[Aerosols and spacers for acute asthma in children. Evolution and time to change the routine].
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Acute Disease↗
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Hypothalamo-pituitary-adrenal axis suppression in asthmatics inhaling high dose corticosteroids.
The frequency of hypothalamo-pituitary-adrenal (HPA) axis suppression in asthmatics taking high dose (greater than 1000 micrograms daily) inhaled corticosteroids is unknown. HPA function was studied in 78 adult asthmatics taking long-term inhaled corticosteroids (median dose 1600 micrograms, range 1200-2650 micrograms daily). All patients except one were using metered dose aerosols; 15 were using large volume spacer devices. Median duration of high dose therapy was 13 months (range 1-54). Sixty-nine patients were taking beclomethasone dipropionate (1500 micrograms, n = 36; 2000 micrograms, n = 26, greater than 2000 micrograms, n = 7) and nine budesonide (1200 micrograms, n = 2; 1600 micrograms, n = 6; 1800 micrograms, n = 1). Four patients, all of whom were taking greater than 2000 micrograms beclomethasone dipropionate, were taking 200-400 micrograms of their total dose intranasally. Twenty-six patients had discontinued long term systemic corticosteroid treatment (at least 5 mg prednisolone daily, or equivalent, for a minimum of 6 months) between 7 months and 22 years prior to assessment. All patients had measurements of 9 am serum cortisol and 24-h urine free cortisol excretion and a short tetracosactrin test. Subnormal results were: 9 am cortisol less than 190 nmol l-1; rise in serum cortisol in response to tetracosactrin less than 200 nmol l-1 and/or achieved cortisol less than 500 nmol l-1; urine free cortisol less than 80 nmol 24 h-1. Hypothalamo-pituitary-adrenal suppression was defined as subnormal results in at least two of the three tests. Tests were performed at least 2 weeks after completion of any short course prednisolone treatments. Suppression was found in 16 (20.5%) patients (1500 micrograms, n = 6; 1600 micrograms, n = 1; 2000 micrograms, n = 7; 2400 micrograms, n = 2). Risk factors identified for this suppression were: (a) previous requirement for long-term systemic corticosteroids (10/26, chi 2 = 6.1, P less than 0.02); and (b) increasing duration of high dose inhaled therapy (median 28.5 months in suppressed vs. 12 months in normal, P less than 0.05). No clear relationship was identified between HPA function and dose, even when corrected for body surface area and there was no relationship between suppression and number of short courses of prednisolone in the preceding 12 months. Screening tests of HPA function should be performed in all asthmatics taking greater than or equal to 1500 micrograms inhaled corticosteroid daily. Unless function has been shown to be normal, all patients taking these doses should carry steroid cards.
Administration, Intranasal↗
Analysis of Trichosporon isolates obtained from the houses of patients with summer-type hypersensitivity pneumonitis.
Summer-type hypersensitivity pneumonitis (SHP) is type III or IV allergies developed by repeated inhalation of arthroconidia of Trichosporon species. We identified 105 strains obtained from the homes of 36 SHP patients by analysis of the intergenic spacer (IGS) 1 region, which is located between the 26S and 5S rRNA genes; in addition, we analyzed the IGS genotypes of the strains. Serologically, Trichosporon species are classified as serotype I, II, III, or I-III. Of the 105 strains, 43 (41.1%), 53 (50.5%), and 9 (8.6%) strains were isolated as serotypes I, II, and III, respectively. Serotype I, II, and III strains were recovered from 19 (52.8%), 29 (80.6%), and 4 (11.1%) of the 36 houses of SHP patients, respectively. No serotype I-III strains were isolated from the houses. Of 43 serotype I strains, 42 (97.7%) were identified as Trichosporon dermatis, and the remaining one was T. terricola. Of 53 serotype II strains, 37 (69.8%) were identified as T. asahii, and the remaining serotype II isolates were T. aquatile (1.9%), T. coremiiforme (7.5%), T. faecale (1.9%), T. japonicum (15.1%), and T. ovoides (3.8%). There were nine serotype III strains comprised of T. montevideense (77.8%) and T. domesticum (22.2%). Intraspecies diversity was found only in T. asahii. This microorganism also causes opportunistic infections (trichosporonosis); seven genotypes of its IGS 1 region have been identified. While the strains of T. asahii obtained from Japanese patients with trichosporonosis were genotype I, the strains from the houses of SHP patients were genotype III. Based on our analysis, we conclude that the strains that play the most significant roles in the development of SHP are T. dermatis, T. asahii genotype 3, and T. montevideense, representing serotypes I, II, and III, respectively.
