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Difficult asthma.

Children with asthma who are not well controlled in spite of optimum therapy outlined in Asthma Management Guidelines are said to have 'difficult-to manage asthma' or 'difficult asthma'. Several phenotypes of this subset of asthma have been described. However, before any child is labeled as difficult asthma a thorough search for an alternative diagnosis should be made. Thus, one should look for recurrent aspiration pneumonia, tuberculosis, foreign body aspiration, tracheomalacia, bronchomalacia, cystic fibrosis etc. Causes of treatment failure range from unidentified exacerbating factors, noncompliance, inappropriate inhalers and spacers and true steroid dependence or resistance. Economics of the treatment and social beliefs should also be taken into consideration at the time of finalizing the management plan. Management involves recognizing and correcting the above factors. However, steroids form the main pillar of treatment. Majority of the patients can be controlled by optimizing inhaled steroid therapy and possibly adding steroid sparing agents. Thus, long acting bata-2 agonists, long acting theophyllines and leukotriene inhibiters may be useful. A few children will require continuous oral steroid therapy and an occasional one may be actually steroid steroid resistant. Such children are best managed at asthma specialist centers where experimental drugs like, methotrexate cyclosporin or IVIG may be tried on an individual basis under close monitoring.

Anti-Asthmatic Agents↗

Relative lung and total systemic bioavailability following inhalation from a metered dose inhaler compared with a metered dose inhaler attached to a large volume plastic spacer and a jet nebuliser.

OBJECTIVE: To compare the lung and systemic delivery of salbutamol following inhalation from a metered dose inhaler (MDI), a MDI attached to a spacer (MDI+SP) and a nebuliser (NEB) using a urinary pharmacokinetic method. METHOD: Twelve healthy subjects each provided urine samples at 0, 30 min and pooled up to 24 h after the start of 5 x 100 microg salbutamol inhaled from MDI and MDI + SP and after 2.5 mg was delivered by NEB. Following nebulisation, the amount of salbutamol trapped on an exhalation filter together with that remaining in the apparatus was determined. The amount left in the spacer and that leaving the MDI mouthpiece was also determined. Thus, for all the methods, the amount available for inhalation from each study dose was determined. RESULTS: The mean (+/- SD) 30-min urinary excretion amounts of salbutamol for MDI, MDI+SP and NEB were 12.6+/-3.5, 27.1+/-6.0 and 16.1+/-4.6 microg, respectively. The mean ratios (90% confidence intervals) for MDI+SP compared with MDI and NEB were 230.2 (186.7, 273.8) and 183.0 (146.4, 219.7) (both P values<0.001), respectively, while that between MDI and NEB was 134 (110.4, 159.1) (P < 0.05). The mean (+/-SD) 24-h urinary excretion values for salbutamol and its metabolite were 287.0+/-46.5, 198.1+/-34.7 and 253.4+/-138.3 microg, respectively. Following inhalation a mean of 202.9+/-51.5 microg was left in the spacer. Similarly, after nebulisation 1387.7+/-88.9 microg was left in the nebuliser chamber, 26.3+/-8.0 microg in the mouthpiece and 553.8+/-68.5 microg exhaled. The mean emitted dose from the MDI was 88.4+/-6.1 microg per actuation. When normalised for the amounts available for inhalation, the mean amounts of salbutamol excreted in the urine during the first 30 min were 2.86+/-0.78, 9.15+/-1.69 and 3.06+/-0.70% following MDI, MDI + SP and NEB, respectively. CONCLUSION: Five 100-microg doses inhaled from a metered dose inhaler attached to a spacer delivered more to the lungs and less to the systemic circulation than either the same doses from a metered dose inhaler used alone or five times the dose given via a jet nebuliser. Spacers should be routinely used instead of nebulisers to manage patients unless they are short of breath.

Adult↗

Emergent management of acute asthma.

