Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma.

BACKGROUND: As asthma symptoms worsen, patients typically rely on short-acting ß2-agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation. METHODS: We conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol-budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide (with each dose consisting of two actuations of 90 µg and 80 µg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 µg of albuterol and 80 µg of budesonide (with each dose consisting of two actuations of 90 µg and 40 µg, respectively [the lower-dose combination group]), or 180 µg of albuterol (with each dose consisting of two actuations of 90 µg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population. RESULTS: A total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P = 0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P = 0.052). The incidence of adverse events was similar in the three trial groups. CONCLUSIONS: The risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.).

The carbon footprint of as-needed budesonide/formoterol in mild asthma: a post hoc analysis.

INTRODUCTION: The use of pressurised metered-dose inhalers (pMDIs) and asthma exacerbations necessitating healthcare reviews contribute substantially to the global carbon footprint of healthcare. It is possible that a reduction in carbon footprint could be achieved by switching patients with mild asthma from salbutamol pMDI reliever-based therapy to inhaled corticosteroid-formoterol dry powder inhaler (DPI) reliever therapy, as recommended by the Global Initiative for Asthma. METHODS: This post hoc analysis included all 668 adult participants in the Novel START trial, who were randomised 1:1:1 to treatment with as-needed budesonide/formoterol DPI, as-needed salbutamol pMDI or maintenance budesonide DPI plus as-needed salbutamol pMDI. The primary outcome was carbon footprint of asthma management, expressed as kilograms of carbon dioxide equivalent emissions (kgCO2e) per person-year. Secondary outcomes explored the effect of baseline symptom control and adherence (maintenance budesonide DPI arm only) on carbon footprint. RESULTS: As-needed budesonide/formoterol DPI was associated with 95.8% and 93.6% lower carbon footprint compared with as-needed salbutamol pMDI (least-squares mean 1.1 versus 26.2 kgCO2e; difference -25.0, 95% CI -29.7 to -20.4; p<0.001) and maintenance budesonide DPI plus as-needed salbutamol pMDI (least-squares mean 1.1 versus 17.3 kgCO2e; difference -16.2, 95% CI -20.9 to -11.6; p<0.001), respectively. There was no statistically significant evidence that treatment differences in carbon footprint depended on baseline symptom control or adherence in the maintenance budesonide DPI arm. CONCLUSIONS: The as-needed budesonide/formoterol DPI treatment option was associated with a markedly lower carbon footprint than as-needed salbutamol pMDI and maintenance budesonide DPI plus as-needed salbutamol pMDI.

Performance of newly developed add-on devices on aerosol delivery in noninvasive ventilated subjects.

Background: Several techniques had been developed to generate aerosolized medications during noninvasive ventilation (NIV) using variable inhalation methods. This study hypothesized that large spacers were more efficient significantly than small spacers and adapters during NIV. Objective: The main objective of this study was to compare the performance of newly developed spacers with standard T-piece in NIV chronic obstructive pulmonary disease (COPD) subjects. Methods: Sixty COPD subjects requiring NIV were included in this study. A dual-limb circuit was used, and the mode of ventilator was set in spontaneous volume-controlled mode. Dual-limb ventilation circuit, consists of inspiratory-limb and expiratory-limb, is pressure and volume controlled in response to subject expiration providing relatively high resistance to expiratory flow. Two experimental sets were evaluated: the first was introducing two preliminary pressurized metered-dose inhalers (pMDI) puffs before the nebulization of 1 ml of a respirable solution of salbutamol by vibrating mesh nebulizer (VMN) using Minimhal and Combihaler. The second was to only nebulize 1 ml of salbutamol respirable solution by VMN using Combihaler, Minimhal, and standard T-piece. Two urine samples were collected after aerosol delivery: urine sample after 30 min. (USAL0.5) as an indicator of lung deposition and all urine pooled 24 h (USAL24) post-inhalation as an indicator of systemic absorption. The amount of salbutamol extracted from urine samples was assayed by high-performance liquid chromatography. Results: Minimhal + pMDI + VMN delivered a higher percentage of salbutamol 30 min post-inhalation than Minimhal + VMN (p < 0.001). Also, Combihaler + pMDI + VMN delivered a higher percentage of salbutamol 30 min post-inhalation than Combihaler + VMN (p < 0.001). Combihaler + VMN delivered a higher percentage of salbutamol 30 min and 24 h post-inhalation than both Minimhal + VMN and T-piece + VMN (p < 0.001). Standard T-piece delivered the lowest aerosol amount delivered to the lung compared to both spacers (p < 0.05). Conclusions: Introducing two pMDI puffs significantly improved aerosol delivery by both spacers. Combihaler significantly improves aerosol delivery more than Minimhal.

