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Salbutamol was included in the prohibited list of the World Anti-Doping Agency (WADA) in 2004. Although systemic intake is banned, inhalation for asthma is permitted but with dosage restrictions. The WADA established a urinary concentration threshold to distinguish accordingly prohibited systemic self-administration from therapeutic prescription by inhalation. This study aimed at evaluating the ability of the WADA threshold to differentiate salbutamol therapeutic use from violation of antidoping rules. Concentration-time profile of salbutamol in plasma and its excretion in urine was characterized through a model-based meta-analysis of individual and aggregate data collected after administration of a large range of doses following different modes of administration and under a variety of conditions. The developed model adequately fitted salbutamol plasma and urine concentration-time profiles of the 13 selected studies. Model-based simulations confirmed that a wide range of salbutamol urine concentrations might be measured after drug intake. Although violation of the WADA Code can be strongly suspected in individuals showing very high salbutamol urine concentrations, uncertainty remains for values close to the WADA threshold as they can be compatible with both permitted therapeutic use and violation. Although not entirely discriminant, the current WADA rule is globally supported by our appraisal. It could be further improved by a slight and reasonable adjustment of inhaled daily dosages allowed for therapeutic use. Our model might help antidoping experts in the evaluation of suspected doping cases through confronting the athlete's urine measurements with their allegations about salbutamol treatment.

To determine the common clinical signs, with onset and duration, treatments given, and outcome in dogs with acute, accidental exposure to salbutamol.Retrospective study.Five hundred and one canine cases reported to the UK's Veterinary Poisons Information Service (VPIS).A review of all records in the VPIS database for dogs exposed to salbutamol was carried out. After applying inclusion and exclusion criteria, the records of 501 dogs were further analyzed. The most common clinical signs were tachycardia (80.6%), tachypnea (32.9%), depression (21.0%), and vomiting (19.2%). The dose was unknown in most cases as the dogs typically pierced a salbutamol inhaler. The blood potassium concentration was measured in at least 142 dogs and hypokalemia was reported in 21.2% (106/501), 18 (17%) of which had associated weakness, twitching, or collapse. Three dogs had paralysis probably as a result of hypokalemia, although no potassium concentration was reported in these cases. Arrhythmias occurred in 17 dogs (3.4%), and 7 required pharmacological intervention. There were no reports of persistent cardiac injury or thermal injury from the compressed gas present in some salbutamol products. Signs were rapid in onset, generally within 1-3 h, and, where time to outcome was recorded (n = 172), 78% of dogs recovered within 24 h. Of the 501 dogs, no treatment was required in 27.9%. Beta-blockers were used in 39.5%, intravenous fluids in 28.7%, and potassium supplementation in 15.8%. Overall, 30 dogs remained asymptomatic (6.0%), 469 recovered (93.6%), and 2 dogs (0.4%) died.Most dogs exposed to salbutamol rapidly develop clinical signs; these were commonly increased heart and respiration rates. Hypokalemia and arrhythmias (particularly ventricular arrhythmias) are potential complications. Any dog that chews a salbutamol inhaler should be assessed promptly for signs of toxicosis. Prognosis in dogs with acute salbutamol exposure is good, but more guarded in those with severe tachycardia and at risk of cardiac injury.

Bronchospasm is a common respiratory adverse event in pediatric anesthesia. First line treatment commonly includes inhaled salbutamol. This review focusses on the current best practice to deliver aerosolized medications to awake as well as anesthetized pediatric patients and discusses the advantages and disadvantages of various administration techniques. Additionally, we detail the differences between various airway devices used in anesthesia. We highlight the unmet need for innovation of orally inhaled drug-products to deliver aerosolized medications during pediatric respiratory critical events such as bronchospasm. It is therefore important that clinicians remain up to date with the best clinical practice for aerosolized drug delivery in order to prevent and efficiently treat pediatric patients experiencing life-threatening respiratory emergencies.

The propellants in metered-dose inhalers (MDIs) are powerful greenhouse gases, which account for approximately 13% of the NHS's carbon footprint related to the delivery of care. Most MDI use is in salbutamol relievers in patients with poorly controlled disease. The UK lags behind Europe in this regard, with greater reliance on salbutamol MDI and correspondingly greater greenhouse gas emissions; roughly treble our European neighbours'. There has been a broad switch towards MDIs in asthma treatment UK over the last 20 years to reduce financial costs, such that the treatment for two-thirds of asthma patients in the UK is dominated by salbutamol MDI. Strategies that replace overuse of reliever MDIs with regimes emphasising inhaled corticosteroids have the potential to improve asthma control alongside significant reductions in greenhouse gas emissions. Real-world evidence shows that once-daily long-acting combination dry-powder inhalers can improve compliance, asthma control and reduce the carbon footprint of care. Similarly, maintenance and reliever therapy (MART) which uses combination reliever and inhaled steroids in one device (usually a dry-powder inhaler) can simplify therapy, improve asthma control, and reduce greenhouse gas emissions. Both treatment strategies are popular with patients, most of whom would be willing to change treatment to reduce their carbon footprint. By focussing on patients who are currently using high amounts of salbutamol MDI, and prioritising inhaled steroids via dry-powder inhalers, there are golden opportunities to make asthma care in the UK more effective, safer, and greener.

PURPOSE Relvar® (fluticasone furoate [FF]/vilanterol [VI]) is a once-daily inhaler with bronchodilator effect lasting 24 h. Our aim was to investigate the short- and long-term effects of FF/VI on exercise-induced asthma (EIA) in adolescents. METHODS Ninety-three adolescent asthmatics aged 12-18 years were referred for evaluation of EIA. Following a positive exercise challenge test (ECT), 22/44 were allocated to a single administration of salbutamol (400 μg) and 22/44 to FF/VI (92/22 μg) in a double-blind method. Thirty-five subjects were reassessed by repeat ECT 30-60 days of FF/VI. RESULTS Median FEV1 change post-ECT at baseline was -22.8% predicted (interquartile range [IQR] -26.1 and -18.0) for salbutamol and -21.0 (IQR -30.7 and -16.8) for FF/VI. Following bronchodilator, FEV1 improved similarly in both groups. Repeat ECT following 30-60 days of FF/VI resulted in negative ECT in 33/35 subjects; the median decrease in FEV1 of these 35 subjects was 22.6% predicted (IQR 29-18) before, and 4.6% predicted (IQR 8.7-2.5) after 30-60 days of FF/VI treatment (p

Background: Acute rhinovirus-induced wheezing is common in young children and may respond to systemic corticosteroid. There are no trials on the efficacy of inhaled beta₂-agonist in this clinical scenario. Objective: To study post hoc the short-term (up to 2 months) efficacy of inhaled beta2-agonist with and without oral corticosteroid in the first acute rhinovirus-induced severe wheezing episode in young hospitalized children. Methods: The study population came from two randomized controlled trials comparing oral prednisolone (2 mg/kg/d for 3 days) to placebo: Vinku (n = 35, NCT00494624) used high-dose regular nebulized salbutamol (0.15 mg/kg 2–4 h intervals) and Vinku2 (n = 60, NCT00731575, EudraCT 2006-007100-42) used inhaled salbutamol on-demand. Both studies used identical detailed follow-up assessments. The primary outcome of the former was the duration of hospitalization and of the latter the occurrence of and the time to a new physician-confirmed wheezing episode within 2 months after discharge. Treatment groups included salbutamol high-dose vs. salbutamol on-demand while adjusting for prednisolone status and acknowledging for interactions with exception of the duration of hospitalization in which prednisolone groups could not be fully used due to protocol differences. Results: Median age of subjects was 13 months, 32% were sensitized and 22% had doctor-diagnosed eczema. In the duration of hospitalization, salbutamol high-dose/placebo versus salbutamol on-demand/placebo groups did not differ (p = .12). In the occurrence of and time to relapse within 2 months, a significant group × treatment interaction was observed (both p = .02), such that high-dose group had less and longer time to relapses than on-demand group in prednisolone arm (both p < .05), but no difference was detected in placebo arm (both p > .26). Conclusions: In young, hospitalized children with first episode of rhinovirus-induced wheezing, high-dose inhaled salbutamol may interact with oral prednisolone. However, further trials are warranted.

The implementation of self-optimizing flow reactors has been mostly limited to model reactions or known synthesis routes. In this work, a self-optimizing flow photochemistry platform is used to develop an original synthesis of the bioactive fragment of Salbutamol and derivatives. The key photochemical steps for the construction of the aryl vicinyl amino alcohol moiety consist of a C-C bond forming reaction followed by an unprecedented, high yielding (80 %), benzylic oxidative cyclization.