In almost no other field is the gap between diagnostic and therapeutic knowledge and its general application so great as it is in asthma. As previously mentioned, most asthma deaths are preventable. Identification of high-risk patients, intensive education about asthma (purpose of each medication; necessity of compliance, particularly with inhaled corticosteroids; proper use of inhalers and spacer devices; home use of PEFR meter), self-treatment of mild or moderate attacks with oral corticosteroids, and written crisis plan for severe attacks explicitly telling the patient what to do and whom to call are necessary. In addition, all potential exacerating factors should be eliminated (external triggers, medication, gastroesophageal reflux, allergic rhinitis, and sinusitis). High doses of inhaled corticosteroids should be provided to all those patients, and referral to a specialist is highly recommended for such high-risk patients.

Acute Disease↗

Systemic beta-adrenoceptor responses to salbutamol given by metered-dose inhaler alone and with pear shaped spacer attachment: comparison of electrocardiographic, hypokalaemic and haemodynamic effects.

1. Seven normal subjects were given cumulative doubling doses of inhaled salbutamol either by metered-dose inhaler (MDI) alone, or in conjunction with a pear shaped spacer attachment (PSS). Dose increments were made every 20 min from 100 micrograms to 2000 micrograms. 2. Plasma potassium (K), electrocardiographic (ECG) and haemodynamic (HR, SBP and DBP) responses were measured at each dose increment. 3. There were falls in K (as mean and 95% CI) in response to salbutamol (P less than 0.001): 3.70 mmol l-1 (3.46-3.95) to 3.20 mmol l-1 (2.91-3.49) MDI, 3.78 mmol l-1 (3.61-3.95) to 3.18 mmol l-1 (3.06-3.30) PSS. 4. Salbutamol produced marked ECG effects including T wave flattening (P less than 0.001): 0.46 mV (0.24-0.68) to 0.22 mV (0.07-0.37) MDI, 0.50 mV (0.23-0.77) to 0.24 mV (0.07-0.41) PSS; and Q-Tc interval prolongation (P less than 0.001): 0.382 s (0.372-0.392) to 0.409 s (0.397-0.421) MDI, 0.378 s (0.358-0.398) to 0.410 s (0.388-0.432) PSS. U waves occurred in five subjects with MDI and in four with PSS. S-T segment depression was present in two subjects with MDI and in three with PSS. These changes were not however associated with ventricular extrasystoles. There were also significant chronotropic effects (P less than 0.001): 63 beats min-1 (57-70) to 79 beats min-1 (69-89) MDI, 58 beats min-1 (53-63) to 75 beats min-1 (69-81) PSS. 5. Comparison of dose-response curves for MDI alone and with PSS showed no significant differences, for any of the variables measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Dynamic change of the upper airway during inhalation via aerosol delivery devices.

Although it is likely that the upper airway is a major factor in the large inter- and intra-subject variation in deposition of inhaled drug aerosols in the lung, data on the configuration of the upper airway during inhalation is sparse. We have developed a unique method, using magnetic resonance imaging, to reconstruct the upper airway in three dimensions during inhalation from aerosol devices used to deliver medication to patients with asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Ten healthy adults were imaged while inhaling from a pressurized metered dose inhaler (pMDI), a spacer used with pMDI (spacer), and a high-resistance dry powder inhaler, the Turbuhaler (DPI). The mean cross-sectional area of the oropharyngeal region was significantly larger (Wilcoxon's signed-rank test with Bonferroni correction, p < 0.0167) when the DPI (281 [143] mm2, mean [SD]) was used compared to the spacer (205 [32] mm2, p = 0.016) or pMDI (152 [48] mm2, p = 0.013). Considerable variations in the cross-sectional areas of the oral cavity, oropharynx, and larynx were seen when compared to the upper trachea. The main cause for this was the varying position of the tongue during inhalation via the devices. Although differences were observed when comparing the total volume of the upper airway during inhalation via the DPI (70 [17] cm3) to the pMDI (56 [20] cm3, p = 0.037) or spacer (59 [12] cm3, p = 0.022), these did not reach significance. This study shows that there are very significant variations in the configuration of the upper airway when different devices are used for inhalation. These changes are likely to be produced by a number of factors, including tongue position, device airflow resistance, and patient effort.

Administration, Inhalation↗

Safety of inhaled corticosteroids delivered by plastic and metal spacers.