The effect of salbutamol sulphate inhalation (an anti-asthmatic medication) on the surfaces of orthodontic Archwires.

OBJECTIVES: This study aimed to compare the surface roughness and friction of different orthodontic archwires after exposure to salbutamol sulphate inhalation, an anti-asthmatic medication. METHODS: Orthodontic archwires (stainless-steel [StSt], nickel-titanium [NiTi], beta-titanium [ß-Ti], and copper-NiTi [Cu-NiTi]) were equally divided into two groups. The exposed groups were subjected to 20 mg salbutamol sulphate for 21 days and kept in artificial saliva. The control groups were only kept in artificial saliva. Surface changes were visualized using scanning electron microscopy (SEM). The average surface roughness (Ra) was evaluated using atomic force microscopy (AFM), and friction resistance forces were assessed using a universal testing machine. Statistical analyses were performed using t-tests and ANOVA followed by post hoc tests. RESULTS: Salbutamol sulphate did not change the surface roughness of StSt and NiTi archwires (p > .05). However, the change in the surfaces of ß-Ti and Cu-NiTi archwires was significant (p < .001). The frictional forces of exposed StSt, NiTi, and Cu-NiTi archwires did not change (p > .05). However, the frictional forces of ß-Ti archwires increased significantly after exposure to salbutamol sulphate (p = .021). Brushing with fluoride after exposure to salbutamol sulphate increased the frictional forces of ß-Ti only (p = .002). CONCLUSIONS: Salbutamol sulphate inhalation significantly affected the surface texture of ß-Ti and Cu-NiTi orthodontic archwires and increased the friction of ß-Ti archwires. These deteriorating effects were not detected on the surface of StSt and NiTi archwires. Therefore, we suggest that ß-Ti and copper titanium archwires should be used cautiously in individuals under salbutamol sulphate inhalation treatment.

Comparison of inhaled salbutamol and salmeterol for the treatment of arterial hypoxaemia in anaesthetized horses: a randomized clinical trial.

OBJECTIVE: To compare the efficacy of inhaled salbutamol with salmeterol for the treatment of arterial hypoxaemia in anaesthetized horses. STUDY DESIGN: Prospective, randomized, clinical study. ANIMALS: A total of 108 client-owned horses (American Society of Anesthesiologists status I-V) anaesthetized for elective and emergency procedures. METHODS: Horses were premedicated with acepromazine [intramuscularly 0.1 mg kg-1 or intravenously (IV) 0.05 mg kg-1] and xylazine (0.6 mg kg-1 IV). Midazolam (0.06 mg kg-1 IV) and ketamine (2.2 mg kg-1 IV) were combined to induce anaesthesia, and isoflurane in oxygen/air mixture (inspired oxygen fraction 0.7) was used for maintenance of anaesthesia. Mechanical ventilation was initiated without delay using the following ventilator settings: tidal volume 10 mL kg-1, respiratory rate 8 breaths minute-1, inspiratory-to-expiratory time ratio 1:2, no positive end-expiratory pressure. If arterial blood gas analysis revealed PaO2 < 100 mmHg (13.3 kPa), the administration of either inhaled salbutamol (2 µg kg-1) or salmeterol (0.5 µg kg-1) was randomly assigned Blood gas analysis was repeated 15 and 30 minutes after treatment. The intervention was considered successful when PaO2 after treatment ≥ 1.2 × PaO2 before treatment (i.e. ≥20% increase). PaO2 at 15 and 30 minutes was compared between groups using Mann-Whitney U test; p < 0.05 was considered significant. RESULTS: Of the 108 horses, 60 were administered salbutamol, 65% and 60% responded successfully at 15 and 30 minutes, increasing their initial PaO2 by 38% and 44%, respectively. The other 48 horses were administered salmeterol, 35% responded successfully at 15 and 30 minutes, increasing their initial PaO2 by 3% and 4%, respectively. PaO2 was significantly higher after salbutamol than after salmeterol at 15 and 30 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: Using the described protocol, inhaled salbutamol was more effective than salmeterol in improving PaO2 in anaesthetized horses with value < 100 mmHg (13.3 kPa).

