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PubMed1991

Clinical efficacy of two beta 2-sympathicomimetics in different inhalers in children with asthma. Comparison of pirbuterol in a breath-actuated inhaler and salbutamol in a customary metered-dose inhaler.

In a controlled clinical crossover trial, the therapeutic effect of pirbuterol (CAS 38677-81-5) in the Autohaler was compared to that of salbutamol in a customary metered-dose aerosol in 17 children with asthma. Each child was randomized to both treatments with a washout period of at least 1 day and at most 13 days. Ten children commenced with salbutamol and then switched over to pirbuterol, and the other 7 vice versa. The main criterion to evaluate efficacy was the forced expiratory volume after 1 s (FEV1). Other efficacy criteria were forced vital capacity (FVC) and peak expiratory flow (PEF). The patients were given detailed instructions on how to use the inhalers. Each treatment was applied in the morning with one shot (0.2 mg pirbuterol or 0.1 mg salbutamol). FEV1, FVC and PEF were measured in all patients 10 min before and 10 min after medication with the whole-body plethysmograph; further measurements were carried out in most patients 60 and 240 min after application. There was a mean increase of 47% in the FEV1 compared to baseline with pirbuterol in the Autohaler compared to a mean increase of only 30% with salbutamol in the customary metered-dose inhaler. The difference is statistically significant (p = 0.036). A linear crossover analysis showed a significant treatment effect 10 min after application in favour of pirbuterol with no significant period effects or interactions (p = 0.020). The increases of FVC and PEF after pirbuterol treatment were also remarkably higher than after salbutamol. No side effects were observed.

Administration, Inhalation↗

PubMed2004

Inhaled fluticasone versus inhaled beclomethasone or inhaled budesonide for chronic asthma.

BACKGROUND: Beclomethasone dipropionate (BDP) and budesonide (BUD) are commonly prescribed inhaled corticosteroids for the treatment of asthma, Fluticasone propionate (FP) is newer agent with greater potency in in-vitro assays. OBJECTIVES: To compare the efficacy and safety of Fluticasone to Beclomethasone or Budesonide in the treatment of chronic asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group trial register (January 2003) and reference lists of articles. We contacted trialists and pharmaceutical companies for additional studies and searched abstracts of major respiratory society meetings (1997 to 2003). SELECTION CRITERIA: Randomised trials in children and adults comparing Fluticasone to either Beclomethasone or Budesonide in the treatment of chronic asthma. Two reviewers independently assessed articles for inclusion and methodological quality. DATA COLLECTION AND ANALYSIS: One reviewer extracted data. Quantitative analyses were undertaken using RevMan analyses 1.0.1. MAIN RESULTS: 48 studies (11,479 participants) met the inclusion criteria. Methodological quality was variable. When compared at a FP:BUD/BDP dose ratio of 1:2, fluticasone produced a significantly greater FEV1 (Weighted Mean Difference (WMD) 0.11 litres, 95% Confidence Interval (CI) 0.01 to 0.20 litres), morning PEF (WMD 13 L/min, 95%CI 5 to 22 L/min) and evening PEF (WMD 11 L/min, 95%CI 1 to 20 L/min). This applied to all drug doses, age groups, and delivery devices, although subgroup analyses suggested that the relative benefit of FP may be greater in more severe patients treated with higher doses of inhaled corticosteroid. No difference between fluticasone and beclomethasone or budesonide were seen for trial withdrawals (Peto OR 0.76, 95%CI 0.53 to 1.09). Symptoms and rescue medication use were widely reported but few trials provided sufficient data for analysis. A higher likelihood of pharyngitis (Peto Odds Ratio 2.16; 95% CI 1.43 to 3.24) was apparent when patients were treated with fluticasone at twice the dose of BDP/BUD, although there was unexplained heterogeneity in this effect between trials. There was no difference in the likelihood of oral Candidiasis. Plasma cortisol and 24 hour urinary cortisol were measured frequently but data presentation was limited. REVIEWERS' CONCLUSIONS: Fluticasone given at half the daily dose of beclomethasone or budesonide leads to small improvements in measures of airway calibre, but it appears to have a higher risk of causing side-effects when given at the same daily dose.

Adult↗

PubMed2005

Inhaled fluticasone versus inhaled beclomethasone or inhaled budesonide for chronic asthma in adults and children.