BACKGROUND: Because of its non-electrostatic properties the metal Nebuchamber (NC) valved holding chamber (VHC) delivers a greater mass of aerosol to the mouth than the polypropylene Aerochamber (AC) VHC. Delivery of more aerosol to the lungs may also increase systemic absorption of inhaled corticosteroids (ICS) and hypothalamo-pituitary-adrenal (HPA) suppression. METHODS: Thirty children (mean 4.3 (SD 0.3) years) received 200 micro g budesonide twice daily by NC or AC, both with the mask provided, in a randomised, two month crossover trial. Twenty four hour urinary free cortisol (UFC) was determined as a measure of HPA suppression. RESULTS: UFC decreased from 42.3 (7.8) nmol UFC/nmol creatinine control to 26.2 (2.4) (p = 0.06 v control) after AC, and to 24.5 (2.5) (p = 0.04 v control) after NC (p = 0.4 AC v NC). CONCLUSIONS: Despite a greater total dose delivered to the mouth, NC is not associated with greater HPA suppression when using 400 micro g/day budesonide under real life conditions in young children.

Anti-Inflammatory Agents↗

The efficacy of a low-dose, monodisperse parasympathicolytic aerosol compared with a standard aerosol from a metered-dose inhaler.

OBJECTIVE: In previous experiments we showed that monodisperse bronchodilator aerosols with a median mass aerodynamic diameter of 2.8 microm induced stronger bronchodilatations than larger aerosols and that the dilatations were clinically relevant at low doses. To discover whether the bronchodilator effects of these low-dose monodisperse aerosols differed from those of standard dosages delivered by metered-dose inhalers, we carried out a comparative trial. METHODS: Ten stable outpatients with a mean forced expiratory volume in 1 s (FEV1) of 58.1% of the predicted value inhaled a placebo aerosol, 8 microg of a 2.8-microm monodisperse ipratropium bromide aerosol and 40 microg from a metered-dose inhaler plus spacer; lung-function measurements followed. Data were analysed with repeated measurements analysis of variance (ANOVA). RESULTS: Greater improvements than with placebo were evident for the forced vital capacity (FVC), the FEV1, the specific airway conductance (sGaw), the peak flow (PEF) and the maximum expiratory flow at 75% of the forced vital capacity (MEF75). In these cases, the low-dose 2.8-microm aerosol proved to be equivalent to the higher-dose metered-dose inhaler. CONCLUSION: By changing the polydisperse characteristic of inhaled aerosols to a monodisperse pattern, the dose of the drug administered can be reduced without loss of efficacy.

Adult↗

Child and parent satisfaction with the use of spacer devices in acute asthma.

OBJECTIVE: To evaluate child and parent satisfaction with the use of spacers in acute asthma. METHODS: All parents of children presenting to the emergency department of Sydney Children's Hospital over a 3-month period with mild to moderately severe acute asthma who were treated with bronchodilators by spacer device were asked to complete an anonymous questionnaire. Children aged 8 years and older completed a separate questionnaire independently. RESULTS: One hundred and eleven of 158 parents (70%) responded. The majority (84%) found it 'easy' or 'very easy' to use the spacer and 85% reported that they intended to use the spacer at home. Of those parents who had previously used a nebulizer (n = 73), 84% said that the spacer was easier to use, 77% said that the spacer was better tolerated by their child and 84% said that overall they preferred the spacer. Seventeen of 31 children aged 8-14 years treated with a spacer (55%) responded to the satisfaction survey. All respondents found it 'easy' or 'OK' to use the spacer and the majority (82%) 'liked it' or thought 'it was OK'. The majority of children (82%) said that they preferred using spacers because it was quicker (29%) or easier to use (53%). CONCLUSION: The use of spacer devices in mild to moderately severe acute asthma is highly acceptable for children and parents; the majority prefer this mode of drug delivery to nebulization.

Acute Disease↗

Evidence-based treatments for acute asthma.