Retrospective study of the changes in dynamic compliance and ventilation/perfusion mismatch following salbutamol inhalation in hypoxaemic mechanically ventilated anaesthetized horses.

OBJECTIVE: To study the changes in dynamic compliance (Cdyn), ventilation/perfusion (V˙/ Q˙) mismatch and haemodynamic variables in hypoxaemic anaesthetized horses whose PaO2 increased following salbutamol inhalation. STUDY DESIGN: Retrospective, clinical, cohort study. ANIMALS: A group of 73 client-owned horses treated with salbutamol when PaO2 <100 mmHg (13.3 kPa) during anaesthesia. METHODS: Horses were divided into two groups: responders (R), where PaO2 after salbutamol ≥1.2 PaO2 before treatment (i.e. ≥20% increase), and non-responders (NR), where PaO2 after salbutamol <1.2 PaO2 before treatment. Demographic data and intraoperative variables before treatment were compared between R and NR. Cdyn, arterial to end-tidal carbon dioxide difference [P(a-E´)CO2], estimated ratio of dead space to tidal volume (est.VD/VT), estimated shunt fraction (F-shunt), heart rate, systolic, mean and diastolic arterial pressure and dobutamine requirements were compared before and after treatment within R and NR. For each variable, the difference (Δ) between values pre- and posttreatment was calculated and compared between groups R and NR. Numerical data were compared using univariate or bivariate analysis and categorical data were compared using chi-square test; p < 0.05. RESULTS: Of the 73 horses 50 were classified as R while 23 horses were classified as NR. There was no statistical difference between R and NR for demographic data or initial intraoperative variables except for body weight [R: 531 (170-715) kg, NR: 540 (420-914) kg]. While salbutamol did not alter Cdyn in either group, it significantly decreased P(a-E´)CO2, est.VD/VT and F-shunt in R only. ΔP(a-E´)CO2, Δest.VD/VT and ΔF-shunt were significantly greater in R (-17.8%, -19.0% and -24.1%, respectively) than in NR (11.5%, 6.6% and -0.3%, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: In hypoxaemic anaesthetized horses responding to inhaled salbutamol by a ≥1.2 increase in PaO2 no change in Cdyn was detected, but indicators of V˙/ Q˙ mismatch improved.

Controlled Trial of Budesonide-Formoterol as Needed for Mild Asthma.

BACKGROUND: In double-blind, placebo-controlled trials, budesonide-formoterol used on an as-needed basis resulted in a lower risk of severe exacerbation of asthma than as-needed use of a short-acting ß2-agonist (SABA); the risk was similar to that of budesonide maintenance therapy plus as-needed SABA. The availability of data from clinical trials designed to better reflect clinical practice would be beneficial. METHODS: We conducted a 52-week, randomized, open-label, parallel-group, controlled trial involving adults with mild asthma. Patients were randomly assigned to one of three treatment groups: albuterol (100 µg, two inhalations from a pressurized metered-dose inhaler as needed for asthma symptoms) (albuterol group); budesonide (200 µg, one inhalation through a Turbuhaler twice daily) plus as-needed albuterol (budesonide maintenance group); or budesonide-formoterol (200 µg of budesonide and 6 µg of formoterol, one inhalation through a Turbuhaler as needed) (budesonide-formoterol group). Electronic monitoring of inhalers was used to measure medication use. The primary outcome was the annualized rate of asthma exacerbations. RESULTS: The analysis included 668 of 675 patients who underwent randomization. The annualized exacerbation rate in the budesonide-formoterol group was lower than that in the albuterol group (absolute rate, 0.195 vs. 0.400; relative rate, 0.49; 95% confidence interval [CI], 0.33 to 0.72; P<0.001) and did not differ significantly from the rate in the budesonide maintenance group (absolute rate, 0.195 in the budesonide-formoterol group vs. 0.175 in the budesonide maintenance group; relative rate, 1.12; 95% CI, 0.70 to 1.79; P = 0.65). The number of severe exacerbations was lower in the budesonide-formoterol group than in both the albuterol group (9 vs. 23; relative risk, 0.40; 95% CI, 0.18 to 0.86) and the budesonide maintenance group (9 vs. 21; relative risk, 0.44; 95% CI, 0.20 to 0.96). The mean (±SD) dose of inhaled budesonide was 107±109 µg per day in the budesonide-formoterol group and 222±113 µg per day in the budesonide maintenance group. The incidence and type of adverse events reported were consistent with those in previous trials and with reports in clinical use. CONCLUSIONS: In an open-label trial involving adults with mild asthma, budesonide-formoterol used as needed was superior to albuterol used as needed for the prevention of asthma exacerbations. (Funded by AstraZeneca and the Health Research Council of New Zealand; Novel START Australian New Zealand Clinical Trials Registry number, ACTRN12615000999538.).