Introduction Failure to expectorate mucus resulting in progressive airway damage is the hallmark of bronchiectasis. Therefore effective airway clearance techniques (ACT) is the key step in its management. The aim of this study was to evaluate the efficacy of 3% hypertonic saline (HS) pre-medication in ACT in children with non cystic fibrosis (non-CF) bronchiectasis. Methods In this randomized crossover control trial five to 15 year old children, diagnosed with non-CF bronchiectasis were randomized either to receive 200 µg of inhaled salbutamol followed by HS nebulization (test) or only 200 µg of inhaled salbutamol, before chest physiotherapy which is the conventional ACT (controls) for 8 weeks. Inhaled salbutamol was administered via a pressurized metered dosed inhaler with a valved holding chamber. After completion of first phase both groups went through one month washout period, before being crossed over to the opposite arms in the second phase. Spirometric parameters and number of exacerbations were recorded at the end of phase I, washout period and phase II. Results Fifty two out of 63 enrolled completed the study. Baseline characteristics of the two groups were similar. A significantly higher mean improvement was seen in predicted forced expiratory volume in 1 s in the HS arm during phase 1 (HS = 14.15 ± 5.50 vs. conventional = 5.04 ± 5.55, p = .001) and phase II (HS = 10.81 ± 5.51 vs. conventional = 3.54 ± 5.13, p = .001) compared to conventional ACT arm. HS group showed a significantly higher mean improvement in predicted forced vital capacity in phase I (HS = 13.77 ± 5.73 vs. conventional = 7.54 ± 4.90, p = .001) and phase II, (HS = 9.42 ± 7.00 vs. conventional = 4.42 ± 4.00, p = .003). Mean number of exacerbations experienced by a single child during phase I (2 months) were significantly less (p = .001) in HS arm (0.42 ± 0.64) compared to that of conventional arm (1.30 ± 1.05) butthis difference was not significant in phase II (HS = 0.65 ± 0.74 and conventional = 1.03 ± 0.77, p = .074). Conclusion Incorporating HS nebulization into ACT is an effective strategy to improve dynamic lung volumes and morbidity in children with non-CF bronchiectasis.

RATIONALE Aerosolized albuterol is widely used, but its tolerability and efficacy in infants with severe bronchopulmonary dysplasia (sBPD) is not well established. OBJECTIVES To compare the tolerability and efficacy of two dose levels of aerosolized albuterol to saline placebo in infants with sBPD. METHODS Single-center, multiple-crossover trial in 24 ventilated very preterm infants with sBPD. Albuterol (1.25 mg, 2.5 mg) and 3 ml of normal saline were administered every 4 h during separate 24-h treatment periods assigned in random order with a 6-h washout phase between periods. The primary outcome was the absolute change (post and pretherapy) in expiratory flow at 75% of exhalation (EF75). Secondary endpoints were changes in ventilator parameters, vital signs, and heart arrhythmia. RESULTS Average within subject EF75 values improved with each therapy: saline placebo ( + 0.45 L/min ± 2.5, p = .04), 1.25 mg of albuterol ( + 0.70 L/min ± 2.4, p

As of 2020, use of beta2 -agonist salmeterol is restricted by the World Anti-Doping Agency (WADA) and is only permitted by inhalation at therapeutic doses not exceeding 200 μg in 24 h. In contrast to beta2 -agonists salbutamol and formoterol, WADA has not established a urine threshold for salmeterol despite its muscle hypertrophic actions observed in animals. Herein, we investigated plasma (0-4 h) and urine (0-24 h) concentrations (by ultra-high-performance liquid chromatography-tandem mass spectrometry [UHPLC-MS/MS]) of salmeterol and α-hydroxysalmeterol after dry powder inhalation at supratherapeutic (400 μg) and high therapeutic (200 μg) doses, and after seven consecutive days of therapeutic inhalation (200 μg × day-1 ) in 11 healthy endurance-trained men. During each trial, participants inhaled salmeterol before 1½ h moderate-intensity cycling. Mean ± SD maximum urine concentrations of salmeterol unadjusted for specific gravity reached 4.0 ± 1.6, 2.1 ± 1.5, and 2.2 ± 1.1 ng × ml-1 for 400 μg, 200 μg, and seven consecutive days of 200 μg, respectively, with corresponding maximum urine concentrations of α-hydroxysalmeterol being 11.6 ± 6.1, 5.7 ± 4.6, and 6.5 ± 2.6 ng × ml-1 . Within the relevant window for doping control (first 6 h post-inhalation), the present data (119 samples), along with 64 biobank urine samples, showed that a combined salmeterol and α-hydroxysalmeterol urine threshold with equal cut-offs of 3.3 ng × ml-1 was superior to a salmeterol-only threshold to discriminate therapeutic (200 μg) from supratherapeutic use (400 μg) with a sensitivity of 24% with 0% false positives when applying the WADA technical document (TD2019DL.v2) method of specific gravity adjustment. Thus, a combination of urine salmeterol and α-hydroxysalmeterol concentrations may be suitable for discriminating between therapeutic and supratherapeutic prohibited inhalation of salmeterol.

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 β-adrenergic sweating during a heat exposure and as a function of individual factors of sex and training status. α- and β-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 (β-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 β-adrenergic sweating was augmented in hot compared with temperate conditions (both P ≤ .014), albeit the relative increase was greater in β (~5.4-fold)- as compared to α (~1.5-fold)-adrenergic-mediated sweating response. However, both α- and β-adrenergic sweating was abolished by atropinization (P = .001). Endurance-trained men showed an augmentation in α- (P = .043) but not β (P = .960)-adrenergic sweating as compared to untrained men. Finally, a greater α- and β-adrenergic sweating response (both P ≤ .001) was measured in habitually active men than in women. We show that heat exposure augments α-and β-adrenergic sweating differently via mechanisms associated with altered muscarinic receptor activity. Sex and training status modulate this response.

OBJECTIVES: Although recent evidence suggests that management of viral bronchiolitis requires something other than guidelines-guided therapy, there is a lack of evidence supporting the economic benefits of phenotypic-guided bronchodilator therapy for treating this disease. The aim of the present study was to compare the cost-effectiveness of phenotypic-guided versus guidelines-guided bronchodilator therapy in infants with viral bronchiolitis. METHODS: A decision analysis model was developed to compare the cost-effectiveness of phenotypic-guided versus guidelines-guided bronchodilator therapy in infants with viral bronchiolitis. Phenotypic-guided bronchodilator therapy was defined as the administration of albuterol in infants exhibiting a profile of increased likelihood of response to bronchodilators. The effectiveness parameters and costs of the model were obtained from systematic reviews of the literature with meta-analyses and electronic medical records. The main outcome was the avoidance of hospital admission after initial care in the emergency department. RESULTS: Compared to guidelines-guided strategy, treating patients with viral bronchiolitis with the phenotypic-guided bronchodilator therapy strategy was associated with lower total costs (US$250.99; 95% uncertainty interval [UI]: US $184.37 to $336.51 vs. US$263.46; 95% UI: US$189.81 to $349.19 average cost per patient) and a higher probability of avoidance of hospital admission (0.7902; 95% UI: 0.7315–0.8356 vs. 0.7638; 95% UI: 0.7062–0.8201), thus leading to dominance. Results were robust to deterministic and probabilistic sensitivity analyses. CONCLUSIONS: Compared to guidelines-guided strategy, treating infants with viral bronchiolitis using the phenotypic-guided bronchodilator therapy strategy is a more cost-effective strategy, because it involves a lower probability of hospital admission at lower total treatment costs.

