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Effects of inhaled albuterol and ipratropium bromide on autonomic control of the cardiovascular system.

STUDY OBJECTIVE: Systemic administration of beta-agonist and anticholinergic drugs markedly impair normal autonomic heart rate control. The purpose of this study was to quantify and compare the effects of therapeutic doses of inhaled albuterol and ipratropium on autonomic control of the cardiovascular system. DESIGN: Randomized, double-blind, placebo-controlled, crossover design study. SETTING: Tertiary-care hospital. SUBJECTS: Twelve healthy male volunteers. INTERVENTIONS: Subjects self-administered four puffs through a spacer device from one of three identical inhalers containing albuterol (100 microg per puff), ipratropium (20 microg per puff), or placebo in three different testing sessions. MEASUREMENTS: ECG and noninvasive continuous BP traces were recorded at baseline and from 45 to 75 min after administration of the drug. Autonomic control of the cardiovascular system was quantified by analysis of spontaneous baroreflex sensitivity and power spectral analysis of heart rate variability. RESULTS: Neither albuterol nor ipratropium caused a significant alteration in baroreflex sensitivity, normalized low-power frequency, or normalized high-power frequency. No adverse effects were reported by subjects. CONCLUSIONS: Inhalation of four puffs of albuterol (400 microg) or ipratropium (80 microg) does not alter the autonomic control of the cardiovascular system in young, healthy male subjects.

Administration, Inhalation↗

Effective application of bronchodilator aerosols from metered-dose inhalers (MDI) via resuscitator-bag and adapter.

UNLABELLED: We developed an adapter enabling the application of therapeutic aerosols from metered-dose inhalers (MDI) via a resuscitator bag. This modification permits the bag to act as a spacer which is commonly acknowledged to be a means of improving the efficiency of inhaled aerosolized drugs by reducing impaction in the upper airways and improving the intrapulmonary deposition of particles small enough for intraalveolar penetration. The normal function of the resuscitator bag remains unchanged enabling use with intubated patients receiving artificial ventilation. METHODS: A total of 24 patients receiving a bronchodilator response test were treated with 200 microg salbutamol from a MDI combined with either a spacer or our bag. Bodyplethysmography and a lung-function-test were performed before and after treatment. RESULTS: Both treatments showed a statistically significant reduction of airways resistance. However, no significant difference between the bag and the spacer could be detected. CONCLUSIONS: We conclude that the modified resuscitator-bag is well suited for the inhalative application of drugs by making use of the established MDI-spacer principle. Use of our modified bag will offer emergency preclinical therapy of bronchospasm for patients in need of rapid effective relief who were formerly dependent on intravenous treatment. Application in anaesthesia and intensive care also seems possible.

Administration, Inhalation↗

Bronchodilator responsiveness testing using raised volume forced expiration in recurrently wheezing infants.

We hypothesized that a new test of infant lung function, less affected by shifts in lung volume, might better detect bronchodilator effects. Using the raised volume forced expiration technique (RVFET), the effect of a bronchodilator on lung function was studied in 22 infants with a history of recurrent wheeze and five healthy infants. Forced expiratory volume in 0.75 s (FEV0.75), forced expiratory vital capacity (FVC), and forced expiratory flow at 75% of FVC (FEF75%) were measured by forcing expiration, using an inflatable jacket from a lung volume set by an inspiratory pressure of 20 cm H2O. A minimum of five measurements were made at baseline and following the administration of 500 microg of salbutamol from a metered dose inhaler via a small volume metal spacer. Changes in lung function in the group of 25 infants who received salbutamol were compared to seven infants who received placebo aerosol. No significant changes occurred in measures of lung function following salbutamol administration when compared to baseline or placebo despite a significant increase in heart rate. A shift in lung volume is unlikely the reason why infants do not demonstrate a change in forced expiration following bronchodilator administration.

Albuterol↗

Efficient delivery to the lungs of flunisolide aerosol from a new portable hand-held multidose nebulizer.