BACKGROUND: Beclomethasone dipropionate (BDP) and budesonide (BUD) are commonly prescribed inhaled corticosteroids for the treatment of asthma. Fluticasone propionate (FP) is newer agent with greater potency in in-vitro assays. OBJECTIVES: To compare the efficacy and safety of Fluticasone to Beclomethasone or Budesonide in the treatment of chronic asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group trial register (January 2004) and reference lists of articles. We contacted trialists and pharmaceutical companies for additional studies and searched abstracts of major respiratory society meetings (1997 to 2003). SELECTION CRITERIA: Randomised trials in children and adults comparing Fluticasone to either Beclomethasone or Budesonide in the treatment of chronic asthma. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed articles for inclusion and methodological quality. One reviewer extracted data. Quantitative analyses were undertaken using RevMan analyses 1.0.1. MAIN RESULTS: Fifty six studies (12, 119 participants) met the inclusion criteria. Methodological quality was variable. Dose ratio 1:2: FP produced a significantly greater FEV1 (0.14 litres, 95% Confidence Interval (CI) 0.06 to 0.22), morning PEF (11.10 L/min, 95%CI 3.12 to 19.09 L/min) and evening PEF (9.31 L/min, 95%CI 5.12 to 13.5 L/min). This applied to all drug doses, age groups, and delivery devices. No difference between FP and BDP/BUD were seen for trial withdrawals. Symptoms and rescue medication use were widely reported but few trials provided sufficient data for analysis. When given at half the dose of BDP/BUD, FP led to a greater likelihood of pharyngitis. There was no difference in the likelihood of oral candidiasis. Plasma cortisol and 24 hour urinary cortisol was measured frequently but data presentation was limited. Dose ratio 1:1: FP produced a statistically significant difference in am PEF (9.58 L/min (95% CI 5.20 to 13.97)), pm PEF (7.41 L/min (95% CI 2.61 to 12.22)), and FEV1 (0.09 L (0.02 to 0.17)). The effects on exacerbations were mixed. There was an increase in the incidence of hoarseness, but no significant difference in pharyngitis, candidiasis, or cough. AUTHORS' CONCLUSIONS: Fluticasone given at half the daily dose of beclomethasone or budesonide leads to small improvements in measures of airway calibre, but it appears to have a higher risk of causing hoarseness when given at the same daily dose. Future studies should attempt to establish the relative efficacy of inhaled steroids delivered with CFC-free propellants.

Adult↗

PubMed2004

Insulin inhalation--Pfizer/Nektar Therapeutics: HMR 4006, inhaled PEG-insulin--Nektar, PEGylated insulin--Nektar.

Nektar Therapeutics (formerly Inhale Therapeutic Systems) has developed a pulmonary drug delivery system for insulin [HMR 4006, Exubera]. The rationale behind developing a pulmonary drug delivery system is to ensure that insulin powder is delivered deep into the lungs, where it is easily absorbed into the bloodstream, in a hand-held inhalation device. The device converts the insulin powder particles into an aerosol cloud for the patient to inhale. No propellants are used. The inhaler requires no power source and the clear chamber ensures that the patient knows immediately when all the insulin has been inhaled. Nektar Therapeutics, developers of the inhalation device and formulation process, has licensed the system to Pfizer. Under the terms of the agreement, Pfizer will lead the clinical development of inhaled insulin, while working with Nektar Therapeutics to develop the technology required for packaging the product. Pfizer has an agreement with Hoechst Marion Roussel (now Aventis Pharma) for developing, manufacturing and promoting inhaled insulin. Under the terms of the collaboration, Aventis Pharma will supply recombinant insulin to Nektar Therapeutics to process it into dry powder for incorporation into the inhaler device. Nektar Therapeutics will receive royalties on sales of inhaled insulin marketed by Pfizer and Aventis Pharma, and milestone payments and research support from Pfizer. Aventis Pharma's codename for the product is HMR 4006.Profil, a CRO in Germany, is cooperating with Pfizer/Aventis Pharma in the development of inhaled insulin. In March 2004, Pfizer and Aventis announced that the European Medicines Evaluation Agency (EMEA) accepted the filing of the MAA for inhaled insulin (Exubera) for the treatment of type 1 and type 2 diabetes mellitus. The two companies are working with the US FDA to determine the timing for the submission of the NDA in the US. Pfizer completed five pivotal phase III clinical trials with inhaled insulin in patients with type 1 and type 2 diabetes mellitus in 120 centres worldwide, and will use a fourth prototype inhaler device that is half the size of the first prototype, and has reduced manufacturing costs. Pfizer and its partner, Aventis Pharma, are conducting additional long-term pulmonary safety data studies in patients with type 1 and type 2 diabetes. Pfizer is also conducting phase III clinical trials with inhaled insulin in paediatric patients aged 6-17 years. Nektar Therapeutics is using its Advanced PEGylation technology to develop a dry powder-inhaled polyethylene glycol (PEG) formulation for delivering peptides efficiently across the lungs and to promote prolonged serum concentration of the peptide. PEG is a neutral, water-soluble, nontoxic polymer comprising any number of repeating units of ethylene oxide. PEGylation is designed to increase the size of the active molecule and ultimately improve drug performance by optimising pharmacokinetics, increasing bioavailability, and decreasing immunogenicity and dosing frequency. The investigation has begun with inhaled, long-acting (PEGylated) insulin [inhaled PEG-insulin, PEGylated insulin--Nektar], and is funded by Pfizer. Preclinical results of a dry powder formulation of inhaled PEG-insulin presented at the 63rd Scientific Sessions of the American Diabetes Association (ADA-2003) [June 2003, New Orleans, LA, USA] demonstrated prolonged systemic activity of insulin in dogs. Nektar Therapeutics was granted US patent 5,997,848 on a method for delivering inhalable insulin. The patent covers a method for delivering of 0.5-15 mg of aerosol dry powder insulin per dosing session in 1-4 individual dosages into the deep lung for systemic absorption. The patent does not specify the formulation of insulin or aerosol delivery device. Nektar Therapeutics estimated in June 2002 that Exubera could earn the company potential revenues of >200 million US dollars.

