S-nitrosylation is required for ß2AR desensitization and experimental asthma.

The ß2-adrenergic receptor (ß2AR), a prototypic G-protein-coupled receptor (GPCR), is a powerful driver of bronchorelaxation, but the effectiveness of ß-agonist drugs in asthma is limited by desensitization and tachyphylaxis. We find that during activation, the ß2AR is modified by S-nitrosylation, which is essential for both classic desensitization by PKA as well as desensitization of NO-based signaling that mediates bronchorelaxation. Strikingly, S-nitrosylation alone can drive ß2AR internalization in the absence of traditional agonist. Mutant ß2AR refractory to S-nitrosylation (Cys265Ser) exhibits reduced desensitization and internalization, thereby amplifying NO-based signaling, and mice with Cys265Ser mutation are resistant to bronchoconstriction, inflammation, and the development of asthma. S-nitrosylation is thus a central mechanism in ß2AR signaling that may be operative widely among GPCRs and targeted for therapeutic gain.

Congenital Long QT Syndrome Unmasked by Albuterol in an Adolescent with Asthma.

BACKGROUND: Patients with congenital long QT syndrome (LQTS) are prone to ventricular dysrhythmia but may be initially asymptomatic with a normal QTc interval on resting electrocardiogram (ECG). Albuterol is listed as a medication that poses a "special risk" to patients with congenital LQTS, but its effects have been rarely described. We present a case of previously unknown, asymptomatic congenital LQTS unmasked by albuterol in an adolescent with asthma. CASE REPORT: A 12-year-old girl with a history of asthma presented to the emergency department (ED) with shortness of breath, wheezing, and tachycardia for 24 h, consistent with acute asthma exacerbation. She received two doses of her home albuterol inhaler 2 h prior to presentation. Initial ECG demonstrated a QTc of 619 ms. Her remaining history, clinical examination, and laboratory workup, including electrolytes, were unremarkable. She was observed with cardiac monitoring before being discharged from the ED in stable condition for next-day outpatient pediatric cardiology follow-up. Resting office ECGs revealed QTcs from 440-470 ms. Exercise stress test revealed QTc prolongation of 520 ms and 500 ms at minute-2 and minute-4 of recovery, respectively. Genetic testing revealed heterozygous pathogenic variants in KCNQ1, consistent with type 1 LQTS. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Albuterol may be a cause of marked QTc prolongation in ED patients with underlying congenital LQTS, which can be a diagnostic clue in previously unidentified patients. Extreme QTc prolongation also serves as an indication in the ED for Cardiology consultation, laboratory evaluation for electrolyte imbalances, and observation with cardiac monitoring.

The effect of oral medications on fMRI brain activation: A randomized, double blind, controlled pilot trial of older women with overactive bladder.

INTRODUCTION AND AIM: Observational studies have associated oral anticholinergic medications for overactive bladder (OAB) with cognitive impairment. This is the first pilot trial to compare the effects of two classes of OAB medications on brain activity in women. We evaluated the effect of anticholinergic versus non-anticholinergic (Non-Ach) interventions on regional brain activation during a cognitive task. METHODS: Twelve cognitively normal women seeking OAB therapy were recruited to a randomized, double-blind, parallel, controlled pilot trial. Whole-brain regional activity at baseline and 29 ± 1 days postintervention was assessed with functional magnetic resonance imaging during a working memory task. Average activation strength by region was compared after anticholinergic, beta-3 agonist, or placebo. Two-way ANOVA compared effects of group and time on average activation strength in anticholinergic versus Non-Ach (beta-3 agonists or placebo) groups. RESULTS: The mean (SD) age and body mass index of 12 women were 61 (7) years and 36 (7) kg/m2. Baseline depression and learning scores differed in the anticholinergic group (n = 3) versus the Non-Ach group (n = 9). Right mamillary body activation postintervention was higher after Non-Ach exposure (F 4.9, p < 0.04). In the full sample of participants at follow-up, there was less activation of the right middle frontal gyrus (p = 0.02), superior frontal gyrus (p < 0.01), and supramarginal (p < 0.01) gyrus. CONCLUSION: Activation strength in brain regions underlying working memory was lower over time, and recognition scores improved. A powered trial is needed to adequately evaluate for differential effects of OAB oral medications on regional brain activation.

Experiences of Diagnosis, Symptoms, and Use of Reliever Inhalers in Patients With Asthma and Concurrent Inducible Laryngeal Obstruction or Breathing Pattern Disorder: Qualitative Analysis of a UK Asthma Online Community.