In order to provide asthmatic patients with an inhaler that does not use chlorofluorocarbon propellants, a novel multidose hand-held nebulizer (RESPIMAT, Boehringer Ingelheim Ltd.) has been developed. This device delivers 200 x 15 microL metered doses of drug solution, but does not use propellants of any kind. In this study of 10 healthy volunteers, the deposition pattern in the lungs and oropharynx of an ethanolic solution of flunisolide delivered via a prototype III multidose nebulizer has been determined by gamma scintigraphy. A comparison was made with the same dose (250 micrograms) of flunisolide delivered by a pressurized metered dose inhaler (MDI) and MDI plus Inhacort spacer. Mean (SD) whole lung deposition from the multidose nebulizer (39.7 (9.9) % of the metered dose) was significantly higher than that from either MDI (15.3 (5.1) %, P < 0.01) or MDI plus spacer (28.0 (7.0) %, P = 0.01). A mean 10.4% of the dose was recovered from an exhaled air filter for the multidose nebulizer, but less than 2% of the dose for MDI or MDI plus spacer. Oropharyngeal deposition was significantly reduced for the multidose nebulizer (39.9 (9.4) %) compared to MDI (66.9 (7.1) %), but was reduced further for the MDI plus spacer (27.3 (11.3) %). The multidose nebulizer delivers an unusually high percentage of an aerosol dose to the lungs, and it "targets" flunisolide to the lungs more effectively than the MDI. The multidose nebulizer could constitute a viable alternative to MDIs in asthma maintenance therapy.

Adult↗

Patients with stable chronic obstructive pulmonary disease can safely undergo intravenous dipyridamole thallium-201 imaging.

BACKGROUND: Patients with chronic obstructive pulmonary disease are usually excluded from intravenous dipyridamole thallium-201 testing. We developed a nurse-administered protocol to screen and pretreat patients so they could be safely tested. METHODS AND RESULTS: We prospectively screened patients referred for intravenous dipyridamole thallium testing and retrospectively reviewed a comparison group of patients who had undergone intravenous dipyridamole testing before our bronchospasm protocol. We studied 492 consecutive patients referred for intravenous dipyridamole thallium testing, separating those with complete data (n = 451) into two groups: group A (n = 72), patients assessed to be at risk for intravenous dipyridamole-induced bronchospasm who received our bronchospasm treatment protocol; and group B (n = 379), patients assessed to be free of risk, who did not receive our bronchospasm protocol. Group C (n = 89) was a retrospective comparison group of patients who had undergone intravenous dipyridamole testing before initiation of the protocol. Patients were considered at risk for an adverse event if any of the following were present: peak flow < or =400 ml at the time of the test (spirometry by nurse) that increased to >400 ml after bronchodilator treatment, wheezing audible with stethoscope, history of chronic obstructive pulmonary disease or asthma or dyspnea on exertion at less than four blocks, or resting respiratory rate >18 breaths/min. The test was considered contraindicated if resting oxygen saturation was <85%, respiratory rate < or =36 breaths/min, or peak flow measured by peak flowmeter <400 ml after bronchodilator inhalant (albuterol or metaproterenol sulfate by spacer) at a dose of up to six puffs. One minute after injections of thallium-201, patients at risk were given 50 mg aminophylline by slow intravenous injection. We looked for major and minor adverse effects and divided them into three categories: (1) minor events (transient headache, abdominal discomfort, or nausea), wheezing (audible by stethoscope but without marked respiratory distress), (2) marked events (severe bronchospasm or severe ischemia defined as wheezing audible with or without stethoscope, respiratory rate >20 breaths/min or increased by 10 from pretest evaluation, oxygen desaturation to <90%, hypoventilation [reduced respiratory rate with decreased mental status], respiratory arrest, chest pain, horizontal ST-segment depression > or =1 mm on the electrocardiogram in any lead, symptomatic hypotension), or (3) other intravenous dipyridamole-induced side effects (persistent headache, dizziness, flushing, nausea, dyspnea, and ischemic chest pain) or anginal equivalent. The protocol properly identified patients with impaired pulmonary function. There was no difference in the frequency of adverse marked events among groups A, B, or C (1 % vs 4% vs 2%, p = 0.25). Patients in group A had more minor side effects than those in group B (53% vs 35%, p = 0.004). Specifically, patients in group A were more likely to wheeze (39% vs 1 %, p = <0.001), but wheezing in group A was self-limited or responded to treatment as described in the protocol. The prevalence of positive thallium-201 scans in group A (44%) compared with group C (49%) was not different (p = 0.15). CONCLUSIONS: A nurse-administered risk assessment and pretreatment protocol (1) properly identified patients with impaired pulmonary function, (2) permitted completion of intravenous dipyridamole testing in patients at risk for bronchospasm without an increased incidence of marked adverse events, and (3) did not appear to influence the interpretation of the thallium test.

Aged↗

Changing delivery methods for obstructive lung diseases.