Asthma is an important health care problem; over 12 million people in the United States suffer from asthma, the majority of whom are young patients. Presentations of acute asthma to emergency departments are common. In the United States, acute asthma presentations account for close to 2 million emergency department visits annually, and these patients often exhibit acute and chronic markers of severe asthma; so controlling asthma is important from many perspectives. We review the evidence for various acute asthma therapies, using the highest levels of evidence, employing systematic reviews (especially those from the Cochrane Collaboration) and evidence from randomized controlled trials to guide therapy decisions. beta agonists and systemic corticosteroids are the cornerstones of initial treatment. Delivery of beta agonists via nebulizer or metered-dose inhaler with spacer device appear to be similarly efficacious. However, recent evidence from studies involving children and adults indicate that addition of ipratropium bromide to early beta agonist treatments may reduce airway obstruction and reduce hospital admissions, especially for more severe asthma. Evidence from systematic reviews indicates that intravenous magnesium sulfate may provide similar benefits in severe asthma. Antibiotics, intravenous beta agonists, and intravenous aminophylline have been shown to add little and may increase adverse effects. Treatment for discharged patients should include systemic corticosteroids for 5-7 days, for all but the mildest asthma. Addition of inhaled corticosteroids should be considered for most patients, since evidence suggests that inhaled corticosteroids may reduce relapses and improve quality of life. Alternative treatments such as long-acting beta agonists and leukotriene antagonists remain unproven in this setting. Linking a discharge plan to close follow-up and asthma education (especially an action plan) needs to be encouraged. Acute asthma is a common problem and treatment has improved dramatically over the past 10 years. Employing the evidence-based practice outlined above should reduce the burden of acute asthma on patients and the health care system.

Acute Disease↗

Children with mild asthma: do they benefit from inhaled corticosteroids?

In children with mild asthma, who show hardly any abnormalities in pulmonary function, objective measurement of the effect of inhaled corticosteroids is difficult. The short term effect of fluticasone propionate (FP) in these children was evaluated, using both subjective and objective parameters. A total of 68 children (5-10 yrs old) were randomly assigned to either FP 250 microg or placebo twice daily as metered-dose inhaler via spacer during 12 weeks. Symptom scores, use of rescue medication, wheezing, parent global evaluation and pulmonary function tests including forced expiratory volume in one second (FEV1), peak expiratory flow (PEF) and bronchial responsiveness (provocation dose of methacholine causing a 20% fall in FEV1 (PD20)) were evaluated. FP-treated versus placebo-treated children showed significant changes in percentage symptom-free days, use of beta2-mimetics, morning and evening PEF, FEV1 % pred and wheezing. No significant improvements were found in parent global evaluation, absolute values of FEV1 nor PD20. These findings show that inhaled corticosteroids are effective in children with mild asthma. This effect can be assessed by both objective and subjective parameters. Early start of inhaled corticosteroids should be considered even when pulmonary function is normal.

Administration, Inhalation↗

First-line therapy for adult patients with acute asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the emergency department.

We designed a larger, double-blind, randomized, prospective trial to test our hypothesis that patients with acute asthma given combination high dose therapy with ipratropium bromide (IB) and beta(2)-agonists will have greater improvement in pulmonary function and fewer hospital admissions than those given beta(2)-agonists alone. One hundred eighty patients (mean age +/- SD, 34.3 +/- 10.5 yr) who presented to an emergency department (ED) for treatment of an exacerbation of asthma (baseline FEV(1) < 50% of predicted) were assigned in a randomized, double-blind fashion to receive albuterol and placebo (n = 92) or albuterol and IB (n = 88). Both drugs were administered through a metered-dose inhaler and spacer at 10-min intervals for 3 h (24 puffs or 2,880 microg of albuterol and 504 microg of IB each hour). Primary outcome measures were improvement in pulmonary function (FEV(1) or peak expiratory flow [PEF]), and hospital admission rates. In both groups, pulmonary function improved significantly over baseline values (p < 0.01). Subjects who received IB had an overall 20.5% (95% CI: 2.6 to 38.4%) (p = 0.02) greater improvement in PEF and a 48.1% (95% CI: 19.8 to 76.4%) (p = 0.001) greater improvement in FEV(1) from the control group. At the end of protocol (3 h), 39% (n = 36) of patients in the control group and 20% (n = 18) in the IB group were admitted (p = 0.01). The use of high doses of IB reduced the risk of hospital admission 49% (relative risk = 0.51, 95% CI: 0.31 to 0.83). Five (95% CI: 3 to 17) patients would need to be treated with high doses of IB to prevent a single admission. Kaplan-Meier-estimated curves of the proportion of patients who reached the discharge threshold during the 3 h of treatment, showed a significant difference in favor of the IB group (log-rank test = 0.005). A subgroup analysis showed that patients most likely to benefit from the addition of high doses of IB were those with more severe obstruction (FEV(1) </= 30% of predicted) and long duration of symptoms before the ED presentation (>/= 24 h). On the contrary, previous use of inhaled beta(2)-agonists did not modify the admission rate and the pulmonary function response to IB. In conclusion, our data support a substantial therapeutic benefit from the addition of IB to albuterol administered in high doses through MDI plus spacer, particularly in patients with FEV(1) less than 30%, and with long duration of symptoms before the ED presentation (>/= 24 h).