Alveolitis, Extrinsic Allergic↗
Delivery systems: the science.
Different delivery devices may be chosen and the prescribing physician requires information on those suitable for patients of different age, together with the reproducibility of the dose inhaled from the chosen device. A large number of different devices are currently available for inhalation therapy. Although the dose of a drug inhaled by a patient from a device may vary by up to 400%, such information is not usually available to the prescribing doctor. Spacer devices, with facemask attachments for younger children, are now the first choice device for delivery of anti-asthma aerosols to those 5 years of age or less. The dose that spacer devices deliver is governed by a variety of factors, including static charge, face mask design, spacer volume, the particular drug used, and the breathing pattern of the child. Nebulizers are generally prescribed for those not tolerating spacer devices. More recent designs, such as the open-vent nebulizer systems deliver the drug more rapidly to adults. The breath-enhanced open-vent systems have the advantage of delivering significantly more drug to older patients. These systems rely on the relatively large tidal volumes of older patients. As a result of their smaller tidal volumes, young children are unlikely to benefit as greatly from these devices. The open-vent system may result in some young children receiving less drug than from a conventional nebulizer.
Adolescent↗
Clinical pharmacology of corticosteroids in bronchial asthma.
It is now recognised that suppression of the inflammatory cascade should be the cornerstone of management in bronchial asthma. Inhaled corticosteroids are the most effective and widely used form of anti-inflammatory therapy for use in patients with asthma. The limited data available on dose-response relationships for inhaled corticosteroids suggest that a plateau occurs for antiasthmatic efficacy above 1600 micrograms either for budesonide and beclomethasone dipropionate with no appreciable differences between the two drugs. However, in most cases it should be possible to achieve adequate asthma control with doses of either drug less than 1000 micrograms with a use of an optimal inhaler device and good compliance. In contrast to topical anti-inflammatory activity in airways, for both local and systemic adverse effects there is a steep dose-response above 1600 micrograms with budesonide and beclomethasone dipropionate. In comparison with oral prednisolone there is still a better risk-benefit ratio even with higher doses of inhaled corticosteroids. There is evidence to suggest that inhaled budesonide may have a slightly more favourable profile in terms of the ratio of topical to systemic activity, particularly for effects on bone metabolism. A significant degree of adrenal suppression is unlikely at doses less than 1600 micrograms of budesonide or beclomethasone, although there is a degree of interindividual variability in the dose-response relationship for this effect, as well as for antiasthmatic activity. Thus, doses of inhaled corticosteroid should be titrated on an individual basis in order to achieve adequate disease control. At doses in excess of 800 micrograms it would seem rational to use a large volume spacer device since this will lessen local adverse effects such as oral candidiasis and dysphonia, as well as reducing systemic absorption and improving lung deposition. Mouth washing may reduce local and systemic adverse effects when using dry powder devices at high doses. Another possible strategy to improve efficacy with higher doses is to increase the dosing frequency from twice to four times daily, although this may at the same time produce an increase in local adverse effects. Fluticasone propionate is a novel inhaled corticosteroid with very high topical anti-inflammatory activity and minimal systemic bioavailability and might, therefore, provide a favourable therapeutic profile at the high end of the dose range. The next decade of research into the clinical pharmacology of inhaled corticosteroids is, therefore, eagerly awaited and will hopefully consolidate improvements in asthma management with this important class of anti-inflammatory drugs.
Administration, Inhalation↗
A comparison of three means of pressurized aerosol inhaler use.
