung, deposition favored the inner zone (assumed to contain the larger airways) over the outer zone (assumed to be dominated by smaller airways and alveoli). Intrapulmonary aerosol distribution in an elderly subject with borderline evidence of airway obstruction differed from that observed in younger subjects. The possible consequences of altered lung elastic recoil, as may occur with aging, for regional dosimetry is discussed.

Treating diabetes with aerosolized insulin.

Because of the pain, inconvenience, and disruption of lifestyle associated with the injection of insulin, many patients with diabetes are noncompliant in terms of treatment regimens that require daily multiple injections. To eliminate the pain and to improve treatment outcome, there has been increasing interest in the development of aerosolized insulin to replace subcutaneously (SC) delivered formulations. Recent studies in human volunteers have shown that when aerosolized insulin is effectively delivered to the alveolar region of the lung, absorption rates and decreases in glucose levels are similar to those achieved with SC-delivered insulin during the fasting state. Other human trials have shown that inhaled insulin also effectively controls postprandial glucose levels. Aerosolized insulin is well-tolerated, and there is no evidence of irritation, hypoglycemia, or changes in pulmonary function when administered over short periods. At present, limitations in the delivery device result in less efficient administration of insulin aerosol compared to SC dosing. However, new devices and different formulations of insulin, which are currently under development, should improve the efficiency. It is likely that the treatment of diabetes with aerosolized insulin will provide an effective alternative means for controlling plasma glucose levels in diabetic individuals. Aerosolized insulin also will serve as a developmental model for this route of administration for a number of other therapeutic peptides that are currently administered by injection only.

Bronchodilator pretreatment improves aerosol deposition uniformity in HIV-positive patients who cough while inhaling aerosolized pentamidine.

OBJECTIVE: To determine the effect of bronchodilator pretreatment on deposition uniformity of aerosolized pentamidine (AP) in HIV-positive patients who coughed while inhaling AP. DESIGN: Nonrandomized control trial. SETTING: A university hospital. PATIENTS: Ten HIV-positive patients who were using AP prophylactically. INTERVENTION: Four patients who coughed during AP administration were pretreated with 10 mg metaproterenol aerosol prior to a second inhalation of AP. MEASUREMENTS: Skew, a measure of overall deposition symmetry, deposition in the apex vs the base of the right lung (A:B ratio), and percentage of change from baseline in peak expiratory flow rate (PEFR). RESULTS: At baseline, the average (+/- SD) skew value for four subjects who coughed (0.89 +/- 0.19) was significantly higher than for six control subjects (0.58 +/- 0.07) (p < 0.01), indicating enhanced nonuniformity of AP distribution. After bronchodilator, no one coughed and the average skew value was normalized to 0.57 +/- 0.13. The A:B ratios at baseline and after metaproterenol were not significantly different, suggesting that deposition of AP in the apex, relative to basal deposition, was not enhanced by bronchodilator treatment. When no bronchodilator was administered, average PEFR decreased to 330 +/- 162 from baseline (410 +/- 84). Average PEFR increased to 429 +/- 85 from baseline (395 +/- 116) after bronchodilator pretreatment. CONCLUSIONS: These results suggest that in addition to relieving cough in patients receiving AP prophylactically, pretreatment with metaproterenol enhances uniformity of distribution of AP and improves PEFR.

Gene therapy in cystic fibrosis.