Managing respiratory emergencies at school: A county-wide stock inhaler program.

BACKGROUND: A total of 15 states allow schools to manage respiratory emergencies among multiple students by using a single albuterol inhaler (stock inhaler) paired with a disposable holding chamber. OBJECTIVE: Our aim was to evaluate implementation barriers and facilitators, as well as satisfaction with a stock inhaler program across K through12 schools in Pima County, Arizona. METHODS: All public, charter, private, and parochial schools were offered supplies, web-based training, and technical assistance at no cost. The RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework was used to evaluate program implementation. School documentation logs were reviewed, school health personnel were surveyed, and a convenience sample of health personnel were interviewed. Chi-square tests evaluated categoric outcomes and Poisson hurdle regression examined stock inhaler use by school organization type, grade levels served, and type of school health personnel employed. RESULTS: In all, 229 schools (68%) participated, reaching 82% of students in the county. A total of 152 schools (66%) used a stock inhaler, accounting for 1038 events. The mean number of puffs administered was 2.7 (SD = 1.2) per event, and most events (79%) involved students with asthma. Although most events (83.9%) resulted in the student returning to class, 15.6% resulted in students being sent home. Only 6 events resulted in 911 calls, and 5 of these led to an ambulance transport. School health personnel reported high levels of satisfaction, and all schools renewed participation for a second year. Program costs were $156 per school. CONCLUSION: With technical assistance, stock inhaler programs can be feasibly implemented by schools in a wide range of settings, thereby increasing their capacity to safely manage respiratory emergencies.

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

BACKGROUND: Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. METHODS: We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 µg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 µg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. RESULTS: The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). CONCLUSIONS: In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

The ß-Adrenergic Agonist Albuterol Improves Pulmonary Vascular Reserve in Heart Failure With Preserved Ejection Fraction.

RATIONALE: Pulmonary vascular resistance fails to decrease appropriately during exercise in patients with heart failure with preserved ejection fraction (HFpEF). Interventions that enhance pulmonary vasodilation might be beneficial in this cohort but could also worsen left atrial hypertension, exacerbating lung congestion. Intravenous ß-agonists reduce pulmonary vascular resistance but are not suitable for chronic use. OBJECTIVE: We hypothesized that the inhaled ß-adrenergic agonist albuterol would improve pulmonary vasodilation during exercise in patients with HFpEF, without increasing left heart filling pressures. METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled trial testing the effects of inhaled albuterol on resting and exercise hemodynamics in subjects with HFpEF using high-fidelity micromanometer catheters and expired gas analysis. The primary end point was pulmonary vascular resistance during exercise. Subjects with HFpEF (n=30) underwent resting and exercise hemodynamic assessment and were then randomized 1:1 to inhaled, nebulized albuterol or placebo. Rest and exercise hemodynamic testing was then repeated. Albuterol improved the primary end point of exercise pulmonary vascular resistance as compared with placebo (-0.6±0.5 versus +0.1±0.7 WU; P=0.003). Albuterol enhanced cardiac output reserve and right ventricular pulmonary artery coupling, reduced right atrial and pulmonary artery pressures, improved pulmonary artery compliance, and enhanced left ventricular transmural distending pressure (all P <0.01), with no increase in pulmonary capillary hydrostatic pressures. CONCLUSIONS: Albuterol improves pulmonary vascular reserve in patients with HFpEF without worsening left heart congestion. Further study is warranted to evaluate the chronic efficacy of ß-agonists in HFpEF and other forms of pulmonary hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02885636.

