Inhaled adrenergic bronchodilators: historical development and clinical application.

The adrenergic bronchodilators that have been developed for oral inhalation represent successive refinement in terms of receptor specificity and duration of action. Beta agonist bronchodilators have durations of 4-6 hours, or, in the case of salmeterol, of up to 12 hours, offering convenient dosing. Inhalation of the aerosol formulations targets the lung directly. The release of levalbuterol now provides an agent with a single isomer active on beta-2 receptors. The currently available agents offer clinicians and patients with reversible obstructive lung disease a choice of sophisticated drugs for airway smooth muscle relaxation. Although improvements in the drugs have reduced adverse effects and beta agonists are considered safe, concerns persist about the effect of beta agonists in asthma. An improved understanding of asthma pathophysiology may lead to more appropriate use of beta agonists in asthma.

Introduction of a single isomer beta agonist.

The release of levalbuterol offers the first approved single-isomer beta agonist for oral inhalation. Data from in vitro studies support the concept that S albuterol is not inactive and may have properties antagonistic to bronchodilation. There is some variability in the results of clinical studies with the separate isomers of albuterol, which suggests the need for further study. The introduction of levalbuterol into general clinical use in managing asthma and chronic obstructive disease should begin to offer additional information on the effects of a single isomer beta agonist in comparison to previous racemic mixtures.

Combining a positive expiratory pressure device with a metered-dose inhaler reservoir system using chlorofluorocarbon albuterol and hydrofluoroalkane albuterol: effect on dose and particle size distributions.

BACKGROUND: Combining a positive expiratory pressure (PEP) device with inhalation of albuterol via metered dose inhaler (MDI) may improve drug delivery to the lung, but may also affect dose availability. PURPOSE: Determine the effect of interposing a PEP device on dose availability of albuterol via MDI and reservoir with either a chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) propellant. METHODS: MDI dose availability of CFC albuterol (Proventil) and HFA albuterol (Proventil HFA) using an Aerosol Cloud Enhancer (ACE) reservoir with and without a PEP device (TheraPEP) attached was determined. Drug availability was assessed using an Andersen 8-stage cascade impactor operated at 28.3 +/- 0.5 L/min. The PEP device was inserted between the reverse-firing ACE and the United States Pharmacopeia induction throat. Drug collected on impactor plates was analyzed spectrophotometrically at 276 nm, and the fine particle fraction was determined as the mass of drug < 4.7 microns. RESULTS: With CFC albuterol, total dose and drug mass < 4.7 microns (means and standard deviations) for the MDI-ACE alone were 44.4 +/- 7.7 micrograms and 33.4 +/- 2.2 micrograms, respectively, and for the MDI-ACE with TheraPEP were 50.1 +/- 6.4 micrograms and 39.8 +/- 14.3 micrograms, respectively. With HFA-albuterol sulfate, total drug and drug mass < 4.7 microns for the MDI-ACE alone, expressed as base drug, were 41.7 +/- 4.2 micrograms and 35.2 +/- 6.3 micrograms, respectively, and for the MDI-ACE with TheraPEP were 48.9 +/- 8.0 micrograms and 44.2 +/- 6.2 micrograms, respectively. There was no significant difference in dose availability between the MDI-ACE alone and with the PEP device attached (Wilcoxon signed-rank test, p > 0.05), for either CFC or HFA albuterol. CONCLUSION: Interposing the TheraPEP device at the MDI-ACE outlet does not change total dose, drug mass < 4.7 microns, or mass median aerodynamic diameter of MDI albuterol, with either CFC or HFA propellants.

The evolution of beta-agonists.