The bronchodilator response to 200 micrograms of fenoterol hydrobromide using 3 different methods of inhalation from a pressurized aerosol metered-dose inhaler, was studied in 13 asthmatic patients. On 4 separate days and in random order, patients received either placebo aerosol or fenoterol aerosol delivered by the patients' own technique, delivered under supervision by a trained member of our staff, and delivered with a spacer device (Aerochamber) attached to the pressurized canister. There was no significant difference in the response to the 3 methods of active drug administration, but there was a significant difference (p less than 0.05) from the placebo control values. Thus, in this group of asthmatics the patients' own method of inhalation, using the standard dose of 200 micrograms of fenoterol from a pressurized aerosol metered-dose inhaler, appears to be as effective a means of bronchodilation as the other techniques used in this study.
Adult↗
Effect of electrostatic charge in plastic spacers on the lung delivery of HFA-salbutamol in children.
AIMS: The effect of the electrostatic charge in plastic spacers in vivo on drug delivery to the lung of hydrofluoroalkane (HFA) salbutamol spray was studied in children. METHODS: Five children, aged 7-12 years, were included in a 3-way crossover randomised single-blind trial. Salbutamol HFA spray was delivered on 3 different study days from plastic spacers with mouthpiece. Pre-treatment of the spacers differed between study days: (a) Non-electrostatic 350 ml Babyhaler (coated with benzalkonium chloride) (b) New 350 ml Babyhaler (rinsed in water), and (c) New 145 ml AeroChamber (rinsed in water). Plasma salbutamol was measured before and 5, 10, 15 and 20 min after inhalation of four single puffs of 100 microg salbutamol. Cmax and Cav (5-20min) were calculated as a reflection of lung dose. RESULTS: For Cmax: (A) Non-electrostatic Babyhaler 4.3 ng ml(-1) (B) New Babyhaler 1.9 ng ml(-1) (C) New AeroChamber 1.6 ng ml(-1): AvsB (95% CI for difference 0.5-4.5 ng ml(-1)), A vs C (95% CI for difference 0.7-4.8 ng ml(-1)). The geometric mean ratio for A:B was 2.4 fold, and for A:C was 2.9 fold. The values for Cav were similar with ratios for A:B of 2.4 fold, and A: C of 4.1 fold. The nonelectrostatic Babyhaler delivered a significantly (P<0.05) higher lung dose (for both Cmax and Cav) than either of the other two spacers. CONCLUSIONS: The electrostatic charge in plastic spacers reduces lung dose in children by more than two-fold. This is clinically significant and the use of potentially electrostatically charged spacers should be avoided.
Absorption↗
Bronchodilator delivery by metered-dose inhaler in ventilator-supported patients.
The optimal dose and technique for administration of bronchodilators with a metered-dose inhaler (MDI) in mechanically ventilated patients have not been established. We studied the efficacy and safety of 10 puffs (90 micrograms/puff) of albuterol administered by an MDI in seven mechanically ventilated patients with chronic obstructive pulmonary disease (COPD). Rapid airway occlusions at constant flow inflation were performed before and at 5-min intervals after administration of albuterol for 60 min. Significant decreases in maximum (Rrsmax; p < 0.01) and minimum inspiratory resistance (Rrsmin; p < 0.01) were present at 5 min and persisted for 60 min after administration of albuterol (p < 0.01 for both parameters). Rrsmax indicates maximal inspiratory resistance while Rrsmin represents the ohmic flow resistance. Intrinsic positive end-expiratory pressure decreased significantly (p < 0.05) 15 min after albuterol administration. Heart rate, blood pressure, and arterial oxygenation did not show significant change after albuterol. In summary, 10 puffs of albuterol given by an MDI and spacer produced significant bronchodilation in ventilator-supported patients with COPD, without producing side effects. In conclusion, higher doses of albuterol given by an MDI and spacer could be used routinely in mechanically ventilated patients with COPD.
Administration, Inhalation↗
Dose-response to bronchodilator delivered by metered-dose inhaler in ventilator-supported patients.