BACKGROUND: Breathing pattern disorders (BPDs) and inducible laryngeal obstruction (ILO) cause similar symptoms to asthma, including dyspnea and chest tightness, with an estimated prevalence of up to one-fifth of patients with asthma. Both conditions can be comorbid with asthma, and there is evidence that they are misdiagnosed and mistreated as asthma. OBJECTIVE: This study aims to explore whether the symptoms of ILO and BPD were topics of discussion in a UK asthma online health community and patient experiences of diagnosis and treatment, in particular their use of reliever inhalers. METHODS: A qualitative thematic analysis was performed with posts from an asthma community between 2018 and 2022. A list of key ILO or BPD symptoms was created from the literature. Posts were identified using the search terms "blue inhaler" and "breath" and included if describing key symptoms. Discussion threads of included posts were also analyzed. RESULTS: The search retrieved a total of 1127 relevant posts: 1069 written by 302 users and 58 posted anonymously. All participants were adults, except 2 who were parents writing about their children. Sex and age were only available for 1.66% (5/302; 3 females and 2 males) and 9.93% (30/302) of participants (27 to 73 years old), respectively. The average number of posts written by each participant was 3.54 (range 1-63). Seven participants wrote >20 posts each. Participants experiencing undiagnosed ILO or BPD symptoms, whether or not comorbid with asthma, expressed frustration with the "one-size-fits-all" approach to diagnosis, as many felt that their asthma diagnosis did not fully explain symptoms. Some suspected or were formally diagnosed with BPD or ILO, the latter reporting relief on receiving a diagnosis and appropriate management. Participants showed awareness of their inappropriate salbutamol use or overuse due to lack of effect on symptoms. BPD and ILO symptoms were frequently comorbid with asthma. The asthma online community was a valuable resource: engagement with peers not only brought comfort but also prompted action with some going back to their clinicians and reaching a diagnosis and appropriate management. CONCLUSIONS: Undiagnosed ILO and BPD symptoms and lack of effects of asthma treatment were topics of discussion in an asthma online community, caused distress and frustration in participants, and affected their relationship with health care professionals, showing that patients experiencing BPD and ILO have unmet needs. Clinicians' education on BPD and ILO diagnosis and management, as well as increased access to appropriate management options, such as respiratory physiotherapy and speech and language therapy, are warranted particularly in primary care. Qualitative evidence that engagement with the online community resulted in patients taking action going back to their clinicians and reaching a diagnosis of ILO and BPD prompts future research on online peer support from an established online health community as a self-management resource for patients.

Extended Stability of Isoproterenol Hydrochloride Injection in Polyvinyl Chloride Bags Stored in Amber Ultraviolet Light Blocking Bags.

Purpose:Evaluate the stability of isoproterenol hydrochloride injection in 0.9% sodium chloride in polyvinyl chloride bags for up to 90 days. Methods: Dilutions of isoproterenol hydrochloride injection to a concentration of 4 µg/mL were performed under aseptic conditions. The bags were stored in amber ultraviolet light blocking bags at room temperature (23°C-25°C) or under refrigeration (3°C-5°C). Three samples of each preparation and storage environment were analyzed on days 0, 2, 14, 30, 45, 60, and 90. Physical stability was performed by visual examination. The pH was assessed at baseline, each analysis day, and upon final degradation evaluation. Sterility of the samples was not assessed. Chemical stability of isoproterenol hydrochloride was evaluated using liquid chromatography with tandem mass spectrometry. Samples were considered stable if there was <10% degradation of the initial concentration. Results: Isoproterenol hydrochloride diluted to 4 µg/mL with 0.9% sodium chloride injection was physically stable throughout the study. No precipitation was observed. At days 2, 14, 30, 45, 60, and 90 all bags diluted to 4 µg/mL had <10% degradation when stored under refrigeration (3°C-5°C) or stored at room temperature (23°C-25°C). Conclusion: Isoproterenol hydrochloride diluted to a concentration of 4 µg/mL with 0.9% sodium chloride for injection in ultraviolet light blocking bags was stable for 90 days at room temperature and under refrigeration.

The beta2 -adrenergic receptor - a re-emerging target to combat obesity and induce leanness?

Treatment of obesity with repurposed or novel drugs is an expanding research field. One approach is to target beta2 -adrenergic receptors because they regulate the metabolism and phenotype of adipose and skeletal muscle tissue. Several observations support a role for the beta2 -adrenergic receptor in obesity. Specific human beta2 -adrenergic receptor polymorphisms are associated with body composition and obesity, for which the Gln27Glu polymorphism is associated with obesity, while the Arg16Gly polymorphism is associated with lean mass in men and the development of obesity in specific populations. Individuals with obesity also have lower abundance of beta2 -adrenergic receptors in adipose tissue and are less sensitive to catecholamines. In addition, studies in livestock and rodents demonstrate that selective beta2 -agonists induce a so-called 'repartitioning effect' characterized by muscle accretion and reduced fat deposition. In humans, beta2 -agonists dose-dependently increase resting metabolic rate by 10-50%. And like that observed in other mammals, only a few weeks of treatment with beta2 -agonists increases muscle mass and reduces fat mass in young healthy individuals. Beta2 -agonists also exert beneficial effects on body composition when used concomitantly with training and act additively to increase muscle strength and mass during periods with resistance training. Thus, the beta2 -adrenergic receptor seems like an attractive target in the development of anti-obesity drugs. However, future studies need to verify the long-term efficacy and safety of beta2 -agonists in individuals with obesity, particularly in those with comorbidities.