BACKGROUND AND OBJECTIVE Non-selective beta-blockers impair the bronchodilator response to beta2 -agonists. Cardio-selective beta1 -blockers are less likely to cause this effect, yet they remain relatively contraindicated in asthma. We investigated whether the response to salbutamol is impaired during cardio-selective beta1 -blocker treatment in people with asthma. METHODS A random-order, double-blind, placebo-controlled, non-inferiority, crossover study was conducted comparing up to 5 mg bisoprolol daily for 2 weeks with matching placebo, with an open-label extension of up to 10 mg bisoprolol daily. After each treatment period, mannitol was inhaled to induce bronchoconstriction with a 15% fall in forced expiratory volume in 1 s (FEV1 ). Immediately after mannitol challenge, salbutamol (100, 100 and 200 μg) was administered via spacer at 5-min intervals with repeated FEV1 measures. The FEV1 recovery with salbutamol was measured as an area under recovery curve (AUC). Based on earlier research, a clinically relevant non-inferiority limit of a 30% reduction in the AUC was set. RESULTS A total of 19 adults with mild asthma and positive inhaled mannitol challenge completed the study. Adjusting for the FEV1 fall induced by mannitol and treatment sequence, the mean AUC response to salbutamol after bisoprolol was 5% lower than after placebo, with a one-sided 95% confidence interval (CI) of 26% lower. Thirteen participants completed the open-label extension up to 10 mg bisoprolol daily with mean AUC 11% higher after bisoprolol with a 95% CI of 5% lower. CONCLUSION The bronchodilator response to rescue salbutamol after mannitol-induced bronchoconstriction is non-inferior during regular treatment with the cardio-selective beta1 -blocker, bisoprolol, compared to placebo. CLINICAL TRIAL REGISTRATION ACTRN12618000306213 at https://www.anzctr.org.au.

Mobile health (mHealth) technologies have the potential to capture dense patient data on the background of real-life behavior. Merck & Co., Inc. (Kenilworth, NJ), in collaboration with Koneksa Health, conducted a phase I clinical trial to validate cardiovascular mHealth technologies for concordance with traditional approaches and to establish sensitivity to detect effects of pharmacological intervention. This two-part study enrolled 18 healthy male subjects. Part I, a 5-day study, compared mHealth measures of heart rate (HR) and blood pressure (BP) to those from traditional methods. Hypotheses of similarity, in the clinic and at home, were tested individually for HR, systolic BP, and diastolic BP, at a 2-sided 0.05 alpha level, with a prespecified criterion for similarity being the percentage differences between the 2 measurements within 15%. Part II, a 7-day, 3-period randomized balanced crossover study, evaluated the mHealth technology's ability to detect effects of bisoprolol and salbutamol. Hypotheses that the changes from baseline in HR were greater in the bisoprolol (reduction in HR) and salbutamol (increase in HR) groups compared with no treatment were tested, at a 1-sided 0.05 alpha level. Linear mixed-effects models, Pearson's correlation coefficients, summary statistics, and exploratory plots were applied to analyze the data. The mHealth measures of HR and BP were demonstrated to be similar to those from traditional methods, and sensitive to changes in cardiovascular parameters induced by bisoprolol and salbutamol.

Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4‐way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol.

Conditions such as asthma and inflammatory bowel disease are characterized by aberrant smooth muscle contraction. It has proven difficult to develop human cell-based models that mimic acute muscle contraction in 2D in vitro cultures due to the nonphysiological chemical and mechanical properties of lab plastics that do not allow for muscle cell contraction. To enhance the relevance of in vitro models for human disease, we describe how functional 3D smooth muscle tissue that exhibits physiological and pharmacologically relevant acute contraction and relaxation responses can be reproducibly fabricated using a unique microfluidic 3D bioprinting technology. Primary human airway and intestinal smooth muscle cells were printed into rings of muscle tissue at high density and viability. Printed tissues contracted to physiological concentrations of histamine (0.01-100 μM) and relaxed to salbutamol, a pharmacological compound used to relieve asthmatic exacerbations. The addition of TGFβ to airway muscle rings induced an increase in unstimulated muscle shortening and a decreased response to salbutamol, a phenomenon which also occurs in chronic lung diseases. Results indicate that the 3D bioprinted smooth muscle is a physiologically relevant in vitro model that can be utilized to study disease pathways and the effects of novel therapeutics on acute contraction and chronic tissue stenosis.

Objectives Transnasal pulmonary aerosol delivery using high-flow nasal cannula (HFNC) devices has become a popular route of aerosol administration in toddlers. Clinically, albuterol is administered using an infusion pump or unit doses. However, little evidence is available to compare the two administration strategies. Methods A toddler manikin (15 kg) with appropriate anatomic airway was connected with collecting filter to a simulator of distressed breathing. HFNC device with mesh nebulizer placed at the inlet of a humidifier at 37°C, with the gas flow set at 25 and 3.75 L/min. Five milligrams of albuterol was delivered in all experiments. With infusion pump administration, albuterol concentrations of 5 and 1 mg/mL were delivered at 4 and 20 mL/hr for 15 minutes. With unit dose administration, 1 mL (5 mg/mL) and 2 mL (2.5 mg/mL) of albuterol were nebulized. Additional tests with mouth open and nebulizers via mask were using 5 mg/1 mL for mesh nebulizer and 5 mg/3 mL for jet nebulizer (n = 3). The drug was eluted from the filter and assayed with UV spectrophotometry (276 nm). Results The inhaled dose was higher with unit dose than infusion pump administration with gas flows of 25 L/min (2.66 ± 0.38 vs 1.16 ± 0.28%; P = .004) and 3.75 L/min (10.51 ± 1.29 vs 8.58 ± 0.68%; P = .025). During unit dose administration, compared with closed-mouth breathing, open-mouth breathing generated a higher inhaled dose at 3.75 L/min and lower inhaled dose at 25 L/min. Compared to the nebulizers via mask with both open and closed-mouth breathing, nebulization via HFNC at 3.75 L/min generated greater inhaled dose, while HFNC at 25 L/min generated lower inhaled dose. Conclusions During transnasal aerosol delivery, the inhaled dose was higher with medication administrated using unit dose than using an infusion pump.

BACKGROUND Asthma is a common pediatric diagnosis for emergency medical services (EMS) transports, however there is a paucity of data on prehospital asthma management. The purpose of this study was to describe prehospital management of pediatric patients with suspected asthma exacerbation. METHODS We conducted a retrospective review of electronic medical records from 24 ground EMS agencies in Southwestern Pennsylvania between 1 January 2014 to 31 December 2017. We identified patients 2 to 17 years with documented wheezing, excluding those with suspected anaphylaxis. Patients with documented respiratory distress were classified as severe asthma. We report descriptive statistics of demographics, vital signs, and management including administration of medications and performance of procedures. RESULTS Of 19 246 pediatric transports, 1078 (5.6%) patients had wheezing. Of these, 532 (49%) met criteria for severe asthma. Patients with severe asthma were more likely to be adolescents compared to those with nonsevere asthma (49.6% vs 6%; P < .001). While rates of intravenous methylprednisolone administration were higher in patients with severe asthma (68/532, 12.8%) compared to those with nonsevere asthma (13/546, 2.4%; P < .001), overall use of steroids was low (7.5%). Other therapies provided included albuterol (n = 699, 64.8%), ipratropium bromide (n = 271, 25.1%), and oxygen (n = 280, 26.0%). One hundred eighty patients (16.7%) received a peripheral IV line. Two patients (0.4%) were given continuous positive airway pressure. CONCLUSION Approximately 6% of pediatric EMS transports are for asthma. Steroid usage was low in even those with severe asthma, representing an area of process improvement. These data provide a baseline to future research to identify interventions that may improve outcomes.

The fish plasma model (FPM) predicts the fish blood plasma concentration of a pharmaceutical from the water concentration to which the fish is exposed and compares it with the human therapeutic plasma concentration (Hther PC) with the postulate that no adverse toxic effects occur below the Hther PC. The present study provides several lines of evidence supporting the FPM for the beta-adrenergic agonist salbutamol, a small cationic molecule at ambient pH. Salbutamol exhibited very low acute toxicity to early and adult life stages of fish. Biomass reduction in fish early life stages was the most sensitive apical endpoint, with no-observed-effect concentrations (NOECs) in the low mg/L range after continuous exposure for up to 120 d. Given that predicted and measured environmental concentrations are at least 1000-fold lower, the risk of salbutamol in freshwater is deemed very low. Increase in heart beat rate and decrease in total triglyceride content in fish also occurred at the low mg/L range and resembled effects known from humans. This finding supports the FPM assumption of conserved targets in fish with similar functionality. Plasma concentrations measured in adult and juvenile fish exposed to water concentrations at approximately the NOECs exceeded Hther PC and even approached plasma concentrations toxic to humans. This result confirms for salbutamol the FPM hypothesis that no adverse (i.e., population-relevant) toxic effects occur in fish below the Hther PC. Environ Toxicol Chem 2019;38:2509-2519. © 2019 SETAC.