Administration, Inhalation↗

PubMed2000

Inhaled vs oral steroids for adults with chronic asthma.

OBJECTIVES: To determine therapeutically equivalent doses of inhaled versus oral steroids for adults with chronic asthma. SEARCH STRATEGY: The Cochrane Airways Group trials register was searched using the terms: (drug delivery systems OR ((nebuli* OR inhal* OR MDI) AND oral*)) AND ( steroid* OR corticosteroid* OR glucocorticoid* OR beclomethasone OR betamethasone OR fluticasone OR cortisone OR dexamethasone OR hydrocortisone OR prednisolone OR prednisone OR triamcinolone). SELECTION CRITERIA: Randomised controlled trials were selected of at least 4 weeks duration and included patients over the age of 15 years with chronic asthma. Trials compared inhaled steroids and oral prednisolone or prednisone; where the maximum dose for inhaled steroids was 2000 mcg/day and prednisolone 60 mg (on alternate days). DATA COLLECTION AND ANALYSIS: Two independent reviewers screened 1285 titles and abstracts from the electronic search, bibliography searches and other contacts. Of these, 10 trials met previously defined inclusion criteria. Two reviewers independently extracted study characteristics, and outcome measures. MAIN RESULTS: All trials were small and no data could be pooled. Carry-over effects were present in at least one cross-over trial. Data from six trials produced the same pattern, in which prednisolone 7.5-12 mg/day appeared to be as effective as inhaled steroid 300-2000 mcg/day. In two trials, inhaled steroid 300-400 mcg/day was more effective than prednisolone 5 mg/day. All doses of inhaled steroid appeared to be more effective than alternate day doses of prednisolone up to 60 mg on alternate days. Side-effect data were reported too variably to permit comparisons. A 30% incidence was reported in one study in patients receiving prednisolone 5 mg/day, none were reported in patients on inhaled steroids. REVIEWER'S CONCLUSIONS: A daily dose of prednisolone 7.5-10 mg/day appears to be equivalent to moderate-high dose inhaled corticosteroids. Side-effects may be present on low doses, so if there is no alternative to oral steroids, the lowest effective dose should be prescribed.

Administration, Inhalation↗

PubMed2005

Assessment of different methods of inhalation from salbutamol metered dose inhalers by urinary drug excretion and methacholine challenge.

AIMS: Methods to determine the lung delivery of inhaled bronchodilators from metered dose inhalers include urinary drug excretion 30 min post inhalation and methacholine challenge (PD20). We have compared these two methods to differentiate lung delivery of salbutamol from metered dose inhalers using different inhalation methods. METHODS: In phase 1 of the study, on randomized study days, 12 mild asthmatics inhaled placebo, one and two 100 microg salbutamol doses from a breath actuated metered dose inhaler, in randomized fashion on different days. In phase 2, they inhaled one 100 microg salbutamol dose from a metered dose inhaler using a SLOW (20 l min(-1)) and a FAST (60 l min(-1)) inhalation technique and a slow inhalation delayed until after they had inhaled for 5 s (LATE). Urinary excretion of salbutamol (0-30 min) and PD20 were measured after each dose. RESULTS: Following placebo, one and two 100 microg salbutamol doses, the geometric mean for PD20 was 0.10, 0.41 and 0.86 mg respectively and the mean (SD) urinary drug excretion after one and two doses was 2.25 (0.65) and 5.37 (1.36) microg, respectively. After SLOW, FAST and LATE inhalations the geometric mean for PD20 was 0.50, 0.40 and 0.42 mg, respectively, and mean (SD) salbutamol excretion was 2.67 (0.84), 1.90 (0.70) and 2.72 (0.67) microg, respectively. Only the amount of drug excreted during the FAST compared with the SLOW and LATE inhalations showed a statistical difference (95% confidence interval on the difference 0.12, 1.54 and 0.06, 1.59 microg, respectively). CONCLUSIONS: Urinary salbutamol excretion but not PD20 showed differences between the inhalation methods used. When using a metered dose inhaler slow inhalation is better and co-ordination is not essential if the patient is inhaling when they actuate a dose of the drug.