Acute Disease↗

The relationship between prescribed and delivered doses of inhaled corticosteroids in adult asthmatics.

A model was developed to estimate the impact of adherence and inhalation technique over time on delivered doses of inhaled corticosteroids (ICS) for asthmatics using metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). Factors affecting inhalation technique include ongoing training, inhalation device, spacer use (with MDIs), and natural ability. Model parameters were derived from a literature review or were estimated from clinical experience. Analyses demonstrated that most patients receive a fraction of prescribed ICS doses over time. The model may be used to better understand the impact of increasing ICS dosages and to estimate the likelihood of patients being underdosed.

Administration, Inhalation↗

A comparison of lung deposition patterns between different asthma inhalers.

Drugs for the treatment and prophylaxis of asthma are delivered to the lungs by inhalation and this is facilitated by the use of pressurized metered dose inhalers (pMDIs), pMDIs with spacer devices and dry powder inhalers (DPIs). Lung deposition of drugs from pMDIs depends upon both the physicochemical nature of the aerosol formulation and the patient's inhalation technique, however, the majority of the dose from a pMDI is deposited in the oropharynx. Large volume spacer devices can reduce oropharyngeal deposition; however, lung deposition may be increased or decreased with a spacer in comparison with a pMDI, according to the design of the spacer, the aerosol formulation, the patient's inhalation technique and the extent to which the electrostatic charge on the spacer is controlled. Lung deposition of drug from DPIs also varies according to the design of the device. One DPI, Turbuhaler, deposits twice as much drug in the lungs as a pMDI, has a lower intersubject variability of lung deposition and results in lower oropharyngeal deposition.

Aerosols↗

Access to spacers and peak flow meters among medicaid patients with asthma.

Asthma morbidity and mortality have increased at alarming rates. Morbidity is significantly higher among minorities and low-income populations. The purpose of this study was to survey pharmacies licensed to provide both asthma medications and durable medical equipment (DME) to evaluate their acceptance of Medicaid as payment for spacers and peak flow meters in patients with Medicaid. Twenty-four pharmacies were identified and completed a telephone survey. Only 64% of the pharmacies licensed to accept Medicaid for DME provide this service. We postulate that improving DME licensing and claims reimbursement will impact medication compliance, as well as asthma morbidity and mortality.

Anti-Asthmatic Agents↗

[The role of inhalation chambers in the treatment of asthma].

Inhalation chambers (spacers), interposed between the aerosol doser and the patient's mouth take 3 forms: lengthened tubes, large volume plastic sacs and conical chamber in the shape of a pear. Their chief advantages are: A greater proportion of the drug reaches the airways, as the deposition in the oropharynx is reduced. Co-ordination of lung and hand, a major obstacle to the correct use of aerosol-dosers, is no longer necessary.

Administration, Inhalation↗

Addition of a spacer device as an alternative in treatment with a metered inhaler.

The effects of 50 + 50 + 100 + 200 micrograms of fenoterol, inhaled from a conventional metered dose inhaler and a metered dose inhaler with an attached spacer device, a tube extension provided with a valve, the so-called aerochamber, respectively, were evaluated in a cumulative dose response study. There were no significant difference in the effect on the lung function or the side-effects following inhalation from the metered dose inhaler with or without an aerochamber.