Objective To quantify aerosol delivery with or without a high flow nasal cannula (HFNC) in place using pressurized metered-dose inhaler (pMDI) and jet nebulizer (JN) with facemask in a simulated spontaneously breathing pediatric lung model. Methods An upper airway model of a 9-month-old infant (Sophia Anatomical Infant Nose-Throat) with an absolute filter distal to the trachea was connected to a breathing simulator to simulate pediatric parameters (tidal volume = 100 mL, respiratory rate = 30 breaths/min, and I:E ratio = 1:1.4). Oxygen at 3 L/min was administered through an infant HFNC (Fisher & Paykel Healthcare Ltd, Auckland, New Zealand) attached to the nares of the model. Albuterol sulfate (2.5 mg/3 mL) was delivered with JN attached to an aerosol facemask and powered by air at 8 L/min. Ventolin Hydrofluoroalkane (HFA) (360 μg) was administered using pMDI connected to a valved holding chamber (VHC) with a facemask. Aerosol was administered to the model with and without HFNC in the nares (n = 3). Drug was eluted from the filter and quantified using spectrophotometry. Independent t tests were performed for data analysis (P Results Aerosol deposition was greater without HFNC (6.05% ± 1.53% and 39.54% ± 8.98% for JN and pMDI/VHC, respectively) than with HFNC using JN (2.91% ± 0.23%; P = .024) and pMDI/VHC (6.04% ± 0.28%; P = .003). Delivery efficiency of pMDI/VHC was greater than JN with or without nasal cannula in place (P = .0001 and .003, respectively). Conclusion Aerosol administered via facemask over HFNC was less efficient than removing HFNC during administration. When delivering medical aerosol by facemask, the benefit of increased aerosol delivery must be weighed against the changes in oxygen delivery and risk of lung derecruitment when nasal prongs are removed.

BACKGROUND AND OBJECTIVE: Mixed inhaler device use for asthma is associated with worse inhaler technique and outcomes. Given that relievers are commonly prescribed as pressurized metred-dose inhalers (pMDI), changing preventers from dry powder inhalers (DPI) to pMDI may improve asthma outcomes. This study aimed to assess the persistence and effectiveness of switching from DPI to pMDI for inhaled corticosteroid and long-acting β2 -agonist combination therapy (ICS/LABA).METHODS: This was a historical cohort study using Ajou University Hospital (Korea) patient records. Persistence of switch was defined as receiving ≥1 pMDI and no DPI after the switch. Effectiveness of switch was assessed as the proportion without severe asthma exacerbation and the proportion achieving risk domain asthma control (RDAC; no asthma-related hospitalization, antibiotics without upper respiratory diagnosis or acute course of oral corticosteroids) and overall asthma control (OAC; RDAC and ≤ 200 μg salbutamol/≤500 μg terbutaline average daily dose) comparing 1 year after and before the switch.RESULTS: Within 85 patients who switched from DPI to pMDI and persisted for a year, higher proportion were free from asthma exacerbation after the switch (mean difference in proportion = 0.129, 95% CI: 0.038-0.220). Switching to pMDI was also associated with better RDAC (75.3% vs 57.7%, P = 0.001) and OAC (57.7% vs 45.9%, P = 0.021). From the entire 117 patients who switched to fixed-dose combination (FDC)/ICS LABA pMDI, 76.1% (95% CI: 69.0-100.0%) patients persisted in the following 6 months.CONCLUSION: Switching to and persisting with pMDI was associated with decreased asthma exacerbations and improved asthma control. The majority of patients persisted with the switch to pMDI for ICS/LABA treatment.

Background Bronchoalveolar lavage (BAL) is a method for the recovery of respiratory secretion from the lower airways. Objectives To investigate if the administration of a single dose of a bronchodilatator in horses with a suspected or confirmed severe equine asthma could improve recovery of bronchoalveolar lavage fluid (BALF). Animals Twenty-eight horses with severe equine asthma. Methods Horses were divided into 2 groups: group "treated" was given salbutamol before endoscopic examination and BALF collection, whereas group "not treated" was not given. BAL was performed with BAL-catheter by instilling 350 mL of sterile saline. Amount of recovered fluid was recorded. Statistical analysis was performed with a two-tailed Student's t test. Results The average fluid recovery in the horses treated with salbutamol was 52% ± 15% (mean +/- SD), compared with 38% ± 13% for the group of horses not treated with salbutamol (P = 0.013). Conclusions and clinical importance Clinicians should consider administration of salbutamol before performing BAL on horses with asthma.

Salmeterol and fluticasone are included in the Prohibited List annually issued by the World Anti-Doping Agency. While for other permitted beta-2 agonists a threshold has been established, above which any finding constitutes an Adverse Analytical Finding, this is not the case with salmeterol. The salmeterol metabolite, α-hydroxysalmeterol, has been described as a potentially more suitable biomarker for the misuse of inhaled salmeterol. In this study, a new and rapid UHPLC-QTOF-MS method was developed and validated for the simultaneous quantification of salmeterol, α-hydroxysalmeterol and fluticasone in human urine and plasma, which can be used for doping control. The analytes of interest were extracted by means of solid phase extraction and were separated on a Zorbax Eclipse Plus C18 column. Detection was performed in a quadrupole time-of-flight mass spectrometer equipped with an electrospray ionization source, in positive mode for the detection of salmeterol and its metabolite and in negative mode for the detection of fluticasone. Method was validated over a linear range from 0.10 to 2.00 ng/ml for salmeterol and fluticasone, and from 1.00 to 20.0 ng/ml for α-hydroxysalmeterol, in urine, whereas in plasma, the linear range was from 0.025 to 0.500 ng/ml for salmeterol and fluticasone, respectively.

BACKGROUND: Transient tachypnea of the newborn is characterized by tachypnea and signs of respiratory distress. Transient tachypnea typically appears within the first two hours of life in term and late preterm newborns. Although transient tachypnea of the newborn is usually a self‐limited condition, it is associated with wheezing syndromes in late childhood. The rationale for the use of salbutamol (albuterol) for transient tachypnea of the newborn is based on studies showing that β‐agonists can accelerate the rate of alveolar fluid clearance. This review was originally published in 2016 and updated in 2020. OBJECTIVES: To assess whether salbutamol compared to placebo, no treatment or any other drugs administered to treat transient tachypnea of the newborn, is effective and safe for infants born at 34 weeks’ gestational age with this diagnosis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2020, Issue 4) in the Cochrane Library; PubMed (1996 to April 2020), Embase (1980 to April 2020); and CINAHL (1982 to April 2020). We applied no language restrictions. We searched the abstracts of the major congresses in the field (Perinatal Society of Australia New Zealand and Pediatric Academic Societies) from 2000 to 2020 and clinical trial registries. SELECTION CRITERIA: Randomized controlled trials, quasi‐randomized controlled trials and cluster trials comparing salbutamol versus placebo or no treatment or any other drugs administered to infants born at 34 weeks' gestational age or more and less than three days of age with transient tachypnea of the newborn. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology for data collection and analysis. The primary outcomes considered in this review were duration of oxygen therapy, need for continuous positive airway pressure and need for mechanical ventilation. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Seven trials, which included 498 infants, met the inclusion criteria. All trials compared a nebulized dose of salbutamol with normal saline. Four studies used one single dose of salbutamol; in two studies, three to four doses were provided; in one study, additional doses were administered if needed. The certainty of the evidence was low for duration of hospital stay and very low for the other outcomes. Among the primary outcomes of this review, four trials (338 infants) reported the duration of oxygen therapy, (mean difference (MD) ‐19.24 hours, 95% confidence interval (CI) ‐23.76 to ‐14.72); one trial (46 infants) reported the need for continuous positive airway pressure (risk ratio (RR) 0.73, 95% CI 0.38 to 1.39; risk difference (RD) ‐0.15, 95% CI ‐0.45 to 0.16), and three trials (254 infants) reported the need for mechanical ventilation (RR 0.60, 95% CI 0.13 to 2.86; RD ‐0.01, 95% CI ‐0.05 to 0.03). Both duration of hospital stay (4 trials; 338 infants) and duration of respiratory support (2 trials, 228 infants) were shorter in the salbutamol group (MD ‐1.48, 95% CI ‐1.8 to ‐1.16; MD ‐9.24, 95% CI ‐14.24 to ‐4.23, respectively). One trial (80 infants) reported duration of mechanical ventilation and pneumothorax but data could not be extracted due to the reporting of these outcomes (type of units of effect measure and unclear number of events, respectively). Five trials are ongoing. AUTHORS' CONCLUSIONS: There was limited evidence to establish the benefits and harms of salbutamol in the management of transient tachypnea of the newborn. We are uncertain whether salbutamol administration reduces the duration of oxygen therapy, duration of tachypnea, need for continuous positive airway pressure and for mechanical ventilation. Salbutamol may slightly reduce hospital stay. Five trials are ongoing. Given the limited and low certainty of the evidence available, we could not determine whether salbutamol was safe or effective for the treatment of transient tachypnea of the newborn.