Administration, Inhalation↗

PubMed2000

Poor inhalation technique, even after inhalation instructions, in children with asthma.

The aim of this study was to evaluate the effect of instructions to children with asthma (given by general practitioners or by pharmacy assistants) on how to inhale from metered dose inhalers with spacers (MDI/s) or dry powder inhalers (DPI). We scored inhalation technique of asthmatic children according to criteria defined by the Netherlands Asthma Foundation, and related the performance to the inhalation instructions given. For each inhaler, a number of steps were considered essential for reliable drug delivery. Patients newly referred for asthma were asked to demonstrate their inhalation technique and to fill out a questionnaire on the inhalation instruction received prior to referral. Children participating in a clinical trial, who had received repeated comprehensive inhalation instructions, served as a control group. Sixty-six newly referred patients (1-14 years of age, median age 5 years; 37 boys) and 29 control patients (5-10 years of age, median age 7 years; 21 boys) completed the study. Sixty patients (91%) had received inhalation instruction prior to referral. Only 29% of these patients, using a dry powder inhaler, performed all essential steps correctly, compared to 67% of children using a metered dose inhaler/spacer combination (P < 0.01). Children who had received comprehensive inhalation instructions with repeated checks of proper inhalation technique at the pharmacy or in the clinical trial setting were more likely to perform all essential steps correctly (79% and 93%, respectively) than children who had received a single instruction by a general practitioner (39%, P < 0.01). Many asthmatic children use their inhalers devices too poorly to result in reliable drug delivery, even after inhalation instruction. Comprehensive inhalation instruction and repeated check-ups are needed to assure reliable inhalation technique.

Administration, Inhalation↗

PubMed2004

Use of a cognitive ergonomics approach to compare usability of a multidose dry powder inhaler and a capsule dry powder inhaler: an open-label, randomized, controlled study.

BACKGROUND: Usability (ease of use) is an important feature of inhalers to ensure optimal dose delivery OBJECTIVE: The aim of this study was to compare the usability of a multidose dry powder inhaler (mDPI) and a capsule dry powder inhaler (cDPI) in older individuals, using a range of qualitative and quantitative techniques from the field of cognitive ergonomics. METHODS: Participants aged >50 years were enrolled in this 2-visit, open-label, randomized, controlled, parallel-group study conducted at Northumbria University, Newcastle upon Tyne, United Kingdom. Participants who had used an inhaler or were inhaler naive were randomized to use the mDPI or cDPI. At visit 1, the inhaler procedure was demonstrated twice by the investigator. Participants then repeated the procedure (although they were not expected to inhale because no drug was to be administered) until they made 3 consecutive correct attempts. They also undertook a range of tests to assess their confidence in using the device, manual dexterity, and self-efficacy At visit 2 (2 days later), participants made a single inhaler attempt before receiving any demonstrations from the investigator; this was intended to simulate clinical practice, in which the patient may not use an inhaler for a few days after it is prescribed. Participants then completed the inhaler procedure 10 times while undertaking a concurrent distracter task. The number of critical errors (ie, those having a high impact on dose delivery) was recorded for all attempts. To facilitate subsequent correlation analyses, an overall performance measure was derived from a combination of the results of the single inhaler trial and the 10 trials with a distracter. RESULTS: Eighty individuals (51 women, 29 men; mean [SD] age, 74.1 [7.5] years) participated in the study(40 participants per device). Forty of the participants (50%) had used an inhaler previously; 40 (50%) were inhaler naive. Based on the overall performance measure, participants testing the mDPI made significantly fewer critical errors than participants testing the cDPI (P < 0.001). Participants rated both inhalers as easy to use but were overconfident concerning their ability to use the 2 devices. CONCLUSIONS: In this study of usability of an mDPI and a cDPI in older participants, participants found both inhalers easy to use, but fewer critical errors were made with the mDPI compared with the cDPI. However, the results suggest a degree of overconfidence and the need for continual monitoring of patients' inhalation technique, especially with the cDPI.

Administration, Inhalation↗

PubMed2001

Comparison of clearance of particles inhaled with bolus and extremely slow inhalation techniques.