Adult↗

A new HFA-134a propellant in the administration of inhaled BDP via the Jet spacer: controlled clinical trial vs the conventional CFC.

This study was carried out with the aim of demonstrating the efficacy and tolerability of beclomethasone dipropionate (BDP) aerosol spray 500 microg b.i.d. via a spacer device (Jet, Chiesi Farmaceutici S.p.A.) using a new HFA-134a formulation or chlorofluorocarbon (CFC) propellant. After having completed a 2-week run-in period, 154 adult patients (77 in each group) with mild-to-moderate persistent asthma were randomised into two groups to receive the study treatment for a duration of 12 weeks in a double-blind, multinational, multicentre, parallel-group design. Morning and evening peak expiratory flow rate (PEFR), use of rescue salbutamol, number of day- and night-time asthma attacks, number of night-time awakenings due to asthma and clinical symptoms were recorded daily by patients on diary cards. Pulmonary function tests (FEV1, FVC, PEFR, FEF25-75%, MEF50 and FEF25) and vital signs were measured at the clinic at study entry, at the start of treatment and every 2 weeks thereafter. Morning serum cortisol (8.00-10.00 a.m.) was measured at the start and at the end of the treatment period. Adverse events were recorded throughout the total study period. Significant improvements over baseline were reported in both groups in terms of lung function, symptoms and use of rescue inhaled salbutamol. Equivalence between groups was demonstrated for the primary end-point morning PEFR, as well as for evening PEFR and FEV1. No statistically significant differences in the comparisons between groups, except for FEF25 (P=0.044), were observed in any of the other efficacy variables. Adverse events were reported in 31% of patients in the BDP-HFA group and in 32% in the CFC group. Adverse drug reactions were 4 and 2 in the two groups, respectively. No drug-related serious adverse events were reported in either of the groups. No signs of relevant adrenal suppression were observed in both groups: 2 patients in each group had final values below the normal range. In conclusion, the BDP-HFA-134a formulation proved to be equivalent in efficacy and comparable in safety to the standard BDP-CFC product over 12 weeks in adult patients with mild-to-moderate persistent asthma.

Administration, Inhalation↗

Albuterol delivery via tracheostomy tube.

HYPOTHESIS: Albuterol delivery through a tracheostomy tube is affected by device (nebulizer vs metered-dose inhaler), interface (mask vs T-piece), bias flow, and humidification. METHODS: A lift bar was placed between the chambers of a dual-chambered lung model such that a ventilator triggered simulated spontaneous breathing at a rate of 20 breaths/min, tidal volume of 0.4 L, and inspiratory-expiratory ratio of 1:2. An 8-mm inner diameter cuffed tracheostomy tube was placed through a semi-circular model that simulated a patient's neck. Four conditions of gas flow and humidification were used for the nebulizer experiments: heated aerosol (approximately 30 L/min, approximately 30 degrees C), heated humidity (approximately 30 L/min, approximately 30 degrees C), high flow without added humidity (approximately 30 L/min), or a nebulizer attached to the tracheostomy tube without additional flow. The nebulizer was filled with 4 mL that contained 2.5 mg of albuterol, and operated at 8 L/min. The nebulizer was tested with a T-piece or tracheostomy mask. For the metered-dose inhaler experiments, a spacer was used and actuation of the inhaler (100 microg per actuation) was synchronized with inhalation (4 actuations separated by > or = 15 s). When the spacer was used without additional flow, a valved T-piece was used with a 1-way valve placed either proximal or distal to the spacer. A filter was attached between the lung model and the distal end of the tracheostomy tube. Albuterol washed from the filter was measured by ultraviolet spectrophotometry. RESULTS: For the nebulizer, the most efficient delivery was with no flow other than that to power the nebulizer and with a T-piece (p < 0.001). The most efficient method for aerosol delivery was metered-dose inhaler with a valved T-piece and placement of the 1-way valve in the proximal position (p < 0.001). The effect of humidity was unclear from the results of this study. CONCLUSIONS: Albuterol delivery via tracheostomy was affected by the delivery device (nebulizer vs inhaler), bias gas flow, and the patient interface.

Administration, Inhalation↗