There are three types of modalities for production of aerosolized medications, but numerous specific devices using these techniques are available. The recognition that children and adults need to use optimal methods to derive maximum therapeutic benefit with minimal side effects has resulted in recent developments such as spacers for pressurized metered-dose inhalers and breath-actuated dry powder inhalers and nebulizers. These methods provide finer aerosols that can be readily inhaled and deposited in the lung with improved efficiency. Delivery systems designed specifically for particular formulations have generally been well studied, but there is a paucity of information from manufactures characterizing the drug aerosols available from their devices. Clinicians are guided by data from drug trials, but must also be furnished with details of the delivery systems to allow them to compare devices and make intelligent choices for their patients. The material presented in this review provides an evaluation of some of the systems currently available for treating asthma and other lung diseases as well as a discussion of devices planned for the future.

Administration, Inhalation↗

How much aerosol reaches the lungs of wheezy infants and toddlers?

Using sodium cromoglycate as a non-toxic marker, we assessed the delivery of aerosol to nine wheezy infants and seven healthy adults. The drug was delivered to the infants by face mask and spacer device from a metered dose inhaler, and by face mask and nebuliser to the infants and the adults who breathed though their noses. The concentration of sodium cromoglycate was estimated in timed urine collections to find out how much of the dose was absorbed from the lung. Only 0.13% to 0.61% of the 20 mg nominal dose was detected in the urine, representing an estimated 0.3% to 1.5% deposited in the lung. Nasal filtration of aerosol could be a critical factor in reducing lung deposition.

Absorption↗

Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes.

Excessive airway narrowing is a cardinal feature of asthma, and results in closure of airways. Therefore, asthmatic patients in whom airway closure occurs relatively early during expiration might be prone to severe asthma attacks. To test this hypothesis, we compared closing volume (CV) and closing capacity (CC) in a group of asthmatic patients with recurrent exacerbations (more than two exacerbations in the previous year; difficult-to-control asthma), consisting of 11 males and two females, aged 20 to 51 yr, with those in a group of equally severely asthmatic controls without recurrent exacerbations (stable asthma) consisting of 13 males and two females aged 18 to 52 yr. Both groups used equivalent doses of inhaled corticosteroids and were matched for sex, age, atopy, postbronchodilator FEV(1), and provocative concentration of methacholine causing a 20% decrease in FEV(1). They were studied during a clinically stable period of their disease. The patients inhaled 400 microg salbutamol via a spacer device, after which TLC and RV were measured by multibreath helium equilibration, together with the slope of Phase 3 (dN(2)), CV, and CC, by single-breath nitrogen washout. CV and CC were expressed as ratios of VC and TLC, respectively, and all data are presented as % predicted (mean +/- SEM). There was no difference in TLC in patients with difficult-to-control asthma and those with stable asthma (106.7 +/- 4.0% predicted versus 101.7 +/- 4.3% predicted, p = 0.40), RV (113.1 +/- 7.8% predicted versus 100.9 +/- 7.1% predicted, p = 0.26), or dN(2) (142.7 +/- 16.3% predicted versus 116.0 +/- 20.2% predicted, p = 0.23). In contrast, CV and CC were increased in the patients with difficult-to-control asthma as compared with the group with stable asthma (CV: 159.5 +/- 26.8% predicted versus 98.8 +/- 12.5% predicted, p = 0.024; CC: 114.0 +/- 6.4% predicted versus 99.9 +/- 3. 6% predicted, p = 0.030). These findings show that asthmatic individuals with recurrent exacerbations have increased CV and CC as compared with equally severely asthmatic but stable controls, even after bronchodilation during well-controlled episodes. The findings imply that airway closure at relatively high lung volumes under clinically stable conditions might be a risk factor for severe exacerbations in asthmatic patients.

Adolescent↗

The epidemiology and therapy of airflow limitation in the elderly.

Airways disease is a frequent problem poorly recognised in older people. Many have reversible airway limitation and do not receive appropriate therapy. As in younger patients, pulmonary function tests are essential as a baseline and in relation to formal trials of treatment in both the diagnosis and management. Preferably, the assessment of all patients with airflow limitation should include a corticosteroid trial to correctly identify all patients who need long term prophylactic therapy. Many older patients have difficulty using the metered dose inhalers and the addition of volume spacer devices, though cumbersome, has many further advantages. In some patients, airflow limitation may be complicated by the presence of cardiac failure, arrhythmias and arterial hypoxia, and these problems also need to be reviewed.