Ten healthy nonsmokers inhaled 6-microm (aerodynamic diameter) Teflon particles labelled with 111In twice, once with the shallow bolus technique (volumetic lung depth 76+/-20 mL ([+/- SD]) and once with the extremely slow inhalation technique (0.05 L/s). The radioactivity in the lungs was measured at 1 and 24 hours as well as at 1, 2, and 3 weeks after both inhalations. The 24-hour lung retention a percentage of lung deposition was significantly lower for the bolus inhalation, 46%+/-9% (+/- SD) than for the extremely slow inhalation, 56%+/-11%. The retention after 21 days as a percentage of the 24-hour retention was 55%+/-9% for the shallow bolus inhalation and 56%+/-10% for the extremely slow inhalation. Also within the subjects, clearance was similar for the 2 modes of inhalation. Deposition of particles inhaled with the 2 modes of inhalation was calculated with 2 model, one being based on Monte (Carlo particle transport together with an asymmetric lung model. Deposition predicted with this model agreed well with the experimental data under the assumption that there are large retained fractions only in small ciliated airways (bronchioli) and not in large ones. For the bolus inhalation, the model predicted 43% to 50% deposition in the bronchial (BB) region of initial lung deposition, 33% to 38% in the bronchiolar (bb) region, and 16% to 22% in the alveolar region. For the extremely slow inhalation, the model predicted 31% to 34% deposition in the BB region, 45% to 47% in the bb region, and 21% to 22% in the alveolar region. In addition, it predicted about the same ratio between bb and alveolar depositions for the 2 modes of inhalation. Thus, both the experimental and theoretical data indicate that the shallow bolus particles to a considerable extent reach both the bb and the alveolar regions and that they do that at about the same extent as the particles inhaled extremely slow. This conclusion is concerning the experimental data based on the assumption that there are no large retained fractions in the BB region. Another interpretation of the similar clearance for the two modes of inhalation is that there are large retained fractions in both the BB and the bb regions and that individual charactristics of clearance of these fractions are of importance rather than the site of deposition.

Administration, Inhalation↗

PubMed2001

Systematic review of clinical effectiveness of pressurised metered dose inhalers versus other hand held inhaler devices for delivering corticosteroids in asthma.

OBJECTIVE: To determine the clinical effectiveness of pressurised metered dose inhalers (with or without spacer) compared with other hand held inhaler devices for the delivery of corticosteroids in stable asthma. DESIGN: Systematic review of randomised controlled trials. DATA SOURCES: Cochrane Airways Group trials database (Medline, Embase, Cochrane controlled clinical trials register, and hand searching of 18 relevant journals), pharmaceutical companies, and bibliographies of included trials. TRIALS: All trials in children or adults with stable asthma that compared a pressurised metered dose inhaler with any other hand held inhaler device delivering the same inhaled corticosteroid. RESULTS: 24 randomised controlled trials were included. Significant differences were found for forced expiratory volume in one second, morning peak expiratory flow rate, and use of drugs for additional relief with dry powder inhalers. However, either these were within clinically equivalent limits or the differences were not apparent once baseline characteristics had been taken into account. No significant differences were found between pressurised metered dose inhalers and any other hand held inhaler device for the following outcomes: lung function, symptoms, bronchial hyper-reactivity, systemic bioavailability, and use of additional relief bronchodilators. CONCLUSIONS: No evidence was found that alternative inhaler devices (dry powder inhalers, breath actuated pressurised metered dose inhalers, or hydrofluoroalkane pressurised metered dose inhalers) are more effective than the pressurised metered dose inhalers for delivery of inhaled corticosteroids. Pressurised metered dose inhalers remain the most cost effective first line delivery devices.

Adult↗

PubMed2003

The inhalation manager: a new computer-based device to assess inhalation technique and drug delivery to the patient.

The rational choice of an inhalation device is a cornerstone in the effective management of asthma and COPD. In this publication, we describe the development of a new system, the Inhalation Manager, which, for the first time, offers the possibility to assess the entire inhalation maneuver of patients using original devices under everyday conditions. So far the Inhalation Manager allows the measurement of inspiratory maneuvers of patients through placebo inhalation devices of the most common breath-actuated CFC-free inhalers in the market for the three main glucocorticosteroids Budesonide [Turbohaler (TH), dry powder inhaler (DPI)], Beclomethasone dipropionate [Autohaler (AH), breath-actuated pressurized metered dose inhaler (pMDI)], and Fluticasone propionate [Diskus (DI), DPI] by means of a pneumotachometer. In addition, it allows allocation of the individual maneuver to the expected drug delivery values (mass output and particle size distribution) of these three devices. In a field trial, the inhalation technique of 628 (TH), 794 (AH), and 795 (DI) patients, respectively, was tested in 72 pulmonologist practices with the Inhalation Manager. For patients in the 18-59-year-old group, the Inhalation Manager detected the following percentages needing improvement: 1.5% for the Autohaler device, 16.7% for the Diskus, and 38.9% for the Turbohaler. In the 60-99-year-old group, percentages needing improvement were 1.5%, 31.5%, and 66.1% for the Autohaler, Diskus, and Turbohaler, respectively. Therefore, the Inhalation Manager could become an essential tool in asthma management by finding the most suitable inhaler for an individual patient and by training the optimal inhalation technique.

Adolescent↗

PubMed2000

Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults.