Association of various weight-based doses of continuous albuterol on hospital length of stay.

Introduction: Continuous albuterol is a mainstay in management of pediatric status asthmaticus. While the National Heart Lung and Blood Institute Asthma Guidelines suggest 0.5 mg/kg/h as the recommended dosage, there is a paucity of evidence comparing different weight-based rates on hospital outcomes.Methods: Patients requiring continuous albuterol for asthma exacerbation from January 2015 to December 2016 were identified using ICD codes. The concentration of albuterol (5 mg/h-20 mg/h) and the duration of treatment were used to determine total albuterol administration. After dividing by patient weight, average weight-based doses were divided into equal quintiles. Unadjusted and length of stay adjusted for age, initial asthma severity score, and administration of magnesium were compared among the quintiles. The same multivariate analysis was used for duration of continuous albuterol.Results: Five hundred thirty-three hospitalizations for asthma were identified of which 289 received continuous albuterol. Weight-based dosage quintiles ranged from lowest (0.07-0.29 mg/kg/h) to the highest (>0.76-3.2 mg/kg/h). Baseline characteristics were similar aside from age, race, and magnesium administration. There was no difference in adjusted length of stay or adjusted duration of continuous albuterol therapy among the five quintiles.Conclusion: No optimal weight-based dose of continuous albuterol was found. Further investigation is needed to see if lower amounts of continuous albuterol may be as efficacious as higher doses. This could improve cost of status asthmaticus management and limit the number of adverse events associated with high exposure to continuous albuterol.

High frequency percussive ventilation as a rescue mode for refractory status asthmaticus - a case study.

INTRODUCTION: A severe asthma exacerbation is called status asthmaticus when symptoms worsen despite conventional medical treatment in the hospital. If arterial blood gas (ABG) values deteriorate and this is accompanied by respiratory muscle fatigue, the patient will require mechanical ventilation. However, mechanical ventilation of the severe asthmatic presents difficult challenges. CASE STUDY: We report on High Frequency Percussive Ventilation (HFPV) used along with continuous inhaled albuterol and neuromuscular blockade, as rescue therapy for a case of acute, severe asthma that was refractory to conventional treatment and conventional mechanical ventilation. RESULTS: This patient's arterial pH was 6.97 when we initiated HFPV, but ten hours post-intubation her ABG values normalized. She was successfully extubated six days later and discharged from ICU the following day. CONCLUSION: This case describes the successful use of HFPV for a status asthmaticus patient failing conventional mechanical ventilation. We have anecdotal evidence of other medical centers using HFPV for these patients but larger studies are needed to verify its efficacy.

Inhaled Albuterol Use and Impaired Lactate Clearance in Patients With Sepsis: A Retrospective Cohort Study.

BACKGROUND: Lactate clearance has become important in the management of sepsis. However, factors unrelated to sepsis-induced hyperlactatemia, including ß-2 adrenergic agonists, can interfere with lactate clearance. OBJECTIVES: To investigate the association of inhaled albuterol with lactate clearance in patients with sepsis. METHODS: This was a single-center retrospective cohort study. Adult patients with sepsis diagnosed in the emergency department from May 2015 to May 2016 with initial lactate levels >2 mmol/L and serial lactate measurements 2 to 6 hours apart were included. Patients were divided into 2 groups based on whether they received inhaled albuterol between lactate measurements. The primary end point was lactate clearance of 10%. Secondary end points included intensive care unit (ICU) consultation and in-hospital mortality. A multivariate logistic regression analysis was performed to assess the effect of inhaled albuterol on lactate clearance. RESULTS: Of 269 patients included, 58 (22%) received inhaled albuterol between lactate measurements. This group had a significantly higher prevalence of pulmonary disease and a lower initial lactate compared to those who did not receive inhaled albuterol. They had a significantly lower rate of lactate clearance (45% vs 77%, P < .001); however, ICU consultation (71% vs 57%, P = .066) and in-hospital mortality (19% vs 22%, P = .64) were not significantly different. A multivariate logistic regression analysis adjusting for age, sex, chronic kidney disease, cirrhosis, cancer, septic shock or severe sepsis, and the amount of intravenous fluids received showed that inhaled albuterol was independently associated with impaired lactate clearance (adjusted odds ratio: 0.26, 95% confidence interval: 0.14-0.50, P < .001). CONCLUSIONS: Inhaled albuterol in patients with sepsis was associated with impaired lactate clearance without an increase in ICU consultation or in-hospital mortality. Impaired lactate clearance in patients with sepsis who receive inhaled albuterol should be interpreted with caution.