Background Acute bronchiolitis is a significant burden on children, their families and healthcare facilities. It mostly affects children younger than two years of age. Treatment involves adequate hydration, humidified oxygen supplementation, and nebulisation of medications, such as salbutamol, epinephrine, and hypertonic saline. The effectiveness of magnesium sulphate for acute bronchiolitis is unclear. Objectives To assess the effects of magnesium sulphate in acute bronchiolitis in children up to two years of age. Search methods We searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, and two trials registries to 30 April 2020. We contacted trial authors to identify additional studies. We searched conference proceedings and reference lists of retrieved articles. Unpublished and published studies were eligible for inclusion. Selection criteria Randomised controlled trials (RCTs) and quasi-RCTs, comparing magnesium sulphate, alone or with another treatment, with placebo or another treatment, in children up to two years old with acute bronchiolitis. Primary outcomes were time to recovery, mortality, and adverse events. Secondary outcomes were duration of hospital stay, clinical severity score at 0 to 24 hours and 25 to 48 hours after treatment, pulmonary function test, hospital readmission within 30 days, duration of mechanical ventilation, and duration of intensive care unit stay. Data collection and analysis We used standard methodological procedures expected by Cochrane. We used GRADE methods to assess the certainty of the evidence. Main results We included four RCTs (564 children). One study received funding from a hospital and one from a university; two studies did not report funding sources. Comparator interventions differed among all four trials. Studies were conducted in Qatar, Turkey, Iran, and India. We assessed two studies to be at an overall low risk of bias, and two to be at unclear risk of bias, overall. The certainty of the evidence for all outcomes and comparisons was very low except for one: hospital re-admission rate within 30 days of discharge for magnesium sulphate versus placebo. None of the studies measured time to recovery, duration of mechanical ventilation, duration of intensive care unit stay, or pulmonary function. There were no events of mortality or adverse effects for magnesium sulphate compared with placebo (1 RCT, 160 children). The effects of magnesium sulphate on clinical severity are uncertain (at 0 to 24 hours: mean difference (MD) on the Wang score 0.13, 95% confidence interval (CI) -0.28 to 0.54; and at 25 to 48 hours: MD on the Wang score -0.42, 95% CI -0.84 to -0.00). Magnesium sulphate may increase hospital re-admission rate within 30 days of discharge (risk ratio (RR) 3.16, 95% CI 1.20 to 8.27; 158 children; low-certainty evidence). None of our primary outcomes were measured for magnesium sulphate compared with hypertonic saline (1 RCT, 220 children). Effects were uncertain on the duration of hospital stay in days (MD 0.00, 95% CI -0.28 to 0.28), and on clinical severity on the Respiratory Distress Assessment Instrument (RDAI) score at 25 to 48 hours (MD 0.10, 95% CI -0.39 to 0.59). There were no events of mortality or adverse effects for magnesium sulphate, with or without salbutamol, compared with salbutamol (1 RCT, 57 children). Effects on the duration of hospital stay were uncertain (magnesium sulphate: 24 hours (95% CI 25.8 to 47.4), magnesium sulphate + salbutamol: 20 hours (95% CI 15.3 to 39.0), and salbutamol: 24 hours (95% CI 23.4 to 76.9)). None of our primary outcomes were measured for magnesium sulphate + epinephrine compared with no treatment or normal saline + epinephrine (1 RCT,120 children). Effects were uncertain for the duration of hospital stay in hours (MD -0.40, 95% CI -3.94 to 3.14), and for RDAI scores (0 to 24 hours: MD -0.20, 95% CI -1.06 to 0.66; and 25 to 48 hours: MD -0.90, 95% CI -1.75 to -0.05). Authors' conclusions There is insufficient evidence to establish the efficacy and safety of magnesium sulphate for treating children up to two years of age with acute bronchiolitis. No evidence was available for time to recovery, duration of mechanical ventilation and intensive care unit stay, or pulmonary function. There was no information about adverse events for some comparisons. Well-designed RCTs to assess the effects of magnesium sulphate for children with acute bronchiolitis are needed. Important outcomes, such as time to recovery and adverse events should be measured.

BACKGROUND: Preterm birth (PTB) remains the foremost global cause of perinatal morbidity and mortality. Thus, the prevention of spontaneous PTB still remains of critical importance. In an attempt to prevent PTB in singleton pregnancies, cervical cerclage, in combination with other treatments, has been advocated. This is because, cervical cerclage is an intervention that is commonly recommended in women with a short cervix at high risk of preterm birth but, despite this, many women still deliver prematurely, as the biological mechanism is incompletely understood. Additionally, previous Cochrane Reviews have been published on the effectiveness of cervical cerclage in singleton and multiple pregnancies, however, none has evaluated the effectiveness of using cervical cerclage in combination with other treatments. OBJECTIVES: To assess whether antibiotics administration, vaginal pessary, reinforcing or second cerclage placement, tocolytic, progesterone, or other interventions at the time of cervical cerclage placement prolong singleton gestation in women at high risk of pregnancy loss based on prior history and/or ultrasound finding of ’short cervix’ and/or physical examination. History‐indicated cerclage is defined as a cerclage placed usually between 12 and 15 weeks gestation based solely on poor prior obstetrical history, e.g. multiple second trimester losses due to painless dilatation. Ultrasound‐indicated cerclage is defined as a cerclage placed usually between 16 and 23 weeks gestation for transvaginal ultrasound cervical length < 20 mm in a woman without cervical dilatation. Physical exam‐indicated cerclage is defined as a cerclage placed usually between 16 and 23 weeks gestation because of cervical dilatation of one or more centimetres detected on physical (manual) examination. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (26 September 2019), and reference lists of retrieved studies. SELECTION CRITERIA: We included published, unpublished or ongoing randomised controlled trial (RCTs). Studies using a cluster‐RCT design were also eligible for inclusion in this review but none were identified. We excluded quasi‐RCTs (e.g. those randomised by date of birth or hospital number) and studies using a cross‐over design. We also excluded studies that specified addition of the combination therapy after cervical cerclage because the woman subsequently became symptomatic. We included studies comparing cervical cerclage in combination with one, two or more interventions with cervical cerclage alone in singleton pregnancies. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts of all retrieved articles, selected studies for inclusion, extracted data, assessed risk of bias, and evaluated the certainty of the evidence for this review's main outcomes. Data were checked for accuracy. Standard Cochrane review methods were used throughout. MAIN RESULTS: We identified two studies (involving a total of 73 women) comparing cervical cerclage alone to a different comparator. We also identified three ongoing studies (one investigating vaginal progesterone after cerclage, and two investigating cerclage plus pessary). One study (20 women), conducted in the UK, comparing cervical cerclage in combination with a tocolytic (salbutamol) with cervical cerclage alone in women with singleton pregnancy did not provide any useable data for this review. The other study (involving 53 women, with data from 50 women) took place in the USA and compared cervical cerclage in combination with a tocolytic (indomethacin) and antibiotics (cefazolin or clindamycin) versus cervical cerclage alone ‐ this study did provide useable data for this review (and the study authors also provided additional data on request) but meta‐analyses were not possible. This study was generally at a low risk of bias, apart from issues relating to blinding. We downgraded the certainty of evidence for serious risk of bias and imprecision (few participants, few events and wide 95% confidence intervals). Cervical cerclage in combination with an antibiotic and tocolytic versus cervical cerclage alone (one study, 50 women/babies) We are unclear about the effect of cervical cerclage in combination with antibiotics and a tocolytic compared with cervical cerclage alone on the risk of serious neonatal morbidity (RR 0.62, 95% CI 0.31 to 1.24; very low‐certainty evidence); perinatal loss (data for miscarriage and stillbirth only ‐ data not available for neonatal death) (RR 0.46, 95% CI 0.13 to 1.64; very low‐certainty evidence) or preterm birth < 34 completed weeks of pregnancy (RR 0.78, 95% CI 0.44 to 1.40; very low‐certainty evidence). There were no stillbirths (intrauterine death at 24 or more weeks). The trial authors did not report on the numbers of babies discharged home healthy (without obvious pathology) or on the risk of neonatal death. AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to evaluate the effect of combining a tocolytic (indomethacin) and antibiotics (cefazolin/clindamycin) with cervical cerclage compared with cervical cerclage alone for preventing spontaneous PTB in women with singleton pregnancies. Future studies should recruit sufficient numbers of women to provide meaningful results and should measure neonatal death and numbers of babies discharged home healthy, as well as other important outcomes listed in this review. We did not identify any studies looking at other treatments in combination with cervical cerclage. Future research needs to focus on the role of other interventions such as vaginal support pessary, reinforcing or second cervical cerclage placement, 17‐alpha‐hydroxyprogesterone caproate or dydrogesterone or vaginal micronised progesterone, omega‐3 long chain polyunsaturated fatty acid supplementation and bed rest.

