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Concept: Nebulizer

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Background Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. Methods In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. Results Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. Conclusions Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319 .).

Concepts: Asthma, Median, Interquartile range, Paracetamol, Aspirin, Normal distribution, Inhaler, Nebulizer

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Problems with the use of inhalers by patients were noted shortly after the launch of the metered dose inhaler (MDI) and persist today. We aimed to assess the most common errors in inhaler use over the last 40 years in patients treated with MDI or dry powder inhalers (DPI).

Concepts: Asthma, Patient, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler, Nebulizer, Drug delivery devices

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Management of life-threatening acute severe asthma in children and adults may require anaesthetic and intensive care. The inhaled route for drug delivery is not appropriate when only small respiratory gas volumes are shifted; the i.v. route may be associated with greater side-effects. Magnesium sulphate i.v. has a place in acute asthma management because it is a mild bronchodilator, and has a stabilizing effect on the atria which may attenuate tachycardia occurring after inhaled and i.v. salbutamol. If intubation and ventilation are required, a reduction in bronchoconstriction by any means before and during these procedures should reduce morbidity. This narrative review aims to show strengths and weakness of the evidence, present controversies, and forward opinions of the author. The review contains a practical guide to the setting up, use and efficiency of nebulizers, metered dose inhalers, and spacers (chambers). It also presents a commonsense approach to the management of severe asthmatics in whom delay in bronchodilatation would cause clinical deterioration. When self-inhaled agents have had no effect, i.v. drugs may help avoid intubation and ventilation. The review includes suggestions for the use of inhaled anaesthetics, anaesthetic induction, and brief notes on subsequent ventilation of the lungs.

Concepts: Asthma, Lung, Magnesium, Magnesium sulfate, Allergy, Epinephrine, Nebulizer, Bronchoconstriction

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Acapella® 27 produces high frequency oscillations and positive expiratory pressure (HFOPEP) for use in bronchial hygiene. However, its performance in aerosol delivery has not been described. The aim of this study was to evaluate the effect of nebulizer configuration in relation to the HFOPEP device on deposition of radiotagged aerosols with healthy subjects.

Concepts: Asthma, Aerosol, Dosage forms, Nebulizer, Aerosol spray, Configuration management, CS gas

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An interaction between device resistance and inhalation flow provides the ‘energy’ to de-aggregate the metered dose of a dry powder inhaler (DPIs). Hence all dry powder inhalers demonstrate flow dependent dose emission but information on this at low flows is not available. We have adapted the compendial method for the Andersen Cascade Impactor (ACI) to include a mixing inlet to determine the aerodynamic dose emission characteristics of a salbutamol Diskus® [DSK], Easyhaler® [EASY] and Clickhaler® [CLICK] and the terbutaline Turbuhaler® [TBH] using flows of 10-60L/min and inhalation volumes of 2 and 4L. All DPIs demonstrated flow dependent dose emission (p<0.001) but there was no difference in the measurements between 2 and 4L. The flow dependent dose emission properties of each DPI started to plateau when the pressure change inside each device, during an inhalation, was between 1-1.5kPa. This corresponds to inhalation flows of 40.1-49.1, 25.4-28.9, 23.6-28.9 and 29.7-36.3L/min through DSK, CLICK, TBH, and EASY. The adapted methodology allows measurements at low flows. The results highlight that the compendial methodology to use an inhaled volume of 4L with the ACI could be replaced by 2L and that the recommendation to make measurements using a pressure drop of 4kPa should be revised.

Concepts: Asthma, Volume, Thermodynamics, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler, Nebulizer

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Asthma is an increasing pathology with poor compliance. Achievement of control is possible but under intensive treatment. In this setting, fluticasone/salmeterol association delivered by dry powder inhalers is a valuable and proved option. A prospective, parallel, open-label, phase IV, multicentre non-inferiority study was conducted to determine therapeutic similarity between 2 different inhalers: Generic DPI and Diskus®, which both deliver a fluticasone/salmeterol association (CAS 80474-14-2/CAS 89365-50-4). A 103 uncontrolled asthmatic patients were randomly assigned in 2 groups, Generic (G) and Diskus® (D), and received the association for 18 weeks through the appropriate device. They were evaluated according to Asthma Quality of Life Questionnaire and GINA/NIH guidelines. To demonstrate non-inferiority, the estimation of the Relative Risk between the Global Score Rate per group with its 95% confidence interval was calculated and compared against a non-inferiority margin obtained from a previous study. The Global Score Rate was 82% for G Group and 83% for D Group. The RR was 1.0124 (95% CI: 0.847-1.210). The margin set at 0.832 was not reached by the lower 95% CI (z=-2.097; p=0.018) pointing out non-inferiority. The results have demonstrated non-inferiority between groups. Thus, the 2 products are therapeutically similar.

Concepts: Asthma, Relative risk, Dry powder inhaler, Inhaler, Nebulizer, Phase IV, Salmeterol, Fluticasone/salmeterol

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Introduction: Computational fluid dynamics (CFD) has recently seen increased use in the design of pharmaceutical inhalers. The use of CFD in the design of inhalers is made difficult by the complex nature of aerosol generation. At present, CFD has provided valuable insight into certain aspects of inhaler performance, though limitations in computational power have prevented the full implementation of numerical methods in the design of inhalers. Areas covered: This review examines the application of CFD in the design of aerosol drug delivery technologies with a focus on pressurized metered-dose inhalers (pMDI), nebulizers and dry powder inhalers (DPIs). Challenges associated with the application of CFD in inhaler design are discussed along with relevant investigations in the literature. Discussions of discrete element modeling (DEM) and the simulation of pharmaceutical aerosol dispersion are included. Expert opinion: The extreme complexity of coupled fluid and aerosol dynamics associated with aerosol generation has somewhat limited the use of CFD in inhaler design. Combined CFD–DEM simulations provide a useful tool in the design of DPIs, though aerosol generation in pMDIs and nebulizers has eluded CFD modeling. The most beneficial use of CFD typically occurs when concurrent CFD and experimental analyses are performed, significantly enhancing the knowledge provided by experiment alone.