OBJECTIVES: To determine the effect of iNO, compared with inhaled placebo, on outcome in AHRF in children and/or adults. SEARCH STRATEGY: Randomised controlled trials (RCT's) were identified from electronic databases; MEDLINE, EMBASE, the Cochrane Library, and CINAHL, as well as from bibliographies of retrieved articles. Relevant journals and conference proceedings were hand searched and authors published in this field were contacted for knowledge of unpublished ongoing trials. SELECTION CRITERIA: RCT's comparing iNO with maximal conventional therapy and inhaled placebo, for AHRF in either children or adults. DATA COLLECTION AND ANALYSIS: Data were extracted and the analyses performed independently by two reviewers. All 5 authors were contacted for missing data. Qualitative assessment of each trial was made according to methodology described by Schulz (Schulz 1995), and analyses according to statistical methods in Review Manager MetaView 3.1. The fixed effect model was applied. Where possible, sub-group analyses were performed to assess the impact of iNO in varied doses. MAIN RESULTS: Five RCT's were evaluated, assessing 535 patients with AHRF. Inhaled nitric oxide made no impact on mortality in trials without cross-over (RR 0.98, 95%CI 0.66, 1.44), or with cross-over of treatment failures to open-label iNO (RR 1.22, 95%CI 0.65, 2.29). Published evidence from one study demonstrated that iNO resulted in a transient improvement in oxygenation in the first 24 hours of treatment: the oxygenation index (OI) showed a mean difference of -3 [95% CI -5.354, -0.646], and PaO2/FiO2 ratio, a mean difference of 35 [95% CI 20.236, 49.764]. Limited data demonstrated no difference in ventilator-free days between treatment and placebo groups, and no specific dose of iNO was significantly advantageous over another. Other clinical indicators of effectiveness, such as duration of hospital and intensive care stay, were inconsistently reported. There were no complications reported to be directly attributable to this treatment. REVIEWER'S CONCLUSIONS: From the data provided to date, iNO had no effect on mortality and only transiently improved oxygenation in AHRF in children and/or adults. There was a lack of data to assess other end points. The long term adverse effects of this drug are not known, as no long term follow-up of trial participants has been reported. If further trials comparing iNO with an inhaled placebo are to proceed, they should be stratified for primary disease and must specifically evaluate clinically relevant outcomes, before any benefit of iNO in AHRF can be excluded.

Acute Disease↗

PubMed2001

The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension.

UNLABELLED: Selective pulmonary vasodilation is an advantageous therapeutic strategy for cardiac surgical patients with increased pulmonary vascular resistance (PVR) and right ventricular failure. We hypothesized that milrinone, an adenosine-3',5'-cyclic monophosphate (cAMP)-selective phosphodiesterase enzyme (PDE) inhibitor may, when nebulized and inhaled, cause selective pulmonary vasodilation and potentiate the vasodilation by inhaled prostacyclin (iPGI(2)). Consequently, we investigated the hemodynamic effects of inhaled milrinone or the combination iPGI(2) + inhaled milrinone in cardiac surgical patients with postoperative mean pulmonary arterial pressure (MPAP) >25 mm Hg and PVR >200 dynes. s(-1). cm(-5). During mechanical ventilation and using a conventional nebulizing system, 9 patients inhaled incremental concentrations of milrinone (0.25, 0.5 and 1 mg/mL) in subsequent 10-min periods (Study Part 1). In the same manner, 11 patients received iPGI(2) (10 microg/mL) followed by the combination of iPGI(2) (10 microg/mL) and inhaled milrinone (1 mg/mL) (Study Part 2). Inhaled milrinone reduced PVR with a maximal effect (-20%, P < 0.001) at the largest concentration. As compared with iPGI(2) alone, iPGI(2) + inhaled milrinone caused a further and prolonged reduction of PVR (-8%, P < 0.05) and increased stroke volume (+5%, P < 0.05). Systemic vascular resistance or mean arterial pressure was not affected by inhalation of either drug(s). The authors conclude that inhalation of the cAMP-selective PDE-inhibitor milrinone selectively dilates the pulmonary vasculature without systemic effects in cardiac surgical patients with pulmonary hypertension. Furthermore, inhaled milrinone appears to potentiate and prolong the pulmonary selective vasodilatory effect of iPGI(2). Inhaled milrinone alone or combined with iPGI(2) may be an important therapeutic option in the treatment of patients with pulmonary hypertension and right ventricular failure. IMPLICATIONS: Pulmonary hypertension may cause or aggravate right heart failure. IV vasodilators reduce systemic blood pressure and might thereby further impair coronary perfusion and right heart performance. In the present study of cardiac surgical patients with pulmonary hypertension, selective pulmonary vasodilation without systemic effects was induced by nebulized, inhaled vasodilators.