BACKGROUND AND OBJECTIVE A characteristic feature of asthma is hypertrophied airway smooth muscle, responsible for bronchoconstriction. This is the target of bronchial thermoplasty (BT). It is known that with increasing time and severity some patients develop remodelled airways with fixed airflow obstruction. The question arises whether these patients will still respond to BT. METHODS Forty-nine consecutive severe asthmatic patients were prospectively evaluated at baseline and then 6 months after BT. The characteristics recorded included medication usage, exacerbation history, spirometry and the Asthma Control Questionnaire 5-Item Version score (ACQ-5). Seven patients were excluded as they did not demonstrate airflow obstruction at baseline (forced expiratory ratio (forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC))

AIM Using a non-invasive lung function technique (interrupter resistance, Rint), we aimed to determine whether a dose-response to salbutamol could be detected in wheezy preschool children and if so, which dose of salbutamol should be administered to routinely evaluate bronchial reversibility. METHOD Wheezy children (3 to

Aim We aimed to identify the frequency, magnitude and risk factors of salbutamol-induced hypoxia in children with acute asthma. Methods This study was conducted at Hacettepe University on children who presented to the paediatric allergy clinic or the paediatric emergency room with acute asthma between July 2014 and June 2015. Vital signs, pulse oximetry-defined oxygen saturation and modified pulmonary index scores were evaluated before and after the first, second and third doses of nebulised salbutamol and repeated one and 10 days later. Results We included 304 patients (65.7% male) from median age of 5.3 years (range 1-18 years). Salbutamol-induced hypoxia was detected in 14.7%, 3.9% and 1.3%, respectively, after the first, second and third doses of salbutamol. The risk factors for hypoxia were younger age and a higher modified pulmonary index score, but the risk factors for salbutamol-induced hypoxia were the number of salbutamol doses given in the last six hours and the presence of aeroallergen sensitisation. The maximum decrease in oxygen saturation after salbutamol was %5. Conclusion Although bronchodilators are the first-line treatment for acute asthma, they caused modest hypoxaemia, especially at repeated doses and, or, in patients with aeroallergen sensitisation.

Background Although previous studies have shown benefits of nebulized hypertonic saline (HS) for improving airway clearance and shortening hospitalization in infants with bronchiolitis, prospective blinded studies in preschool children with acute viral wheezing are limited. Objectives To determine nebulized 3% HS efficacy in young children admitted with acute viral wheezing. Methods This double-blind, randomized controlled trial was conducted in children aged 6 months to 5 years admitted with acute viral wheezing from July 1st to December 31st 2016. Patients were randomized to receive inhalation of 2.5 mg salbutamol dissolved in either 3% HS or normal saline (NS). Clinical data, asthma clinical severity score, and length of hospital stay (LOS) were recorded. Results A total of 47 patients were enrolled (22 in HS and 25 in NS) without significant differences in demographic data and baseline clinical scores. Median LOS and median time of oxygen therapy were significantly shorter in HS than NS group: 48 versus 72 h, P = 0.021 and 36 versus 72 h, P = 0.025, respectively. HS patients had significantly improved asthma clinical severity scores, respiratory rates and oxygen saturation at 12 h compared to NS group (P-value 0.042, 0.032, and 0.043). There were no adverse events. Conclusion In children under 5 years admitted with acute viral wheezing, nebulized hypertonic saline/salbutamol significantly shortened hospital stay length, time of oxygen therapy, and improved asthma clinical severity score faster than normal saline/salbutamol.

Background There are limited data regarding the comparability of medication exposure information during pregnancy from maternal report and medical records, including for rheumatoid arthritis and asthma-related medications. Methods This study included pregnant women with rheumatoid arthritis (n = 216) and asthma (n = 172) enrolled in the MothertoBaby Pregnancy Studies (2009-2014). Women reported types and dates of medications used through semi-structured telephone interviews up to three times during pregnancy and once after delivery, and medical records were obtained. We calculated Cohen's kappa coefficients and 95% confidence intervals (CIs) and per cent agreement for agreement between report and records. Results For rheumatoid arthritis, prednisone was reported most frequently (53%). During pregnancy, kappa coefficients for rheumatoid arthritis medications ranged from 0.32 (95% CI 0.15, 0.50) for ibuprofen, with 84.3% agreement, to 0.90 (95% CI 0.84, 0.96) for etanercept with 95.4% agreement, and was 0.44 (95% CI 0.33, 0.55) for prednisone, with 71.3% agreement. For asthma, albuterol was reported most frequently (77.9%). During pregnancy, kappa coefficients for asthma medications ranged from 0.21 (95% CI 0.08, 0.35), with 64.5% agreement for albuterol to 0.84 (95% CI 0.71, 0.96) for budesonide/formoterol, with 96.5% agreement. Where kappas for any use during pregnancy were less than excellent (i.e. ≤0.80), medication use was more frequently captured by report than record. Conclusions Agreement was higher for medications typically used continuously than sporadically. Information on medication use from medical records alone may not be adequate when studying the impact of intermittently used medications during pregnancy on perinatal outcomes.

Introduction The impulse oscillometry (IOS) indices absolute and relative difference between respiratory resistance at 5 and 20 Hz (R5-20 and R5-20%, respectively) and the area under the reactance curve (AX) are postulated to reflect small airway function. Data on their cutoff values to evaluate bronchodilator responsiveness (BDR) or between-visit changes after interventions are limited in young children. Methods We evaluated the BDR of 103 healthy children aged 2-7 years, who received either salbutamol (n = 84) or placebo (n = 19) in order to determine cutoff values for BDR of R5-20, R5-20%, and AX. We then determined the repeatability within and between two IOS measurements 7-14 days apart in young children aged 4-8 years with asthmatic symptoms (n = 43), including cutoff values for significant between-visit changes. Results The investigated IOS parameters showed marked BDR (fifth percentile cutoff of 75-110% of the baseline value) in healthy children, whereas no significant changes were seen after inhalation of placebo. The agreement within the triplicate IOS measurement was excellent (ICC > 0.80), and the agreement of results between visits was good (ICC > 0.60). A change in R5-20, R5-20%, and AX of 0.65, 1.08, and 0.84 z-scores, respectively, would exceed 95% confidence intervals for between-visit variability. Conclusion We introduce cutoff values for BDR of R5-20, R5-20%, and AX, and their repeatability indices and cutoff limits for significant between-visit changes. These IOS parameters may show greater variability than the conventional IOS indices during follow-up, but the between-visit agreement remains good, providing potentially useful endpoints for monitoring lung function in young children.

Objectives American Thoracic Society/European Respiratory Society (ATS/ERS) spirometry interpretation guidelines recommend ≥15 min between pre- and post-bronchodilator testing to evaluate for a bronchodilator response. We aimed to lengthen the time between albuterol administration and post-bronchodilator testing to adhere to ATS/ERS guidelines and evaluated if lengthening this wait time would increase the percentage of patients classified as bronchodilator responsive. Methods We compared the proportion of patients with a positive bronchodilator response between two groups of children with asthma, one group in which post-bronchodilator administration wait times were not standardized (pre-intervention) to another in which the wait time was extended to 15 min to adhere to ATS/ERS standards (post-intervention). We also determined the effect of this intervention on clinic appointment duration. Results The analysis included 271 patients (145 pre-intervention and 126 post-intervention). The average wait time in the pre-intervention group was 6.5 ± 2.1 (mean ± SD) minutes compared to 16.2 ± 3.2 min (P < 0.001) post intervention, and clinic times increased from 83.0 ± 29.6 min to 91.7 ±22.5 min (P < 0.007) from the pre- to post-intervention group, respectively. In adjusted regression analysis, there was no significant change in FEV1% predicted between the two groups. Conclusions In a busy pediatric pulmonary clinic, while we successfully lengthened time between albuterol administration and post-bronchodilator testing in the vast majority of patients, no difference was seen in the percentage of patients classified as bronchodilator responsive. Results from this study appear to question the ATS/ERS recommended 15 min post-bronchodilator administration wait time for children.