Influence of the external cephalic version attempt on the Cesarean section rate: experience of a type 3 maternity hospital in France.

PURPOSE: To define the effects of attempted external cephalic version (ECV) in a low-risk population for breech delivery in a maternity hospital where breech vaginal delivery is widely practiced. MATERIALS AND METHODS: Retrospective exposed-unexposed study including 204 patients presented with a live singleton fetus breech presentation on third-trimester ultrasound and who delivered at Reims University Hospital between January 1st, 2013 and July 1st, 2018. RESULTS: 121 patients received ECV. Cesarean section rate was lower (OR with no adjustment 0.42 [0.24-0.76] p = 0.004) but without significant difference in the exposed patients after adjustment. This difference was significant between exposed and unexposed patients in the subgroup of 51 primiparous (OR = 0.14 [0.04-0.52] p = 0.002) and 51 multiparous (OR = 0.26 [0.08-0.89] p = 0.028) but not in the subgroup of 102 nulliparous. There was no difference in fetal impact other than neonatal management in the delivery room, which is less needed in exposed primiparous women. Attempted ECV significantly decreased the breech rate (72.5 vs 100%, p < 0.001). There were 7 (5.79%) complications. Three factors favored success: high uterine height (p = 0.011), a non-elevated BMI (p = 0.006) and an earlier term at ECV (p = 0.003). CONCLUSION: The attempt of ECV in the Reims University Hospital does not significantly reduce the Cesarean section rate and has no effect on neonatal status.

Performance of Low Air Volume Dry Powder Inhalers (LV-DPI) when Aerosolizing Excipient Enhanced Growth (EEG) Surfactant Powder Formulations.

Efficient delivery of dry powder aerosols dispersed with low volumes of air is challenging. This study aims to develop an efficient dry powder inhaler (DPI) capable of delivering spray-dried Survanta-EEG powders (3-10 mg) with a low volume (3 mL) of dispersion air. A series of iterative design modifications were made to a base low air volume actuated DPI. The modifications included the replacement of the original capsule chamber with an integral dose containment chamber, alteration of the entrainment air flow path through the device (from single-sided (SS) to straight through (ST)), change in the number of air inlet holes (from one to three), varying the outlet delivery tube length (45, 55, and 90 mm) and internal diameter (0.60, 0.89, and 1.17 mm). The modified devices were evaluated by determining the influence of the modifications and powder fill mass on aerosol performance of spray-dried Survanta-EEG powders. The optimal DPI was also evaluated for its ability to aerosolize a micronized powder. The optimized dose containment unit DPI had a 0.21 mL powder chamber, ST airflow path, three-0.60 mm air inlet holes, and 90 mm outlet delivery tube with 0.89 mm internal diameter. The powder dispersion characteristics of the optimal device were independent of fill mass with good powder emptying in one 3 mL actuation. At 10 mg fill mass, this device had an emitted mass of 5.3 mg with an aerosol Dv50 of 2.7 µm. After three 3 mL actuations, >85% of the spray-dried powder was emitted from the device. The emitted mass of the optimal device with micronized albuterol sulfate was >72% of the nominal fill mass of 10 mg in one 3 mL actuation. Design optimization produced a DPI capable of efficient performance with a dispersion air volume of 3 mL to aerosolize Survanta-EEG powders.

Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: a case series.