Administration, Inhalation↗

PubMed1990

Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a pressurised metered dose inhaler, as a dry powder, and as a nebulised solution.

The lung dose and deposition patterns of drug delivered by dry powder inhaler are not known. The effects of inhaling 400 micrograms salbutamol delivered by dry powder inhaler (two 200 micrograms salbutamol Rotacaps), by pressurised metered dose inhaler, and by Acorn nebuliser were studied in nine subjects with chronic stable asthma. Technetium-99m labelled Teflon particles were mixed with micronised salbutamol in the pressurised metered dose inhaler and in the capsules; technetium-99m labelled human serum albumin was mixed with the salbutamol solution for the nebuliser study. The pressurised metered dose inhaler deposited 11.2% (SEM 0.8%) of the dose within the lungs; this was significantly more than the dose deposited by the dry powder inhaler (9.1% (0.6%], but did not differ significantly from the dose delivered by the nebuliser (9.9% (0.7%]. Distribution within the peripheral third of the lung was significantly greater with the nebuliser than with the other two systems; FEV1 improved to a significantly greater extent after inhalation of 400 micrograms salbutamol from the pressurised metered dose inhaler (35.6% from baseline) than from the nebuliser (25.8%) or dry powder inhaler (25.2%). Thus after inhalation of similar doses of salbutamol a larger proportion of drug was deposited within the lungs when it was inhaled from a metered dose inhaler than from a dry powder system; the nebuliser achieved the greatest peripheral deposition. The bronchodilator response seems to depend on the amount of drug within the lungs rather than its pattern of distribution.

Administration, Inhalation↗

PubMed1994

Relative bioavailability of salbutamol to the lung following inhalation using metered dose inhalation methods and spacer devices.

BACKGROUND: Inhalation aids do not require coordination between actuation of a metered dose inhaler (MDI) with inspiration and reduce oropharyngeal impaction. The delivery of salbutamol to the lung and systemic availability following inhalation with three commonly used spacers and an open mouth technique have been evaluated using a simple noninvasive technique based on urinary excretion 30 minutes and 24 hours after the dose. METHODS: Ten healthy subjects inhaled, on randomised study days, 4 x 100 micrograms from a Ventolin MDI and, subsequently, with the aid of a Volumatic, Bricanyl Spacer, and Nebuhaler spacer device. In addition, an open mouth inhaler technique was evaluated. Urine samples were collected 0-30 minutes and 0.5-24 hours after inhalation. From these samples the relative bioavailability to the lung (urinary salbutamol excretion 30 minutes after dosing) and the systemic bioavailability of the dose (24 hour urinary excretion of salbutamol and its metabolite) for each inhalation method was obtained. RESULTS: The mean (SD) urinary excretion of salbutamol 30 minutes after inhalation using the MDI alone and with the Volumatic, Bricanyl Spacer, Nebuhaler, and open mouth technique was 2.83 (0.78)%, 3.37 (0.69)%, 4.09 (0.91)%, 4.34 (1.60)%, and 3.49 (0.98)%, respectively, expressed as a percentage of the nominal dose. The nebuhaler and Bricanyl Spacer spacer devices were found to increase the relative bioavailability of salbutamol to the lung compared with the MDI alone. Compared with the MDI the inhalation aid increases were much greater than the intra-individual variability of the urinary excretion method. In 11 individuals who each repeated the same inhalation procedure on four separate occasions, the mean (SD) coefficient of variation was 8.24 (2.36)%. The mean (SD) 24 hour urinary excretion of salbutamol and its metabolites was 26.6 (6.79), 27.0 (7.95), and 55.6 (9.74)% of the salbutamol dose for the Volumatic, Nebuhaler, and MDI, respectively. Similar values following the open mouth method and Bricanyl Spacer were 48.9 (10.97)% and 43.8 (11.57)%. These values, representing the systemic availability of the inhaled dose, were lower when inhaling with the aid of the Volumatic and Nebuhaler than inhalation from the MDI alone. CONCLUSIONS: Spacer devices improve pulmonary bioavailability of salbutamol and reduce the systemically available dose.

Administration, Inhalation↗

PubMed1995

Recent trends in the use of inhaled beta 2-adrenergic agonists and inhaled corticosteroids in Saskatchewan.