Aim Infants hospitalised for bronchiolitis undergo examinations and treatments not supported by current research evidence and we investigated practice variations with regard to Finnish children under the age of two. Methods This prospective, multicentre cohort study was conducted in paediatric units in three university hospitals in Finland from 2008 to 2010. Hospital medical records were reviewed to collect data on clinical course, testing and treatment. Data were analysed separately for children meeting our strict definition of bronchiolitis, aged under 12 months without a history of wheezing, and a loose definition, aged 12–23 months or with a history of wheezing. Results The median age of the 408 children was 8.1 months. Clinical management varied between the three hospitals when stratified by strict and loose bronchiolitis subgroup definitions: complete blood counts ranged from 15–95% vs 16–94%, respectively, and the other measures were chest x-ray (16–91% vs 14–72%), intravenous fluids (2–47% vs 2–41%), use of nebulised epinephrine (10–84% vs 7–50%), use of salbutamol (18–21% vs 13–84%) and use of corticosteroids (6–23% vs 60–76%). Conclusion The clinical management of bronchiolitis varied considerably with regard to the three hospitals and the two definitions of bronchiolitis. A stronger commitment to evidence-based bronchiolitis guidelines is needed in Finland.

Background We wanted to compare cold dry air challenge (CACh) induced changes in spirometric parameters with changes in nitrogen multiple breath washout (N2MBW) parameters in pediatric asthma patients during clinical remission over the past year (ie, with “inactive asthma”). As N2MBW assesses ventilation heterogeneity we expected to gain detailed information about peripheral airways contribution. Methods In subjects with normal spirometry N2MBW, spirometry and body plethysmography were performed at baseline, after CACh, and after salbutamol inhalation. An initial measurement of the fraction of exhaled nitric oxide (FeNO) was conducted. Results Forty-three (20 female) subjects, mean age 13.7 years (range 6.5-18.6) performed reproducible N2MBW measurements. Ten were tested hyperresponsive (23.3%) and 33 normoresponsive (76.7%). Baseline spirometry and body plethysmography as well as FRC (N2MBW) were similar in both groups. Scond (0.031 vs 0.022), Sacin (0.057 vs 0.067), and FeNO (92.0 vs 28.5 ppb) were not statistically different between hyperresponsive and nomoresponsive subjects at baseline. Subjects with airway hyperresponsiveness (AHR) showed significant increases in lung clearance index (LCI, P = 0.011) and Scond (P = 0.008) after CACh, and significant decreases after salbutamol (LCI: P = 0.005; Scond: P = 0.005). In contrast, normoresponsive subjects showed no relevant changes after CACh, and only a decrease of Scond after salbutamol (P = 0.007). There were significant correlations between the CACh induced changes in FEV1 and changes in LCI (r = −0.45, P = 0.003), Scond (r = −0.30, P = 0.047), and Sacin (r = −0.47, P = 0.008), respectively. Conclusion Our study provides evidence of small airway involvement in children and adolescents with inactive asthma and airway hyperresponsiveness.

For convenience, many pediatric hospitals are preparing solutions for continuous nebulized albuterol using the 0.5% 20-ml multidose albuterol dropper bottle. This product contains benzalkonium chloride (BAC) that, by itself, produces bronchospasm that is dose dependent and cumulative. The bronchoconstrictive effects of BAC are greater in patients with more severe airway obstruction and increased airway responsiveness. Use of BAC-containing albuterol during severe acute asthma exacerbations may antagonize the bronchodilator response to albuterol, prolong treatment, and increase the risk of albuterol-related systemic adverse effects. Such a deleterious effect of BAC is difficult to detect because some patients improve slowly or may even worsen during treatment. We recommend that only preservative-free albuterol products be used.

Background: Around 16 million cases of whooping cough (pertussis) occur worldwide each year, mostly in low‐income countries. Much of the morbidity of whooping cough in children and adults is due to the effects of the paroxysmal cough. Cough treatments proposed include corticosteroids, beta2‐adrenergic agonists, pertussis‐specific immunoglobulin, antihistamines and possibly leukotriene receptor antagonists (LTRAs). Objectives: To assess the effectiveness and safety of interventions to reduce the severity of paroxysmal cough in whooping cough in children and adults. Search methods: We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 1), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, the Database of Abstracts of Reviews of Effects (DARE 2014, Issue 2), accessed from The Cochrane Library, MEDLINE (1950 to 30 January 2014), EMBASE (1980 to 30 January 2014), AMED (1985 to 30 January 2014), CINAHL (1980 to 30 January 2014) and LILACS (30 January 2014). We searched Current Controlled Trials to identify trials in progress. Selection criteria: We selected randomised controlled trials (RCTs) and quasi‐RCTs of any intervention (excluding antibiotics and vaccines) to suppress the cough in whooping cough. Data collection and analysis: Two review authors (SB, MT) independently selected trials, extracted data and assessed the quality of each trial for this review in 2009. Two review authors (SB, KW) independently reviewed additional studies identified by the updated searches in 2012 and 2014. The primary outcome was frequency of paroxysms of coughing. Secondary outcomes were frequency of vomiting, frequency of whoop, frequency of cyanosis (turning blue), development of serious complications, mortality from any cause, side effects due to medication, admission to hospital and duration of hospital stay. Main results: We included 12 trials of varying sample sizes (N = 9 to 135), mainly from high‐income countries, including a total of 578 participants. Ten trials recruited children (N = 448 participants). Two trials recruited adolescents and adults (N = 130 participants). We considered only three trials to be of high methodological quality (one trial each of diphenhydramine, pertussis immunoglobulin and montelukast). Included studies did not show a statistically significant benefit for any of the interventions. Only six trials, including a total of 196 participants, reported data in sufficient detail for analysis. Diphenhydramine did not change coughing episodes; the mean difference (MD) of coughing spells per 24 hours was 1.9; 95% confidence interval (CI) ‐4.7 to 8.5 (N = 49 participants from one trial). One trial on pertussis immunoglobulin reported a possible mean reduction of ‐3.1 whoops per 24 hours (95% CI ‐6.2 to 0.02, N = 47 participants) but no change in hospital stay (MD ‐0.7 days; 95% CI ‐3.8 to 2.4, N = 46 participants). Dexamethasone did not show a clear decrease in length of hospital stay (MD ‐3.5 days; 95% CI ‐15.3 to 8.4, N = 11 participants from one trial) and salbutamol showed no change in coughing paroxysms per day (MD ‐0.2; 95% CI ‐4.1 to 3.7, N = 42 participants from two trials). Only one trial comparing pertussis immunoglobulin versus placebo (N = 47 participants) reported data on adverse events: 4.3% in the treatment group (rash) versus 5.3% in the placebo group (loose stools, pain and swelling at injection site). Authors' conclusions: There is insufficient evidence to draw conclusions about the effectiveness of interventions for the cough in whooping cough. More high‐quality trials are needed to assess the effectiveness of potential antitussive treatments in patients with whooping cough