Theoretically, cystic fibrosis transmembrane conductance regulator (CFTR) gene replacement during the neonatal period can decrease morbidity and mortality from cystic fibrosis (CF). In vivo gene transfers have been accomplished in CF patients. Choice of vector, mode of delivery to airways, translocation of genetic information, and sufficient expression level of the normalized CFTR gene are issues that currently are being addressed in the field. The advantages and limitations of viral vectors are a function of the parent virus. Viral vectors used in this setting include adenovirus (Ad) and adeno-associated virus (AAV). Initial studies with Ad vectors resulted in a vector that was efficient for gene transfer with dose-limiting inflammatory effects due to the large amount of viral protein delivered. The next generation of Ad vectors, with more viral coding sequence deletions, has a longer duration of activity and elicits a lesser degree of cell-mediated immunity in mice. A more recent generation of Ad vectors has no viral genes remaining. Despite these changes, the problem of humoral immunity remains with Ad vectors. A variety of strategies such as vector systems requiring single, or widely spaced, administrations, pharmacologic immunosuppression at administration, creation of a stealth vector, modification of immunogenic epitopes, or tolerance induction are being considered to circumvent humoral immunity. AAV vectors have been studied in animal and human models. They do not appear to induce inflammatory changes over a wide range of doses. The level of CFTR messenger RNA expression is difficult to ascertain with AAV vectors since the small size of the vector relative to the CFTR gene leaves no space for vector-specific sequences on which to base assays to distinguish endogenous from vector-expressed messenger RNA. In general, AAV vectors appear to be safe and have superior duration profiles. Cationic liposomes are lipid-DNA complexes. These vectors generally have been less efficient than viral vectors but do not stimulate inflammatory and immunologic responses. Another challenge to the development of clinically feasible gene therapy is delivery mode. Early pulmonary delivery systems relied on the direct instillation of aerosolized vectors, which can result in the induction of adverse reactions because vector is delivered into the lung parenchyma. More recent studies have examined the potential for using spray technologies to target aerosolized AAV vectors to the larger central airways, thereby avoiding alveolar exposure and adverse effects. Comparisons of lung deposition with nebulized delivery of aerosol and spray delivery indicate that spraying results in a more localized deposition pattern (predominantly in the proximal airways) and significantly higher deposition fractions than nebulization. These findings could lead to more efficient and targeted lung delivery of aerosolized gene vectors in the future.

Targeting aerosol deposition in patients with cystic fibrosis: effects of alterations in particle size and inspiratory flow rate.

STUDY OBJECTIVE: To determine if aerosolized medications can be targeted to deposit in the smaller, peripheral airways or the larger, central airways of adult cystic fibrosis (CF) patients by varying particle size and inspiratory flow rate. DESIGN: Randomized clinical trial. SETTING: Outpatient research laboratory. PATIENTS: Nine adult patients with CF. INTERVENTIONS: Patients inhaled an aerosol comprised of 3.68+/-0.04 microm saline solution droplets (two visits) or 1.01+/- 0.2 microm saline solution droplets (two visits) for 30 s, starting from functional residual capacity and breathing at a slow or faster inspiratory flow rate. On all visits, the saline solution was admixed with the radioisotope (99m)Tc. Immediately after inhalation, a gamma camera recorded the deposition pattern of the radioaerosol in the lungs. Deposition images were analyzed in terms of the inner:outer zone (I:O) ratio, a measure of deposition in an inner zone (large, central airways) vs. an outer zone (small airways and alveoli). MEASUREMENTS AND RESULTS: For the 3.68-microm aerosol, I:O ratios averaged 2.29+/-1.45 and 2.54+/-1.48 (p>0.05), indicating that aerosol distribution within the lungs was unchanged while breathing at 12+/-2 L/min vs. 31+/-5 L/min, respectively. For the 1.01-microm aerosol, I:O ratios averaged 2.09+/-0.96 and 3.19+/-1.95 (p<0.05), indicating that deposition was predominantly in the smaller airways while breathing at 18+/-5 L/min and in the larger airways while breathing at 38+/-8 L/min, respectively. CONCLUSIONS: These results suggest that the targeted delivery of an aerosol to the smaller, peripheral airways or the larger, central airways of adult CF patients may be achieved by generating an aerosol comprised of approximately 1.0-microm particles and inspiring from functional residual capacity at approximately 18 L/min and approximately 38 L/min, respectively.

The lung as an alternative route of delivery for insulin in controlling postprandial glucose levels in patients with diabetes.