Age Factors↗

Ten asthma pearls every primary care physician should know.

Asthma is often easily identified and effectively treated. However, presenting symptoms are variable, and many cases of asthma may not be obvious or typical. Since asthma affects about 5% of the US population, primary care physicians should be prepared to identify and manage both atypical and classic types. Atypical symptoms include disturbed sleep, chest tightness, and persistent cough without audible wheezing. Occupational factors should be suspected in all cases of adult-onset asthma. The patient's history and results of simple pulmonary function tests are useful in diagnosing, staging, and managing asthma. A beta 2 agonist delivered by metered-dose inhaler (e.g., albuterol) should provide prompt relief of most exacerbations. Inhaled corticosteroid therapy delivered via a spacer helps prevent exacerbations and has an important role in long-term control of moderate and severe asthma. If symptoms do not improve with the use of standard asthma medications, alternative diagnoses should be considered.

Anti-Asthmatic Agents↗

Inhaled therapy for acute adult asthma.

PURPOSE OF REVIEW: To evaluate recent developments on emergency department inhalotherapy in non-intubated acute adult asthma patients. RECENT FINDINGS: There is evidence that high-flow oxygen can be associated with hypercarbia, and that full humidification of the inspired gases should be recommended. On the contrary, there is a lack of evidence to support the role of heliox in the initial treatment of acute asthma. Specific short-acting inhaled beta(2)-agonists are the drugs of choice. A more rapid and profound bronchodilatation with fewer side effects and less time of treatment can be achieved when sufficient doses are given using pressurized meter dose inhalers and large-volume valved-spacers, particularly in patients with the most severe obstruction. Findings argue against the routine use of continuous nebulization. High and repetitive doses of ipratropium bromide in combination with beta(2)-agonists are indicated as first line treatment of severe acute asthma. There is insufficient evidence that inhaled corticosteroids alone are as effective as systemic corticosteroids. Finally, the combination of nebulized magnesium and albuterol provides no benefit in addition to that provided by therapy with albuterol in patients with mild-to-moderate asthma exacerbations. SUMMARY: According to the latest evidence, the goals of treatment may be summarized as follows: maintenance of adequate arterial oxygen saturation with supplemental oxygen, relief of airflow obstruction by administration of inhaled beta-agonists and anticholinergics, and reduction of airway inflammation and prevention of future relapses by using early administration of systemic corticosteroids.

Acute Disease↗

Future options for aerosol delivery to children.

There is an increasing awareness of the importance of reliable aerosol delivery, with emphasis on the dose delivered to the lungs, optimal clinical control, cost-effectiveness, and safety in children. Dose prescription should relate to the expected lung dose rather than the factory-dispensed dose, as at present. The device determines the lung dose. Clearly, therefore, the device should be considered an integral part of the prescription. Drug approval processes should clearly specify the device, and discourage the use of other devices. This would rationalize the choice of devices. Important new insights into factors essential for drug delivery to the airways have been acquired in recent years. Nasal inhalation increases systemic bioavailability, reduces lung dose, and adds to its variability; hence, face masks to prevent nasal breathing have been developed. Similarly, dead space in the inspiratory line causes a proportional reduction in lung dose; hence, attention should be paid to reducing such dead space. Plastics in spacers cause a rapid loss of drug due to electrostatic attraction of the aerosol. The residence time of the aerosol, i.e., the time available for inhalation, is increased in nonelectrostatic spacers, allowing less compliant children enough time to obtain a full dose. Eliminating the electrostatic charge can change the lung dose by several times; hence, nonelectrostatic materials should be used in future spacer devices. Compliance is the biggest problem in drug delivery to children. The inhaler design process should be reversed, adapting technology to the child. Interactive microchip technology should provide intelligent devices that react to correct handling and breathing maneuvers. An intelligent nebulizer has been developed that adapts nebulization to the child's breathing pattern, nebulizing only during inhalation and avoiding loss of aerosol during exhalation. An automatic device (AirPac) has been developed that transforms a dry-powder inhaler, Turbuhaler, into a spacer. In addition to the general advantages of spacer treatment, this device offers the advantage of a drug aerosol delivered without use of propellants or additives. The mechanical actuation ensures highly repeatable drug delivery. Finally, a nonelectrostatic, tower-shaped spacer provides a stable aerosol, which remains airborne for a prolonged period. The spacer is equipped with a face mask that prevents nasal breathing. Such features should improve our ability to treat young children with inhaled drug aerosols.