Inhaled beta-agonists have become the mainstay of bronchodilator therapy for reactive airway diseases, either alone or in conjunction with other medications. The history of the development of beta-agonists is a fascinating one that spans more than 5000 years. Scientific investigation for the past several hundred years has elucidated the physiology of bronchoconstriction and bronchodilation. In the past decade, a wealth of knowledge has come forth since the discovery of the beta-adrenoceptor which, along with advances in pharmacology, have helped answer the questions of how beta-agonists work. From these advancements, three classes of beta-agonists have been developed: catecholamines, resorcinols, and saligenins. The chemical structures of the more commonly used agents in each class, their interaction with the beta-adrenoceptor, and their beneficial and adverse effects are discussed. Review of the duration of action of these agents may suggest a new way of classifying them into ultrashort-acting, short-acting, intermediate-acting, and long-acting.

Recent developments in respiratory care pharmacology.

Bronchoactive inhaled aerosol drugs target the respiratory tract directly and seek to minimize systemic exposure and reduce side effects. Common delivery devices such as the metered dose inhaler, the small volume nebulizer, or the dry powder inhaler each deliver approximately the same fraction of dose (10%) to the lungs, although their dose amounts are not equivalent. Major respiratory drug groups are reviewed, and include the beta-adrenergic and anticholinergic bronchodilators, mucolytic agents, corticosteroids, mediator antagonists, anti-infective agents, and exogenous surfactants. New agents in each group are identified and briefly described, along with the clinical use and most commonly observed side effects for each class of drugs.

Reservoir design and dose availability with long-term metered dose inhaler corticosteroid use.

The effect of reservoir design and long-term use with inhaled metered dose inhaler (MDI) corticosteroids on aerosol dose availability was examined. Beclomethasone dipropionate (Vanceril) was delivered by MDI with three brands of available reservoir devices: the AeroChamber, the OptiHaler, and the Aerosol Cloud Enhancer (ACE). An in vitro lung model simulated inspiration. Long-term use was simulated by exhausting five MDI canisters of beclomethasone through each sample of reservoir tested. Each canister exhausted through a reservoir represented approximately 1 month of use with one drug. Total inhaled dose was collected at the reservoir mouthpiece and measured using a spectrophotometric assay. Dose delivery was measured before simulated use and after each MDI canister was exhausted through the reservoir. Three samples of each brand were tested with cleaning and three samples were tested without cleaning. With cleaning, the AeroChamber, OptiHaler, and ACE delivered significantly different average doses of 16.6, 10.3, and 8.7 micrograms per MDI actuation, respectively, (P = 0.0017) over time of use. Changes in dose delivery over time of use were not significant (P = 0.2011). Without cleaning, the same three brands averaged 21.1, 9.7, and 7.8 micrograms per MDI actuation, respectively, (P = 0.0019), and changes in dose delivery over time were not significant (P = 0.3265). Reservoir design can affect the delivery of an inhaled corticosteroid, although the delivery over 4 to 5 months remained stable.

Inhalation of single vs multiple metered-dose bronchodilator actuations from reservoir devices. An in vitro study.