STUDY OBJECTIVES: To determine the efficacy of the lung as an alternative route of delivery for insulin in controlling glucose below diabetic levels (11.2 mmol/L) 2 h after the ingestion of a meal in patients with type 2 diabetes mellitus. DESIGN: Single-blinded, nonrandomized, placebo-controlled pilot study consisting of two visits. SETTING: A primary care facility. PATIENTS: Seven patients with type 2 diabetes mellitus. INTERVENTIONS: On the first study visit, fasting glucose levels were normalized. Then, patients inhaled 1.5 U/kg insulin by aerosol into the lungs 5 min before ingesting a test meal. On the second visit, patients inhaled placebo aerosol 5 min before ingesting the same meal. On both visits, plasma samples were collected and analyzed for glucose levels for 3 h during the postprandial state. MEASUREMENTS AND RESULTS: No one coughed after inhalation of insulin aerosol or demonstrated hypoglycemia. During the postprandial period, glucose levels were significantly lower at 20 min (5.12+/-1.08 mmol/L), 1 h (7.87+/-0.73 mmol/L), 2 h (8.05+/-1.24 mmol/L) and 3 h (7.50+/-1.43 mmol/L) following inhalation of insulin than when the placebo was used. Data for the placebo were 10.36+/-1.23 mmol/L at 20 min, 14.0+/-1.68 mmol/L at 1 h, 16.18+/-1.45 mmol/L at 2 h, and 14.37+/-2.11 mmol/L at 3h (for all comparisons, p < 0.05). On the insulin visit, glucose levels were < 11.2 mmol/L 2 h after the meal in six of seven patients. None attained this level at the placebo visit. In addition, glucose levels were within the normal postprandial range of < 7.84 mmol/L in four of seven patients 2 h after eating on the insulin visit. CONCLUSIONS: These results suggest that, once plasma glucose levels are normalized, postprandial glucose levels can be maintained below diabetic levels by delivering 1.5 U/kg insulin into the lungs 5 min before the ingestion of a meal.

Radioaerosol assessment of lung improvement in cystic fibrosis patients treated for acute pulmonary exacerbations.

We compared bronchopulmonary distribution homogeneity of a radioaerosol before and after hospitalization in 20 patients with cystic fibrosis (CF) with pulmonary exacerbations in order to assess lung improvement. Deposition homogeneity was quantified in terms of skew (an index of distribution symmetry), derived from frequency distribution histograms generated from gamma camera images of the lungs following radioaerosol inhalation. Lower skew values indicate enhanced distribution homogeneity. Right lung skew (RLS) was significantly reduced following therapy (1.00 +/- 0.49 to 0.84 +/- 0.47), whereas skew in the left lung was unchanged (0.95 +/- 0.38 to 0.87 +/- 0.40). The reduction in RLS was significant in patients with Shwachman-Kulczycki (SK) clinical scores less than 50 (1.27 +/- 0.53 to 0.90 +/- 0.42), but not in patients with scores greater than 50 (0.81 +/- 0.38 to 0.80 +/- 0.52). These results indicate that treatment affected the right lung more than the left lung, particularly in patients with SK scores less than 50, and suggests that radioaerosol lung imaging may be valuable in identifying sites of impairment to be targeted during treatment. Statistically, skew was less sensitive an indicator of acute change than several other clinical indices that improved following hospital treatment.

Homogeneity of bronchopulmonary distribution of 99mTc aerosol in normal subjects and in cystic fibrosis patients.

We characterized the bronchopulmonary distribution of a 0.9 percent saline aerosol (1.12 microM) labelled with 99mTc sulfur colloid in nine normal subjects and five patients with CF. Homogeneity of distribution was quantified using indices derived from computerized analysis of Anger camera pulmonary images including skew (a measure of distribution asymmetry) and kurtosis (a measure of distribution range). Aerosol clearance in 97 minutes (a measure of large, central airway deposition) was also assessed. Values of skew and kurtosis were reproducible for the patients with CF and were significantly elevated compared to the normal subjects. Reproducibility of skew and kurtosis were not studied in the normal subjects. Clearance was not significantly different in the two groups. We conclude that the bronchopulmonary distribution of this radioaerosol is nonuniform in patients with CF, compared to normal subjects, and clearance may be impaired in patients with CF who are severely ill.

A pilot study examining the relationship between stress and serum cortisol concentrations in women with asthma.