Aerosols↗

[Evaluation of the influence of patient age and spacer device volume on aerosol lung deposition].

OBJECTIVE: To evaluate the efficacy of three frequently used spacer devices to deliver aerosol to the lung, and to compare radioaerosol deposition with each device in different age groups. METHODS: Nine healthy, non-smoking volunteers were recruited: three adults and six children, including three toddlers and three school age children. Qualitative and semi-quantitative analysis of radioaerosol deposition in the lung were carried out. Yet, two small-volume devices (Aerochamber and Inal-Air) and one large-volume device (Flumax) were compared. Each patient inhaled 99mtechnetium-phytate. The device was filled during 30 seconds with radioaerosol. Oxygen was used as the driving gas. During 10 seconds, the patients inhaled the radioaerosol. The radiation emitted at the front and back of the chest was measured. The radiation inside the device was also measured. RESULTS: The quantitative evaluation of lung deposition revealed that the younger the patient, the less aerosol was deposited in the lung with the large-volume spacer device (Flumax). The difference between small-volume devices (Aerochamber and Inal-Air) was not significant. CONCLUSION: Small-volume spacers are the most appropriate for children. Large-volume devices should only be used by adolescents and adults.

Administration, Inhalation↗

Comparative study of budesonide as a nebulized suspension vs pressurized metered-dose inhaler in adult asthmatics.

The study objective was to compare the effect of budesonide administered as a nebulized suspension as compared to a spray with a spacer in adult asthmatics. In a double-blind, double-dummy crossover study, 26 adult patients with moderately severe unstable asthma were randomized to three 4-week treatment periods with budesonide 0.8 mg b.i.d. administered by a pressurized metered-dose inhaler (pMDI) with spacer (Nebuhaler) and budesonide 1 mg and 4 mg b.i.d. administered by a Pari Inhalier Boy jet nebulizer. The nebulizer was activated only during inspiration. The total mass output was similar from the two devices but their fraction of small particles differed by a factor of 2 in favour of pMDI. Effect was evaluated from daily home measurements of peak expiratory flow (PEF), need of beta 2-agonist and symptom scores. Plasma cortisol and budesonide levels were measured in a subgroup of 10 patients. A consistent trend showed the nebulizer treatment to be at least as efficient as the pMDI plus spacer treatment. In actual fact, the apparent order of effect was: 4 mg nebulized suspension treatment > or = 1 mg nebulized suspension treatment > or = 0.8 mg pMDI with spacer treatment. Plasma budesonide and plasma cortisol also exhibited dose-related levels independent of device. The adverse effects reported appeared to be related to the dose rather than delivery device. Accordingly, the effect was related to total mass output, rather than to the small particle fraction of the budesonide aerosol. These results attest to the efficiency of jet-nebulized budesonide suspension, and indicate nebulized budesonide to be equipotent to standard budesonide therapy delivered by pMDI with Nebuhaler, provided nebulization is synchronized with inspiration and no loss of aerosol occurs during expiration.

Adult↗

[Do our asthma patients still use inhalers incorrectly?].

AIM: To determine how skilled our patients with asthma are in performing different steps in the use of different inhalation devices, and to identify variables that may influence correct inhalation technique (IT). DESIGN: Descriptive, cross-sectional study. SETTING: An urban primary care center. PARTICIPANTS: 141 patients with asthma. MAIN OUTCOME MEASURES: Performance of a practical test to evaluate each step in IT for different devices according to SEPAR-semFYC guidelines. One point was scored for each step that was performed correctly, and the technique was considered correct if the total score was >9. The main outcome variable was the percentage of patients who performed the IT correctly. RESULTS: About three-fourths of the participants (77.3%) were women; mean age was 56.08 +/- 18.99 years. Inhalation technique was incorrect in 53.9% of the patients (51.06% of those who used a pressurized canister inhaler, 59.1% of those who used a PCI+spacer, 38.5% of those who used a Turbuhaler, and 37.5% of those who used an Accuhaler). The highest error rates were seen in exhaling completely before beginning the inhalation (63.78%), holding the breath after inhalation for as long as possible (65.94%), and breathing out slowly after the inhalation (64.86%). Better IT was seen in younger patients with higher levels of education (P=.007). There were no statistically significant differences in the rest of the variables. CONCLUSIONS: A large percentage of patients performed inhalations incorrectly. We cannot conclude that any given device is superior. The variables related with correct IT were age and level of education. Greater health education efforts are needed to teach patients how to use inhalation systems correctly.

Asthma↗