BACKGROUND: Mechanically ventilated patients with COVID-19 have a mortality of 24-53%, in part due to distal mucopurulent secretions interfering with ventilation. DNA from neutrophil extracellular traps (NETs) contribute to the viscosity of mucopurulent secretions and NETs are found in the serum of COVID-19 patients. Dornase alfa is recombinant human DNase 1 and is used to digest DNA in mucoid sputum. Here, we report a single-center case series where dornase alfa was co-administered with albuterol through an in-line nebulizer system. METHODS: Demographic and clinical data were collected from the electronic medical records of five mechanically ventilated patients with COVID-19-including three requiring veno-venous extracorporeal membrane oxygenation-treated with nebulized in-line endotracheal dornase alfa and albuterol, between March 31 and April 24, 2020. Data on tolerability and response were analyzed. RESULTS: The fraction of inspired oxygen requirements was reduced for all five patients after initiating dornase alfa administration. All patients were successfully extubated, discharged from hospital and remain alive. No drug-associated toxicities were identified. CONCLUSIONS: Results suggest that dornase alfa will be well-tolerated by patients with severe COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and several have been recently registered.

Improved muscle function in a phase I/II clinical trial of albuterol in Pompe disease.

This 24-week, Phase I/II, double-blind, randomized, placebo-controlled study investigated the safety and efficacy of extended-release albuterol in late-onset Pompe disease stably treated with enzyme replacement therapy at the standard dose for 4.9 (1.0-9.4) years and with no contraindications to intake of albuterol. Twelve of 13 participants completed the study. No serious adverse events were related to albuterol, and transient minor drug-related adverse events included muscle spasms and tremors. For the albuterol group, forced vital capacity in the supine position increased by 10% (p < .005), and forced expiratory volume in one second increased by 8% (p < .05); the six-minute walk test increased 25 m (p < .05; excluding one participant unable to complete muscle function testing); the Gross Motor Function Measure increased by 8% (p < .005) with the greatest increases in the Standing (18%; p < .05) and Walking, Running, and Jumping (11%; p < .005) subtests. No significant improvements would be expected in patients with late-onset Pompe disease who were stably treated with enzyme replacement therapy. The placebo group demonstrated no significant increases in performance on any measure. These data support a potential benefit of extended-release albuterol as adjunctive therapy in carefully selected patients with late-onset Pompe disease based on ability to take albuterol on enzyme replacement therapy (NCT01885936).

Salbutamol use in relation to maintenance bronchodilator efficacy in COPD: a prospective subgroup analysis of the EMAX trial.

BACKGROUND: Short-acting ß2-agonist (SABA) bronchodilators help alleviate symptoms in chronic obstructive pulmonary disease (COPD) and may be a useful marker of symptom severity. This analysis investigated whether SABA use impacts treatment differences between maintenance dual- and mono-bronchodilators in patients with COPD. METHODS: The Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids 1:1:1 to once-daily umeclidinium/vilanterol 62.5/25 µg, once-daily umeclidinium 62.5 µg or twice-daily salmeterol 50 µg for 24 weeks. Pre-specified subgroup analyses stratified patients by median baseline SABA use (low, < 1.5 puffs/day; high, ≥1.5 puffs/day) to examine change from baseline in trough forced expiratory volume in 1 s (FEV1), change in symptoms (Transition Dyspnoea Index [TDI], Evaluating Respiratory Symptoms-COPD [E-RS]), daily SABA use and exacerbation risk. A post hoc analysis used fractional polynomial modelling with continuous transformations of baseline SABA use covariates. RESULTS: At baseline, patients in the high SABA use subgroup (mean: 3.91 puffs/day, n = 1212) had more severe airflow limitation, were more symptomatic and had worse health status versus patients in the low SABA use subgroup (0.39 puffs/day, n = 1206). Patients treated with umeclidinium/vilanterol versus umeclidinium demonstrated statistically significant improvements in trough FEV1 at Week 24 in both SABA subgroups (59-74 mL; p < 0.001); however, only low SABA users demonstrated significant improvements in TDI (high: 0.27 [p = 0.241]; low: 0.49 [p = 0.025]) and E-RS (high: 0.48 [p = 0.138]; low: 0.60 [p = 0.034]) scores. By contrast, significant reductions in mean SABA puffs/day with umeclidinium/vilanterol versus umeclidinium were observed only in high SABA users (high: - 0.56 [p < 0.001]; low: - 0.10 [p = 0.132]). Similar findings were observed when comparing umeclidinium/vilanterol and salmeterol. Fractional polynomial modelling showed baseline SABA use ≥4 puffs/day resulted in smaller incremental symptom improvements with umeclidinium/vilanterol versus umeclidinium compared with baseline SABA use < 4 puffs/day. CONCLUSIONS: In high SABA users, there may be a smaller difference in treatment response between dual- and mono-bronchodilator therapy; the reasons for this require further investigation. SABA use may be a confounding factor in bronchodilator trials and in high SABA users; changes in SABA use may be considered a robust symptom outcome. FUNDING: GlaxoSmithKline (study number 201749 [NCT03034915]).