In nonintubated patients, metered-dose inhalers (MDIs) are accepted as the most convenient, efficient, and cost effective method of administering inhaled bronchodilators. Recent studies have demonstrated the efficacy of MDIs in ventilator-supported patients; however, the optimal dose of a bronchodilator from a MDI is unknown. We determined the response to increasing doses of albuterol administered by a MDI and cylindrical spacer to 12 mechanically ventilated patients with chronic obstructive pulmonary disease (COPD). Four, eight, and 16 puffs of albuterol were given at 15-min intervals. Rapid airway occlusion were performed before and at 5-min intervals after albuterol for 80 min. Respiratory mechanics were also measured for 60 min in another group of seven patients with COPD who received four puffs of albuterol. Significant decrease in airways resistance occurred after administration of albuterol (p < 0.001). The decrease in airway resistance with four puffs of albuterol was comparable to that observed with cumulative doses of 12 puffs (p = 0.12) and 28 puffs (p = 0.25). Heart rate increased significantly (p < 0.01) after a cumulative dose of 28 puffs. The decrease in airway resistance was sustained for 60 min in the group that received only four puffs of albuterol (p < 0.003). In conclusion, four puffs of albuterol given by a MDI and spacer provided the best combination of bronchodilator effect and safety in stable mechanically ventilated patients with COPD.
Administration, Inhalation↗
Formoterol inhaled as dry powder or via pressurized metered-dose inhaler in a cumulative dose-response study.
Formoterol administered by a dry-powder (DP) capsule inhaler was compared with a pressurized metered-dose inhaler (pMDI) with regard to bronchodilating and systemic effects. The study used a double-blind, crossover, double-dummy technique. Twelve patients with moderate reversible asthma in a stable phase were examined on two separate study days, and the inhalers were given in randomized order. After baseline measurements, increasing doses of formoterol were given at intervals of 75 min. FEV1 and heart rate and tremor measurements were repeated after each dose, and the doses were 12 + 12 + 24 + 48 micrograms, giving a total dose of 96 micrograms. The peak expiratory flow rate (PEFR) was recorded in the morning before the first dose, after the last dose, and then repeatedly at home until 19 h after the last dose. There was an equal increase in ventilatory capacity at each dose level, independent of inhaler device. Repeated PEFR measurements after the last dose did not reveal any differences in duration of effect. There was a slight but statistically significant increase in heart rate and tremor after the highest doses of the DP formulation compared to the pMDI. These systemic effects can probably be explained by the reduced oral deposition of the aerosol caused by using a spacer. This study indicates that the DP and pMDI formulations of formoterol are equipotent in bronchodilation.
Administration, Inhalation↗
Inhalation therapy with metered-dose inhalers and dry powder inhalers in mechanically ventilated patients.
Pressurized metered-dose inhalers (pMDIs) are commonly employed for administering bronchodilator aerosols to mechanically ventilated patients. Although it is feasible to employ dry powder inhalers in ventilator circuits, the presence of humidity in the ventilator circuit could reduce their efficiency. A complex array of factors influence drug delivery from pMDIs during mechanical ventilation, and subtle differences in the method of administration can markedly alter aerosol deposition in the lower respiratory tract. However, when the technique of administration is optimized, the efficiency of drug delivery from pMDIs in mechanically ventilated patients is comparable to that in ambulatory patients. Significant bronchodilator effects are observed with as few as 4 puffs from a pMDI and cylindrical spacer. In mechanically ventilated patients, pMDIs are a cost-effective, convenient, and safe method for delivering bronchodilator aerosols.
Administration, Inhalation↗
Effective control of asthma with hydrofluoroalkane flunisolide delivered as an extrafine aerosol in asthma patients.