Concepts: Fluid mechanics, Computer simulation, Computational fluid dynamics, Metered-dose inhaler, Navier–Stokes equations, Dry powder inhaler, Inhaler, Nebulizer

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Substituting spacer by another in noninvasive ventilation (NIV) involves many variables, e.g. total emitted dose (TED), mass median aerodynamic diameter (MMAD), type of spacer, total lung deposition and total systemic absorption, which must be adjusted to ensure patient optimum therapy. Data mining based on artificial neural networks and genetic algorithms were used to model in vitro inhalation process, predict and optimize bioavailability from inhaled doses delivered by metered dose inhaler (MDI) using different spacers in NIV. Modeling of data indicated that in vitro performance of MDI-spacer systems was dependent mainly on fine particle dose (FPD), fine particle fraction (FPF), MMAD and to lesser extent on spacer type. Ex vivo model indicated that amount of salbutamol collected on facemask filter was directly affected by FPF. In vivo model (24hQ) depended directly on spacer type, FPF and TED. Female patients showed higher 0.5hQ and 24hQ values than males. AeroChamber VC spacer demonstrated higher TED and 24hQ in vivo values. Results indicated suitability of MDI-spacer systems in achieving appropriate in vitro inhalation performance. The possibility of modeling and predicting both ex vivo and in vivo capabilities of MDI-spacer systems from knowledge of in vitro attributes enabled detailed focus on important variables required to deliver safe and accurate doses of salbutamol to ventilated patients.

Concepts: Asthma, In vivo, In vitro, Neural network, Metered-dose inhaler, Inhaler, Ex vivo, Nebulizer

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BACKGROUND: Snorting or smoking heroin is a known trigger of acute asthma exacerbation. Heroin abuse may be a risk factor for more severe asthma exacerbations and intubation. Heroin and other opioids provoke pulmonary bronchoconstriction. Naloxone may play a role in decreasing opioid-induced bronchospasm. There are no known clinical cases describing the effect of naloxone on opioid-induced bronchospasm. METHODS: This is an observational study in which nebulized naloxone was administered to patients with suspected heroin-induced bronchospasm. Patients with spontaneous respirations were administered 2 mg of naloxone with 3 mL of normal saline by nebulization. We describe a case series of administrations for suspected heroin-induced bronchospasm. RESULTS: We reviewed 21 administrations of nebulized naloxone to patients with suspected heroin-induced bronchospasm. Of these, 19 patients had a clinical response to treatment documented. Thirteen patients displayed clinical improvement (68%), 4 patients had no improvement (21%), and 2 patients worsened (10%). Of the 2 patients who had clinical decline, none required intubation. Of the patients who improved, 1 patient received only nebulized naloxone and 1 patient received naloxone and albuterol together. Seven patients showed clinical improvement after the administration of albuterol, atrovent, and naloxone together as a combination. Four patients showed additional improvement when the naloxone was administered after the albuterol and atrovent combination. CONCLUSION: Naloxone may play a role in reducing acute opioid-induced bronchoconstriction, either alone or in combination with albuterol. Future controlled studies should be conducted to determine if the addition of naloxone to standard treatment improves bronchospasm without causing adverse effects.

Concepts: Improve, Asthma, Opioid, Morphine, Heroin, Naloxone, Nebulizer, Salbutamol

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Errors in the use of different inhalers were investigated in patients naive to the devices under investigation in a multicentre, single-visit, randomised, open-label, cross-over study. Patients with chronic obstructive pulmonary disease (COPD) or asthma were assigned to ELLIPTA vs DISKUS (Accuhaler), metered-dose inhaler (MDI) or Turbuhaler. Patients with COPD were also assigned to ELLIPTA vs Handihaler or Breezhaler. Patients demonstrated inhaler use after reading the patient information leaflet (PIL). A trained investigator assessed critical errors (i.e., those likely to result in the inhalation of significantly reduced, minimal or no medication). If the patient made errors, the investigator demonstrated the correct use of the inhaler, and the patient demonstrated inhaler use again. Fewer COPD patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS, 9/171 (5%) vs 75/171 (44%); MDI, 10/80 (13%) vs 48/80 (60%); Turbuhaler, 8/100 (8%) vs 44/100 (44%); Handihaler, 17/118 (14%) vs 57/118 (48%); Breezhaler, 13/98 (13%) vs 45/98 (46%; all P<0.001). Most patients (57-70%) made no errors using ELLIPTA and did not require investigator instruction. Instruction was required for DISKUS (65%), MDI (85%), Turbuhaler (71%), Handihaler (62%) and Breezhaler (56%). Fewer asthma patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS (3/70 (4%) vs 9/70 (13%), P=0.221); MDI (2/32 (6%) vs 8/32 (25%), P=0.074) and significantly fewer vs Turbuhaler (3/60 (5%) vs 20/60 (33%), P<0.001). More asthma and COPD patients preferred ELLIPTA over the other devices (all P⩽0.002). Significantly, fewer COPD patients using ELLIPTA made critical errors after reading the PIL vs other inhalers. More asthma and COPD patients preferred ELLIPTA over comparator inhalers.

Concepts: Asthma, Patient, Chronic obstructive pulmonary disease, Metered-dose inhaler, Dry powder inhaler, Inhaler, Nebulizer, Theophylline