Relationship between age and bronchodilator response at diagnosis in adult-onset asthma.

BACKGROUND: Possible variation in bronchodilator response (BDR) according to age at the diagnosis of adult-onset asthma is unknown. Our aim was to assess if BDR in FEV1 is related to age at diagnosis of adult-onset asthma and how many subjects fulfill the 400 mL criterion of BDR, the suggested cut-off for asthma-like reversibility in asthma-COPD overlap (ACO). METHODS: A total of 1030 patients with adult-onset asthma were included; 245 from SAAS (Seinäjoki Adult Asthma Study, Finland) and 785 from COREA (Cohort for Reality and Evolution of Adult Asthma in Korea) cohorts. BDR in FEV1 at the diagnosis of asthma was assessed. Patients were divided into groups based on age at asthma diagnosis: < 40, 40-59.9, and ≥ 60 years. The cohorts were analyzed separately. RESULTS: BDR % in FEV1 did not differ between the groups of different age at asthma diagnosis and no correlation between BDR and age was found. Of patients aged ≥40 years, only 18% (SAAS-cohort) and 5% (COREA-cohort) reached the 400 mL BDR in FEV1. After exclusion of possible ACO patients, the results remained similar. CONCLUSION: By using two large cohorts of steroid-naive patients with asthma, we have shown that BDR at diagnosis of asthma is constant over large age span range, and the limit of 400 mL in BDR in FEV1 is rarely reached. TRIAL REGISTRATION: Seinäjoki Adult Asthma Study is registered at ClinicalTrials.gov with identifier number NCT02733016 .

The relative contribution of α- and ß-adrenergic sweating during heat exposure and the influence of sex and training status.

While human eccrine sweat glands respond to adrenergic agonists, there remains a paucity of information on the factors modulating this response. Thus, we assessed the relative contribution of α- and ß-adrenergic sweating during a heat exposure and as a function of individual factors of sex and training status. α- and ß-adrenergic sweating was assessed in forty-eight healthy young men (n = 35) and women (n = 13) including endurance-trained (n = 12) and untrained men (n = 12) under non-heat exposure (temperate, 25°C; n = 17) and heat exposure (hot, 35°C; n = 48) conditions using transdermal iontophoresis of phenylephrine (α-adrenergic agonist) and salbutamol (ß-adrenergic agonist) on the ventral forearm, respectively. Adrenergic sweating was also measured after iontophoretic administration of atropine (muscarinic receptor antagonist) or saline (control) to evaluate how changes in muscarinic receptor activity modulate the adrenergic response to a heat exposure (n = 12). α- and ß-adrenergic sweating was augmented in hot compared with temperate conditions (both P ≤ .014), albeit the relative increase was greater in ß (~5.4-fold)- as compared to α (~1.5-fold)-adrenergic-mediated sweating response. However, both α- and ß-adrenergic sweating was abolished by atropinization (P = .001). Endurance-trained men showed an augmentation in α- (P = .043) but not ß (P = .960)-adrenergic sweating as compared to untrained men. Finally, a greater α- and ß-adrenergic sweating response (both P ≤ .001) was measured in habitually active men than in women. We show that heat exposure augments α-and ß-adrenergic sweating differently via mechanisms associated with altered muscarinic receptor activity. Sex and training status modulate this response.