BACKGROUND: Inhaled corticosteroids are established as maintenance therapy for persistent asthma. A new aerosol formulation of flunisolide delivers a small particle size by using a hydrofluoroalkane (HFA) propellant with a built-in spacer. OBJECTIVE: To compare efficacy and safety of two different flunisolide formulations, HFA and chlorofluorocarbon (CFC), with placebo treatment over a range of doses. METHODS: The multicenter, randomized, double-blind, placebo-controlled trial consisted of a 2-week, active run-in phase with CFC flunisolide 500 microg, twice daily, followed by 12 weeks of double-blind treatment with placebo, HFA flunisolide (85, 170, or 340 microg, twice daily), or CFC flunisolide (250, 500, or 1,000 microg, twice daily). Patients (N = 669) were nonsmokers, at least 12 years of age, with mild to moderate asthma who were being treated with inhaled corticosteroids. Outcome measures were change from baseline in forced expiratory volume in 1 second (FEV1), peak expiratory flow rate, as needed albuterol use, nocturnal awakenings, and asthma symptoms. RESULTS: After 12 weeks of treatment, patients receiving 170 microg, twice daily, and 340 microg, twice daily, of HFA flunisolide showed a significant (P < 0.01) improvement in percentage increase in FEV1 (12.22% at 170 microg, twice daily, and 14.69% at 340 microg, twice daily) compared with the placebo group (5.35%). At one-third the dose of CFC flunisolide, HFA flunisolide provided similar improvement in pulmonary function versus placebo. Both formulations demonstrated comparable linear dose dependency for the change from baseline in FEV1 without any evidence of cortisol suppression. Outcome values for all seven secondary efficacy measures were numerically superior in patients receiving HFA flunisolide compared with the CFC formulation. Both formulations seemed to be safe and well tolerated. CONCLUSIONS: HFA flunisolide provides comparable efficacy and safety at one-third the dose of CFC flunisolide.
Administration, Inhalation↗
Study on serum and urinary cortisol levels of asthmatic patients after treatment with high dose inhaled beclomethasone dipropionate or budesonide.
BACKGROUND: The potential for long-term adverse effects from inhaled corticosteroids relates to their systemic absorption. With increasing use of high dose inhaled corticosteroids, there is need to establish whether similar doses of beclomethasone dipropionate (BDP) and budesonide (BUD) produce clinically important differences in untoward side effects specially hypothalamo-pituitary-adrenal (HPA) axis suppression. METHODS: Fifteen asthmatic patients were started on BDP or BUD (2000 microg/day) through spacer for six weeks. Serum cortisol (9 AM and 4 PM), 24-hour urinary steroid and pulmonary function testing parameters were performed. RESULTS: The serum cortisol levels were not found to be suppressed with either BDP or BUD. Similarly no significant changes were found in 24 hours urinary excretion of steroids with either of the drugs. Significant improvement was found in values of forced expiratory volume in the first second (FEV1) with BDP. With BUD the changes in forced vital capacity (FVC) and FEV1 were found to be significant. CONCLUSION: BDP or BUD in high doses of 2000 microg/day given upto six weeks through spacer are equally effective for treatment of bronchial asthma and do not cause any significant change in serum and urinary cortisol levels, and adrenal function/HPA axis.
Administration, Inhalation↗
Spacers and holding chambers: Not the last word, we hope--a reply.
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Administration, Inhalation↗
Pharmacology and pharmacokinetics of topical corticosteroid derivatives used for asthma therapy.
Although systemic corticosteroids provide additional therapeutic benefit for persons with refractory asthma, their side effects make them less than optimal agents. Introduction of beclomethasone dipropionate (BDP), the first corticosteroid that is clinically useful when delivered by aerosol, provided a major advance in asthma therapy. Patients who were previously maintained on daily systemic steroids could be transferred to inhaled steroids with no loss of medical benefit and significant improvement in the function of the hypothalamic-pituitary-adrenal axis. The value of BDP and subsequent topical corticosteroids lies in their pharmacologic properties. These agents possess increased intrinsic potency when administered by inhaler. At the same time they have considerably lower systemic potency than corticosteroids such as hydrocortisone and dexamethasone in aerosol form. This is because the fraction of the topically useful compounds that is swallowed, which is substantial, is rapidly inactivated by first-pass metabolism in the liver. Absorption of unmetabolized drug through the pulmonary circulation accounts for most of the systemic effect of topical corticosteroids. Use of spacers in the aerosol delivery device can further increase the efficacy of these substances, or allow lowering of the dose.
Administration, Inhalation↗
[Treatment of asthma using aerosols].