The mechanism (s) by which stress exacerbates asthma is unknown. One explanation could be a reduction in endogenous serum cortisol concentrations as a result of stress. Our objective was to determine if a reduction in morning serum cortisol concentrations is associated with higher levels of stress in women with asthma. In this pilot study, seven women with a history of allergic-asthma were prospectively assigned to either low, moderate, or high stress groups based on a combination of their level of current stress and their resources to cope with the stress. After stress group assignment, women donated a morning blood sample, which was analyzed for serum cortisol concentration by an independent laboratory whose personnel were blinded to the subjects' stress status. Three women were assigned to the low stress group, two to the moderate stress group and two to the high stress group. Serum cortisol concentrations ranged from 8 to 23 microg/dl, averaging 14 +/- 6 microg/dl. A Spearman rank correlation indicated that serum cortisol concentrations were significantly inversely related to the stress groupings (r(s) = -0.915; P = 0.025). These results suggest that a reduction in morning serum cortisol concentration may be associated with higher levels of stress and lower resources to cope with the stress in women with allergic-asthma.

In vivo measurements of aerosol dose and distribution: clinical relevance.

Mathematical and in vitro models, that incorporate particle diameter, normal breathing frequencies and tidal volumes, have been used to predict the deposition fraction of respirable aerosols within the lungs. Although very useful in drug development, determinations of dose and the distribution of dose based solely on such models may be less accurate than in vivo measurements, which are performed under conditions that combine the effects of all the factors that determine aerosol deposition, including the effect of disease. Gammascintigraphy provides a method for in vivo quantification of the total deposited fraction and the distribution of the dose within the lower respiratory tract. Using this technology, it has been shown that deposition fraction in the lower respiratory tract may vary between 1-30% of the dose actuated from an MDI or nebulizer. This wide range in deposited dose suggests that variations in the clinical response to inhaled aerosols may be explained by alterations in the dose delivered, especially if the aerosolized medication has a narrow therapeutic range. Alterations in the distribution of inhaled drugs within the lungs may also affect the clinical response, such that some disorders may best be treated by targeting drug to specific locations of the lung, while others may respond best to homogeneous distribution of aerosolized drug. In vivo measurements would provide confirmation of the dose deposited as well as the pattern of distribution, which should improve the therapeutic outcome of most aerosolized medications.

Time to peak insulin level, relative bioavailability, and effect of site of deposition of nebulized insulin in patients with noninsulin-dependent diabetes mellitus.

Seven fasting patients with noninsulin-dependent diabetes mellitus (NIDDM) inhaled 1.0 U/kg of body weight of nebulized regular pork insulin by mouth or were subcutaneously (sc) injected with 0.1 U/kg of body weight of insulin in the upper arm on two different occasions. The time to peak insulin level was compared for the two treatment modalities. Insulin bioavailability after inhalation was quantified relative to sc injected insulin. Deposition of a radiolabeled insulin surrogate aerosol (insulin diluent) in the larger central airways versus the peripheral airways, expressed as the inner-to-outer (I:O) ratio, and in the lung apex versus the lung base, expressed as the apex-to-basal (A:B) ratio, was quantified with gamma scintigraphy. Ratios were related to glucose responses after inhalation of insulin. Times to peak insulin level were similar for the two methods of treatment, averaging 43 +/- 16 and 64 +/- 40 minutes after inhalation and sc injection of insulin, respectively. The bioavailability of inhaled insulin averaged 14.7% +/- 5.8% relative to sc injected insulin. This was significantly less than the average bioavailability of deposited drug (18.9% +/- 5.3%) relative to sc injected insulin (P < 0.05). I:O and A:B ratios for the surrogate aerosol averaged 1.3 +/- 0.4 and 0.7 +/- 0.2, respectively. Linear regression analysis revealed that the maximum percentage of decrease in glucose after insulin inhalation was significantly related to the A:B ratio such that percentage decrease in glucose was greater in patients who demonstrated a lower A:B ratio (P = 0.003). Percentage decrease in glucose was not related to the I:O ratio. These results indicate that the bioavailability of nebulized insulin inhaled by mouth is approximately 20% when calculated in terms of drug deposited and suggest that increasing the distribution of insulin aerosol to the base of the lung enhances the glucose response in patients with NIDDM during the fasting state.