OBJECTIVE: To examine recent trends in the use of inhaled beta 2-adrenergic agonists and inhaled corticosteroids for the treatment of asthma among Saskatchewan residents and to determine whether these trends are in keeping with widely publicized guidelines recommending a reduction in the use of agents to treat symptoms (i.e., inhaled beta 2-adrenergic agonists) and increased use of prophylactic agents (i.e., inhaled corticosteroids). DESIGN: Descriptive pharmacoepidemiologic study conducted with the use of data from the computerized database of the Saskatchewan Prescription Drug Plan. SETTING: Saskatchewan. PATIENTS: Saskatchewan residents 5 to 54 years of age who received one or more outpatient prescriptions for drugs to treat asthma (inhaled drugs, ingested beta 2-adrenergic agonists and ingested methylxanthines) from 1989 to 1993. OUTCOME MEASURES: Epidemiologic trends, calculated for each year: number of prescriptions per 1,000 persons; number of patients who received prescriptions for inhaled corticosteroids, inhaled beta 2-adrenergic agonists and any type of drug to treat asthma; mean number of such prescriptions per patient; and weighted mean amount of salbutamol, fenoterol and beclomethasone dispensed per patient. RESULTS: There has been an increase in the proportion of the population receiving prescriptions for drugs to treat asthma. The number of patients receiving these drugs per 1,000 people rose during the study period from 33.38 to 46.59 for any drug to treat asthma, from 24.70 to 33.77 for inhaled beta 2-adrenergic agonists and from 6.1 to 19.9 for inhaled corticosteroids. The mean number of prescriptions per patient decreased steadily for all drugs to treat asthma (from 5.34 in 1989 to 3.88 in 1993), for inhaled beta 2-adrenergic agonists (from 4.35 to 3.09) and for inhaled corticosteroids (from 2.98 to 2.25). The weighted mean amount of inhaled salbutamol dispensed per patient per year decreased by 40%, from 178.08 mg in 1989 to 109.14 mg in 1993. The weighted amount of fenoterol dispensed per patient per year declined even more, by 58%, from 387.91 mg in 1989 to 164.00 mg in 1993. Conversely, the weighted amount of inhaled beclomethasone dispensed per patient per year increased by 35% from 46.95 mg in 1989 to 63.50 mg in 1992, then dropped to 56.17 mg per year in 1993. CONCLUSION: These data demonstrate a substantial change in Saskatchewan in the prescribing of drugs to treat asthma; they suggest that many physicians responded to current guidelines advocating increased attention to prevention of airway inflammation in the treatment of asthma.

Administration, Inhalation↗

PubMed2001

Systematic review of clinical effectiveness of pressurised metered dose inhalers versus other hand held inhaler devices for delivering beta (2 )agonists bronchodilators in asthma.

OBJECTIVES: To determine the clinical effectiveness of pressurised metered dose inhalers compared with other hand held inhaler devices for delivering short acting beta(2) agonists in stable asthma. DESIGN: Systematic review of randomised controlled trials. DATA SOURCES: Cochrane Airways Group specialised trials database (which includes hand searching of 20 relevant journals), Medline, Embase, Cochrane controlled clinical trials register, pharmaceutical companies, and bibliographies of included trials. TRIALS: All trials in children or adults with stable asthma that compared the pressurised metered dose inhaler (with or without a spacer device) against any other hand held inhaler device containing the same beta(2) agonist. RESULTS: 84 randomised controlled trials were included. No differences were found between the pressurised metered dose inhaler and any other hand held inhaler device for lung function, blood pressure, symptoms, bronchial hyperreactivity, systemic bioavailability, inhaled steroid requirement, serum potassium concentration, and use of additional relief bronchodilators. In adults, pulse rate was lower in those using the pressurised metered dose inhaler compared with those using Turbohaler (standardised mean difference 0.44, 95% confidence interval 0.05 to 0.84); patients preferred the pressurised metered dose inhaler to the Rotahaler (relative risk 0.53, 95% confidence interval 0.36 to 0.78); hydrofluoroalkane pressurised metered dose inhalers reduced the requirement for rescue short course oral steroids (relative risk 0.67, 0.49 to 0.91). CONCLUSIONS: No evidence was found to show that alternative inhaler devices are more effective than standard pressurised metered dose inhalers for delivering acting beta(2 )agonist bronchodilators in asthma. Pressurised metered dose inhalers remain the most cost effective delivery devices.

Adrenergic beta-Agonists↗

PubMed2000

Inhaled corticosteroids for asthma therapy: patient compliance, devices, and inhalation technique.

BACKGROUND: Patient compliance, inhalation devices, and inhalation techniques influence the effectiveness of inhaled medications. METHODS: This article presents the results of a systematic literature review of studies measuring compliance with inhaled corticosteroids, measuring inhalation technique with different inhalation devices, and estimating the proportion of inhaled drug that is deposited in the lung. RESULTS: Overall, patients took the recommended doses of inhaled medication on 20 to 73% of days. Frequency of efficient inhalation technique ranged from 46 to 59% of patients. Education programs have been shown to improve compliance and inhalation techniques. The lung deposition achieved with different inhalers depends on particle size as well as inhaler technique. CONCLUSION: This review demonstrates that multiple factors may come between a prescription of an inhaled corticosteroid and the arrival of that medicine at its target organ, the lung.

Adrenal Cortex Hormones↗