UNLABELLED: Differences in inhalation technique with reservoir or spacer devices may affect metered-dose inhaler (MDI) dose availability to a patient. PURPOSE: This study examined the effect of single vs multiple actuations of an MDI into reservoir devices on dose delivery of albuterol, with three clinically available reservoir brands. METHODS: An in vitro lung model simulated inspiration from the MDI reservoir system. Albuterol (Proventil; Schering) was delivered by MDI, with the Monaghan Aerochamber, the Diemolding Healthcare Division (DHD) aerosol cloud enhancer (ACE), and the Schering InspirEase, using standardized volumes and inspiratory flows of 30 L min(-1). The MDI was actuated into each brand of reservoir 1, 2, or 3 times in rapid succession, followed by a single inhalation. Aerosol dose at the reservoir mouthpiece was captured on a cotton filter, dissolved in ethanol, and measured with a spectrophotometer at 278 nm. RESULTS: For all three brands of reservoir, less accumulated dose of drug is delivered with multiple actuations than with multiple single actuations each followed by inhalation. The total dose in milligrams increased significantly with two multiple actuations compared with one actuation in the Aerochamber and ACE (p<0.01), but not in the InspirEase (p>0.05). The Aerochamber, ACE, and InspirEase delivered a mean total dose (SD) of 0.0264 mg (0.012), 0.0271 mg (0.007), and 0.0136 mg (0.006), respectively, with one actuation compared to 0.0485 mg (0.011), 0.0453 mg (0.013), and 0.0218 mg (0.009) with two multiple actuations. The increase in total dose with three multiple actuations was not significant compared to two actuations for any of the brands tested (p>0.05). Although total dose increased with multiple actuations, a decline in efficiency was seen with two and three multiple actuations, compared to single actuation. The dose delivered per actuation decreased for the Aerochamber, ACE, and InspirEase from 0.0264 mg (0.012), 0.0271 mg (0.007), and 0.0136 mg (0.006) with one actuation, to 0.0243 mg (0.006), 0.0226 mg (0.006), and 0.0109 mg (0.005), respectively, with two multiple actuations, for losses of 8.0%, 16.6%, and 19.9% in dose per actuation for each brand. A further decline in delivery per actuation to 0.0164 mg (0.001), 0.0184 mg (0.004), and 0.0097 mg (0.005) for the 3 brands, respectively, was found with 3 multiple actuations before inhalation. This was a loss of 37.9%, 32.1%, and 28.7% of the dose per single actuation in each brand. There was no significant difference between the Aerochamber and the ACE in dose availability with 1, 2, or 3 actuations, but both of these brands provided significantly more drug than the InspirEase. CONCLUSION: Maximal aerosol bronchodilator from an MDI reservoir was given by single actuations each followed by a breath. Two rapid actuations followed by a breath will give a significant accumulation of dose with some loss when compared to two single actuations each followed by inhalation. Three multiple actuations led to a loss of approximately one third of the drug dose obtainable with three single actuations each followed by inhalation, for all three brands.

A comparison of the effects of assist-control, SIMV, and SIMV with pressure support on ventilation, oxygen consumption, and ventilatory equivalent.

OBJECTIVE: To quantify the ventilatory efficiency of different modes of mechanical ventilation used to achieve full ventilatory support in normal subjects. Modes compared were assist-control, synchronized intermittent mandatory ventilation (SIMV), and SIMV with 10 cm H2O (0.98 kPA) of pressure support. DESIGN: Prospective, randomized blocks repeated measures design. Subjects served as their own controls. SETTING: A university affiliated pulmonary laboratory. SUBJECTS: Ten healthy volunteers, aged 31-54 years. OUTCOME MEASURES: Minute volume, respiratory rate, average tidal volume, oxygen consumption, and ventilatory equivalent. INTERVENTION: Baseline spontaneous ventilation data collection was followed by mechanical ventilation by mouthpiece in each of three modes in a random sequence. All modes used a machine set rate of 12 breaths per minute, VT of 10 cc/kg of ideal body weight, inspiratory time of 1 second, square wave flow pattern and a sensitivity of -1 cm H2O (-0.09806 kPa) to achieve full ventilatory support. Data were collected continuously for 5 minutes and the mean values were reported. Ventilatory equivalent for oxygen is a measure of the efficiency of the ventilatory pump at various work loads and was calculated by dividing VE (BTPS) by the VO2 (STPD). RESULTS: There were significant differences by mode of mechanical ventilation in average tidal volume (p = 0.02), minute volume (p = 0.02), oxygen consumption (p = 0.04), and ventilatory equivalent (p = 0.01) using ANOVA. There was no significant difference (p = 0.66) by mode of ventilation in respiratory rate. Pairwise follow-up comparisons for these variables found that SIMV with pressure support produced a significantly greater average tidal volume, minute volume, oxygen consumption, and ventilatory equivalent than SIMV alone. SIMV with pressure support also produced a significantly greater minute volume and ventilatory equivalent than assist-control. There were no significant differences between assist-control and SIMV. All three modes produced a lower ventilatory equivalent and higher oxygen consumption than spontaneous breathing. CONCLUSIONS: SIMV with pressure support significantly increased minute volume and ventilatory equivalent when compared with assist-control or SIMV alone, and thus was the most efficient mode of full ventilatory support for our subjects. We found no difference in ventilatory efficiency between assist-control and SIMV. All three mechanical modes were less efficient for our subjects than spontaneous breathing. The inspiratory time of 1 second used in this study, although common in clinical practice, may be inadequate for some patients.