Mouthpiece diameter affects deposition efficiency in cast models of the human oral airways.

We examined the effect of altering mouthpiece diameter to 1.5, 2.0, and 2.7 cm on the deposition efficiency of inertial size particles (2, 4, and 8 microm) in adult human oral-pharyngeal-laryngeal (OPL) airway cast models at various inspiratory flow rates (30, 60, 90, and 120 L/min). Deposition efficiency of 2-microm particles was unaffected by changes in mouthpiece diameter at all flow rates. Deposition of 4-microm particles decreased significantly with the 2.0- and 2.7-cm mouthpieces compared to the 1.5 cm mouthpiece at 60, 90, and 120 L/min (p < 0.01). Deposition of 4-microm particles was significantly reduced with the 2.7-cm mouthpiece compared to the 2.0-cm mouthpiece at 90 and 120 L/min (p < 0.05). Deposition efficiency of 8 microm particles decreased significantly with the 2.0- and 2.7-cm mouthpieces compared to the 1.5-cm mouthpiece at 60 L/min (p < 0.05), and with the 2.7-cm mouthpiece compared to the 1.5-cm mouthpiece at 120 L/min (p < 0.05). These results suggest that the effect of mouthpiece diameter varies with particle size, with 2- and 8-microm particles least affected. However, our findings may have important implications for improving the future design of mouthpieces of devices that deliver particles with 4-microm diameters and require inspiratory flow rates of > or = 60 L/min (i.e., DPIs) for adequate drug delivery.

Preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients.

OBJECTIVE: To maximize deposition of an aerosolized dose of insulin (mean +/- SD = 0.99 +/- 0.06 U/kg of body weight) in the lungs of subjects with non-insulin-dependent diabetes mellitus (NIDDM), and investigate its efficacy in normalizing plasma glucose levels during the fasting state. DESIGN: Nonrandomized, placebo-controlled trial. SETTING: A primary care facility. PATIENTS OR OTHER PARTICIPANTS: Six nonobese, nonsmoking volunteers with NIDDM. No subjects withdrew from the study. INTERVENTION: Aerosolized insulin was administered by oral inhalation after a 12-hour period of fasting. Aerosol was generated by a raindrop nebulizer from regular 500 U/mL pork insulin. During inhalation, inspiratory flow was regulated at 17 L/min. Plasma samples were collected after inhalation and analyzed for insulin and glucose levels. MAIN OUTCOME MEASURES: Plasma insulin and glucose levels. RESULTS: Deposition of the aerosol was maximized within the lungs, with 79% +/- 17% of the inhaled dose depositing below the larynx. Geometric mean fasting plasma insulin level was 71 pmol/L (11.8 microU/mL), rising to 269 pmol/L (44.8 microU/mL) after insulin inhalation. Average time to peak insulin level was 40 +/- 34 minutes. The mean fasting plasma glucose level (12.63 +/- 2.59 mmol/L [225.5 +/- 46.3 mg/dL]) was reduced to within the normal range in five subjects and was almost normal in the sixth subject (5.52 +/- 0.89 mmol/L [98.6 +/- 15.9 mg/dL]). Average maximum decrease in plasma glucose from baseline was 55% +/- 10% (n = 6) vs 13% +/- 9% after placebo aerosol inhalation (n = 3). No side effects were reported following insulin or placebo aerosol inhalation. CONCLUSIONS: These preliminary results indicate that a dose of approximately 1.0 U of aerosolized insulin per kilogram of body weight, delivered by oral inhalation and deposited predominantly within the lungs, is well tolerated and can effectively normalize plasma glucose levels in patients with NIDDM.

The effect of aerosol distribution on airway responsiveness to inhaled methacholine in patients with asthma.