The vast majority of clinicians in Europe now prescribe beta-2 agonists as first-line therapy for patients with asthma. Inhaler devices may deliver rapidly acting (beta-2 sympathomimetics) and more slowly acting (anticholinergic) bronchodilator therapy as well as prophylactic medication (sodium cromoglycate and topical corticosteroids). The metered dose inhaler (MDI) is most often prescribed, but at least 50% of patients cannot use this device efficiently and 10-15% of those who can, develop an inefficient technique. The vast majority of those patients are able to use a single-dose dry power inhaler. Recent studies have shown that a multidose dry power system can be used by most patients and is preferred to the MDI by over two-thirds of patient. The large volume spacer systems have been shown to be as good as the MDI and nebulizer systems in the management of asthma, and they are easier to use than the MDI. Nebulisers are of value in chronic asthma in children who cannot use other delivery systems. The role of nebulisers for the domiciliary treatment of asthma in adults, however, remains controversial.
Administration, Inhalation↗
The choice of inhalers in adults and children over six.
Available delivery systems for ambulatory use include the conventional suspension pressurized metered dose inhaler (MDI), the conventional MDI with add-on devices such as spacing chambers and several powder delivery systems. Gas-driven or ultrasonic nebulizers are also available but are generally reserved for in-hospital use or for the treatment of the most severely obstructed patients. It is difficult to select one best system for use in older children, adolescents and adults; all available systems have their deficiencies and these are outlined here. The most widely prescribed device, the MDI, is misused by some patients with claims of up to one-third of clinic patients showing inadequate inhaler technique. In the 1990s, the MDI has also been criticized for liberating chlorofluorocarbons (CFCs). On occasion, the adjuvants are said to precipitate cough. In some countries, the production of generic or second entry inhalers has been accompanied by vexing concerns over the bioequivalence of therapeutic aerosols. The problem of patient coordination with the inhaler is meant to be dealt with by a variety of add-on devices. Spacing chambers and reservoir systems improve drug delivery and treatment efficacy for some patients. Unfortunately, there are relatively few data on patient spacer technique or optimal teaching methods. There is considerable potential for patient misuse of these superficially simple devices. One common problem is that the devices become dirty and worn but are seldom replaced by patients. A more subtle problem is electrostatic drug adherence to the spacing chamber thereby reducing drug delivery.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
Albuterol delivery by metered-dose inhaler with a pediatric mechanical ventilatory circuit model.
STUDY OBJECTIVE: To determine albuterol delivery by metered-dose inhaler (MDI) in an in vitro pediatric mechanical ventilatory circuit model. The influence of a spacing device, endotracheal tube (ETT) diameter and length, and air humidity was also investigated. DESIGN: An albuterol MDI canister was connected to an AeroVent spacer or Airlife MDI adapter and ETT 4.0, 5.0, or 6.0 mm at commercially available and equal lengths. The ETT tip was attached to an in-line filter holder with a 1-microns type A/E glass fiber filter. Ventilator settings were fractional concentration of inspired oxygen 50%, tidal volume 250 ml, inspiratory:expiratory (I:E) ratio 1:3, rate 25 breaths/minute, temperature 35 degrees C, and a decelerating flow pattern. Ten albuterol canisters were activated two times each (total 2000 micrograms) into dry (4.0-, 5.0-, and 6.0-mm ETT) and humidified air (4.0- and 6.0-mm ETT) and repeated in triplicate. Percentage MDI output was determined by weighing the filter before and after drug administration (balance sensitivity 10 micrograms). Significant differences (p < or = 0.05) among the groups with and without a spacer and in dry and humidified air were determined by ANOVA with Scheffe's multiple comparison test. Multiple regression was used to determine significant associations between ETT diameter and length and delivery. MAIN RESULTS: With the AeroVent spacer in humidified air, delivery with the 4.0- and 6.0-mm ETT was approximately 2.3% and 5%, respectively. The spacer and dry air significantly improved delivery. CONCLUSIONS: In humidified air, the dose of albuterol by MDI with an AeroVent spacer should be doubled for children intubated with 6.0-mm ETT, and four puffs administered for every one puff desired for 4.0-mm ETT. The results of this investigation should prove useful in initial clinical trials of albuterol MDI in ventilator-dependent infants and children.
Administration, Inhalation↗