Evaluation of a reservoir device for metered-dose bronchodilator delivery to intubated adults. An in vitro study.

UNLABELLED: We investigated the use of a reservoir device for delivery of a MDI bronchodilator aerosol using a lung model of an intubated, mechanically ventilated adult. METHODS: Albuterol (Proventil) was delivered with a MDI using three methods. In method 1, the MDI was attached directly onto the ETT using a commercially available actuator/adapter. In method 2, the Monaghan AeroVent reservoir was placed on the inspiratory limb of the ventilator circuit just before the patient Y connector. In method 3, the AeroVent was placed between the patient Y connector and the ETT. Standardized ventilator settings with a Servo 900C were used for all three methods (VE = 9.6 L; respiratory rate = 12 breaths per minute; TI = 20 percent of 1 s). Aerosol drug delivery was measured at the distal tip of the ETT using a spectrophotometric technique. Percentage of amount delivered was calculated from measured delivery of the MDI. RESULTS: The MDI directly on the ETT delivered 7.3 percent of the total dose to the end of the ETT. The AeroVent on the inspiratory limb increased this to 32.1 percent and the AeroVent between the Y connector and the ETT delivered 29 percent. Both reservoir delivery methods delivered significantly more drug than direct placement of the MDI on the ETT (p less than 0.01) but did not differ from each other (p greater than 0.05). CONCLUSIONS: Use of the AeroVent reservoir chamber significantly increased bronchodilator delivery by aerosol with an MDI in an adult lung model of an intubated patient on ventilatory support.

Quantitative buffy coat analysis. A hematologic screen applicable to the selection of apheresis donors.

Quantitative buffy coat analysis was performed on samples of venous blood with the QBC (Clay Adams Division of Becton Dickinson, Rutherford, NJ) Hematology System and the results for platelet counts, white blood cell counts, and microhematocrits were compared with those obtained by reference methods. At the established cut-off, values for apheresis donors the with-in run reproducibility (CV) of the platelet count was 6.8%; of the white blood cell count, 8.6%; and of the microhematocrit, 1.75%. Over the range of values studied, the platelet count showed the poorest correlation with the reference method (R = 0.72023) and the greatest dispersion of QBC values at a given reference value. Correlation coefficients for QBC and reference methods for white blood cell counts and hematocrits were 0.88887 and 0.89778, respectively. Predicted ranges of reference values for platelet counts and white blood cell counts, based on QBC measurements, were too wide at lower levels of the normal range to be clinically meaningful. When used in a screening mode to determine if results from apheresis donors exceeded specific cut-off values, the QBC system performed well as determined by high predictive values for results above the selected cut-offs. Misclassification errors with the QBC system were more likely to result in rejection of acceptable donors than acceptance of those with low platelet or white cell counts.

Evaluation of two electronic respiratory rate monitoring systems.

Two electronic systems for monitoring respiratory rates in critical care patients were evaluated--one a system using impedance sensors and the other a system using thermistor sensors. The thermistor sensor, attached to a nasal cannula or air-entrainment mask, was connected to a sensitivity calibrating control and a digital display module. The impedance system consisted of three electrocardiogram chest leads connected to an identical digital display module. Each of 10 patients was simultaneously monitored by both systems; indicated rates from the two systems were then compared to a counted control rate to determine accuracy. Data were collected at 17 successive half-hour intervals. Analysis of variance of the data gave a significant F ratio for differences among the three methods of rate monitoring. The impedance system gave readings progressively higher and the thermistor system gave readings progressively lower than the counted control rates. This study indicates that this configuration for both impedance and thermistor sensing lacks the desired accuracy for respiratory rate monitoring but may be suitable for apnea alarms.