It has been demonstrated that airway deposition of inhaled aerosols is more heterogeneous in patients with asthma than in normal subjects. Nevertheless, the influence of abnormal airway deposition on responses to bronchoactive aerosols is poorly understood. We altered bronchopulmonary deposition heterogeneity of methacholine aerosol in nine asymptomatic patients with asthma by controlling inspiratory flow at high (approximately 60 L/min) versus low (approximately 12 L/min) rates on 2 study days and determined the effect on the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) (often used as a measure of airway responsiveness). Deposition uniformity was quantified from gamma-camera scans of the lungs in terms of the distribution of a technetium-labeled aerosol that was inhaled rapidly or slowly before the inhalation of methacholine. Increased deposition in an inner (large, central airways) versus an outer (peripheral airways and alveoli) zone of the right lung (inner/outer ratio, greater than 1) and higher values of skew (an index of deposition asymmetry) and kurtosis (an index of deposition range) indicated enhanced heterogeneity of deposition. Mean (+/- SD) inner/outer ratio was significantly higher during rapid inspiration compared to slow inspiration with 2.91 +/- 0.51 and 1.84 +/- 0.30, respectively (p less than 0.01). Mean skew and kurtosis were also significantly higher after rapid inspiration, with 1.12 +/- 0.35 and 3.86 +/- 1.25, respectively, compared to 0.74 +/- 0.36 and 2.64 +/- 0.77 after slow inhalation (p less than 0.01). Geometric mean PD20 methacholine was significantly reduced when the aerosol was inhaled rapidly, with 5.9 cumulative methacholine units compared to 15.7 units after slow inhalation (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Eucapnic voluntary hyperventilation of compressed gas mixture. A simple system for bronchial challenge by respiratory heat loss.

Eucapnic voluntary hyperventilation (EVH) of cold, dry air has been shown to be an effective stimulus for bronchoconstriction in people with reactive airways. The system for respiratory heat exchange (RHE) challenge can be greatly simplified from what is presently used. A relationship was derived which predicts that a single fraction of inspired CO2 (0.0489) will produce near normal alveolar CO2 over a wide range of voluntary hyperventilation. This relationship was verified in 19 normal subjects who performed a total of 110 periods of hyperventilation with minute ventilation (VE) randomly distributed between 40 and 105 L/min. The experimentally determined CO2 production of the voluntary hyperventilation was found to be 3.72 ml/min per L/min over a range of VE from 40 to 105 L/min. Next, a group of 10 patients with exercise-induced asthma (EIA) were challenged with a standard exercise protocol, ventilating ad libitum from a source of dry air at room temperature. On another day, the same pattern of VE, and hence RHE, was required of them using the simplified EVH scheme. The average decreases in forced expiratory volume in one second and specific airway conductance were 32 +/- 10% and 66 +/- 13%, respectively, after the exercise challenge, and 33 +/- 12% and 73 +/- 12% after EVH. The difference between corresponding mean values was not significant. We conclude that a simplified EVH challenge can be done using a single dry gas mixture without the need for cooling inspired gas or monitoring end-tidal fraction of CO2. This test can be used to identify and study patients with EIA without the requirement for an exercise challenge or the need for elaborate gas conditioning and monitoring equipment.

The effect of inspiratory flow rate regulation on nebulizer output and on human airway response to methacholine aerosol.

Increased inspiratory flow rate has been demonstrated to decrease pulmonary deposition of inhaled aerosols. To study the effect of inspiratory flow rate regulation on the physiologic response to an active substance administered by aerosol, we compared the effect of high unregulated flow rate (66 to 212 L/min) with regulated low flow rate (20 to 35 L/min) on nebulizer output and on the pulmonary response to methacholine in patients with asthma. Four No. 646 DeVilbiss nebulizers were used in sequence with a nebulization dosimeter to deliver tenfold incremental concentrations of methacholine aerosol (mass median aerodynamic diameter = 1.52 micron; geometric standard deviation = 1.96) ranging from 0.025 to 25 mg/ml. When flow was unregulated, nebulizer output was not greater than when flow was regulated, but coefficients of variation of output were significantly greater (p less than 0.01). The PD20 on the two unregulated days was significantly different (p = 0.01), whereas the PD20 on the two flow regulated days was not significantly different (p greater than 0.05). We conclude that regulation of inspiratory flow rate at rates within the range of tidal breathing significantly decreases variability in nebulizer output and variation of pulmonary responses to methacholine challenge.