Background Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about whether regular (daily) long-acting beta2-agonists (LABA) are safe when used in combination with inhaled corticosteroids (ICS). This updated Cochrane Review includes results from two large trials that recruited 23,422 adolescents and adults mandated by the US Food and Drug Administration (FDA). Objectives To assess the risk of mortality and non-fatal serious adverse events (SAEs) in trials that randomly assign participants with chronic asthma to regular formoterol and inhaled corticosteroids versus the same dose of inhaled corticosteroid alone. Search methods We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data as well as FDA submissions in relation to formoterol. The date of the most recent search was February 2019. Selection criteria We included randomised clinical trials (RCTs) with a parallel design involving adults, children, or both with asthma of any severity who received regular formoterol and ICS (separate or combined) treatment versus the same dose of ICS for at least 12 weeks. Data collection and analysis We used standard methodological procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors of the studies. We assessed our confidence in the evidence using GRADE recommendations. The primary outcomes were all-cause mortality and all-cause non-fatal serious adverse events. Main results We found 42 studies eligible for inclusion and included 39 studies in the analyses: 29 studies included 35,751 adults, and 10 studies included 4035 children and adolescents. Inhaled corticosteroids included beclomethasone (daily metered dosage 200 to 800 µg), budesonide (200 to 1600 µg), fluticasone (200 to 250 µg), and mometasone (200 to 800 µg). Formoterol metered dosage ranged from 12 to 48 µg daily. Fixed combination ICS was used in most of the studies. We judged the risk of selection bias, performance bias, and attrition bias as low, however most studies did not report independent assessment of causation of SAEs.DeathsSeventeen of 18,645 adults taking formoterol and ICS and 13 of 17,106 adults taking regular ICS died of any cause. The pooled Peto odds ratio (OR) was 1.25 (95% confidence interval (CI) 0.61 to 2.56, moderate-certainty evidence), which equated to one death occurring for every 1000 adults treated with ICS alone for 26 weeks; the corresponding risk amongst adults taking formoterol and ICS was also one death (95% CI 0 to 2 deaths). No deaths were reported in the trials on children and adolescents (4035 participants) (low-certainty evidence).In terms of asthma-related deaths, no children and adolescents died from asthma, but three of 12,777 adults in the formoterol and ICS treatment group died of asthma (both low-certainty evidence).Non-fatal serious adverse eventsA total of 401 adults experienced a non-fatal SAE of any cause on formoterol with ICS, compared to 369 adults who received regular ICS. The pooled Peto OR was 1.00 (95% CI 0.87 to 1.16, high-certainty evidence, 29 studies, 35,751 adults). For every 1000 adults treated with ICS alone for 26 weeks, 22 adults had an SAE; the corresponding risk for those on formoterol and ICS was also 22 adults (95% CI 19 to 25).Thirty of 2491 children and adolescents experienced an SAE of any cause when receiving formoterol with ICS, compared to 13 of 1544 children and adolescents receiving ICS alone. The pooled Peto OR was 1.33 (95% CI 0.71 to 2.49, moderate-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 8 had an non-fatal SAE; the corresponding risk amongst those on formoterol and ICS was 11 children and adolescents (95% CI 6 to 21).Asthma-related serious adverse eventsNinety adults experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 102 with ICS alone. The pooled Peto OR was 0.86 (95% CI 0.64 to 1.14, moderate-certainty evidence, 28 studies, 35,158 adults). For every 1000 adults treated with ICS alone for 26 weeks, 6 adults had an asthma-related non-fatal SAE; the corresponding risk for those on formoterol and ICS was 5 adults (95% CI 4 to 7).Amongst children and adolescents, 9 experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 5 on ICS alone. The pooled Peto OR was 1.18 (95% CI 0.40 to 3.51, very low-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 3 had an asthma-related non-fatal SAE; the corresponding risk on formoterol and ICS was 4 (95% CI 1 to 11). Authors' conclusions We did not find a difference in the risk of death (all-cause or asthma-related) in adults taking combined formoterol and ICS versus ICS alone (moderate- to low-certainty evidence). No deaths were reported in children and adolescents. The risk of dying when taking either treatment was very low, but we cannot be certain if there is a difference in mortality when taking additional formoterol to ICS (low-certainty evidence).We did not find a difference in the risk of non-fatal SAEs of any cause in adults (high-certainty evidence). A previous version of the review had shown a lower risk of asthma-related SAEs in adults taking combined formoterol and ICS; however, inclusion of new studies no longer shows a difference between treatments (moderate-certainty evidence).The reported number of children and adolescents with SAEs was small, so uncertainty remains in this age group.We included results from large studies mandated by the FDA. Clinical decisions and information provided to patients regarding regular use of formoterol and ICS need to take into account the balance between known symptomatic benefits of formoterol and ICS versus the remaining degree of uncertainty associated with its potential harmful effects.

Background Pulse wave analysis (PWA) and laser Doppler fluximetry (LDF) are non-invasive methods of assessing macrovascular endothelial function and microvascular reactivity respectively. The aim of this study was to assess the correlation between macrovascular endothelial function assessed by PWA and microvascular reactivity assessed by LDF. Method 297 healthy and non-smoking subjects (159 females, mean age (±SD) 23.56 ± 4.54 years) underwent microvascular reactivity assessment using LDF followed by macrovascular endothelial function assessments using PWA. Results Pearson's correlation showed no correlation between macrovascular endothelial function and microvascular reactivity (r = -0.10, P = 0.12). Conclusion There was no significant correlation between macrovascular endothelial function assessed by PWA and microvascular reactivity assessed by LDF in healthy subjects.

Objective To examine changes in children's albuterol use and out-of-pocket (OOP) costs in response to increased copayments after the Food and Drug Administration banned inhalers with chlorofluorocarbon (CFC) propellants. Setting Four health maintenance organizations (HMOs), two that increased copayments for albuterol inhalers that went from generic CFC-containing to branded CFC-free versions, and two that retained generic copayments for CFC-free inhalers (controls). We included children with asthma aged 4–17 years with commercial coverage from 2007 to 2010. Design Interrupted time series with comparison series. Data We obtained enrollee and plan characteristics from enrollment files, and utilization data from pharmacy and medical claims; OOP expenditures were extracted from pharmacy claims for two HMOs with cost data available. Findings There were no significant differences in albuterol use between the group with increased cost-sharing and controls with respect to changes after the policy change. There was a postpolicy increase of $6.11 OOP per month per child using albuterol among those with increased cost-sharing versus $0.36 in controls; the difference between groups was significant (p

Objective Racemic albuterol and levalbuterol are used to treat acute episodes of asthma. The main objective of this study was to compare levalbuterol therapy to albuterol therapy on incidence rates of subsequent emergency department (ED) visits and hospitalizations. Method We conducted a retrospective cohort study of asthmatic children who had pharmacy refills for levalbuterol/albuterol in the South Carolina Medicaid database in 2002-2011. Children receiving levalbuterol were matched to those receiving albuterol using propensity score matching technique. For ED visits and separately for hospitalizations, multivariable negative binomial regression was used to estimate the two group-specific incidence rates and the incidence rate ratio (IRR). Results A total of 8,172 asthmatic patients aged 2-18 years were identified in the South Carolina Medicaid database. During the 12-month follow-up period, the levalbuterol group had fewer asthma-related ED visits and hospitalizations: 939 (11.49%) children had asthma-related ED visits (levalbuterol: 8.76%; albuterol: 14.21%), and 89 (1.09%) children had asthma-related hospitalizations (levalbuterol: 1.07%; albuterol: 1.12%). Comparing the levalbuterol group to the albuterol group, the adjusted IRR estimate was 0.57 (95% confidence interval [CI], 0.49-0.65) for of asthma-related ED visits, and 0.93 (95%CI, 0.99-1.63) for hospitalizations. Children filling levalbuterol also had a lower IRR of all-cause ED visit (0.88; 95%CI, 0.82-0.95), but similar IRR of all-cause hospitalizations (1.08; 95%CI, 0.82-1.42). Conclusion This observational study of children aged 2-18 demonstrated levalbuterol prescription fills were associated with reduced ED visits, but not hospitalizations. Additional research may be necessary to assess this association. Pediatr Pulmonol. 2017;52:516-523. © 2016 Wiley Periodicals, Inc.

A quick and specific pretreatment method based on a series of extraction clean-up disks, consisting of molecularly imprinted polymer monoliths and C18 adsorbent, was developed for the specific enrichment of salbutamol and clenbuterol residues in food. The molecularly imprinted monolithic polymer disk was synthesized using salbutamol as a template through a one-step synthesis process. It can simultaneously and specifically recognize salbutamol and clenbuterol. The monolithic polymer disk and series of C18 disks were assembled with a syringe to form a set of tailor-made devices for the extraction of target molecules. In a single run, salbutamol and clenbuterol can be specifically extracted, cleaned, and eluted by methanol/acetic acid/H2 O. The target molecules, after a silylation derivatization reaction were detected by gas chromatography-mass spectrometry. The parameters including solvent desorption, sample pH, and the cycles of reloading were investigated and discussed. Under the optimized extraction and clean-up conditions, the limits of detection and quantitation were determined as 0.018-0.022 and 0.042-0.049 ng/g for salbutamol and clenbuterol, respectively. The assay described was convenient, rapid, and specific; thereby potentially efficient in the high-throughput analysis of β2 -agonists residues in real food samples.