Therapeutics effects of inhaled magnesium sulfate combined with adrenergic beta-2 agonist on children with acute asthma: Systematic review and meta-analysis.

AIM: To review the evidence on the effectiveness of inhaled magnesium sulfate (MgSO4) combined with beta-2 (B2) agonist as compared to inhaled B2 agonist alone in treating pediatric patients with moderate to severe asthma attacks METHODS: The search was conducted on five electronic databases namely the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, PubMed, Science Direct, and Google Scholar. RESULTS: Eight trials were included in the review. All studies involved a total of 1585 children aged 2-17 years with moderate to severe asthma attacks. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials. Three studies that assessed the effect of inhaled MgSO4 as adjunctive therapy on vital signs revealed no effect of inhaled MgSO4 on vital signs (SMD -0.11, 95% CI 0.27-0.04, p = 0.16, I2 = 68%). Two studies that assessed the effect of inhaled MgSO4 as adjunctive therapy on asthma severity score (ASS) revealed no effect of inhaled MgSO4 on ASS (SMD 0.22, 95% CI 0.01-0.44, Z = 2.01, p = 0.04, I2 = 88%). Two studies that assessed the effect of inhaled MgSO4 as adjunctive therapy on peak expiratory flow rate (PEFR) revealed a large effect of B2 agonist alone on PEFR (SMD 2.02, 95% CI 0.83-3.2, p < 0.001, I2 = 98%). CONCLUSION: This review does not support the use of inhaled MgSO4 as adjunctive therapy to B2 agonist for asthmatic children.

Olodaterol exerts anti-inflammatory effects on COPD airway epithelial cells.

BACKGROUND: Airway inflammation is a key feature of chronic obstructive pulmonary disease (COPD) and inhaled corticosteroids (ICS) remain the main treatment for airway inflammation. Studies have noted the increased efficacy of ICS and long-acting beta 2 agonist (LABA) combination therapy in controlling exacerbations and improving airway inflammation than either monotherapy. Further studies have suggested that LABAs may have inherent anti-inflammatory potential, but this has not been well-studied. OBJECTIVE: We hypothesize that the LABA olodaterol can inhibit airway inflammation resulting from exposure to respiratory syncytial virus (RSV) via its binding receptor, the ß2-adrenergic receptor. METHODS: Human bronchial epithelial brushing from patients with and without COPD were cultured into air-liquid interface (ALI) cultures and treated with or without olodaterol and RSV infection to examine the effect on markers of inflammation including interleukin-8 (IL-8) and mucus secretion. The cell line NCI-H292 was utilized for gene silencing of the ß2-adrenergic receptor via siRNA as well as receptor blocking via ICI 118,551 and butaxamine. RESULTS: At baseline, COPD-ALIs produced greater amounts of IL-8 than control ALIs. Olodaterol reduced RSV-mediated IL-8 secretion in both COPD and control ALIs and also significantly reduced Muc5AC staining in COPD-ALIs infected with RSV. A non-significant reduction was seen in control ALIs. Gene silencing of the ß2-adrenergic receptor in NCI-H292 negated the ability of olodaterol to inhibit IL-8 secretion from both RSV infection and lipopolysaccharide stimulus, as did blocking of the receptor with ICI 118,551 and butaxamine. CONCLUSIONS: Olodaterol exhibits inherent anti-inflammatory properties on the airway epithelium, in addition to its bronchodilation properties, that is mediated through the ß2-adrenergic receptor and independent of ICS usage.

Position statement: asthma in Latin America. IS short-acting beta-2 agonist helping or compromising asthma management?

In Latin-America, with 603 million inhabitants, the average prevalence of asthma is estimated at 17%, but with wide fluctuations, ranging from 5% in some cities (Mexico) to 30% in Costa Rica. The risk of severe exacerbations seems to be higher in Latin America compared with other regions. A majority of patients uses daily quick-relief medication, with the belief that it is the most important treatment because of its rapid onset of action; without treating the underlying inflammation. Overuse of short-acting beta2 agonists (SABAs) is associated with increased risk of asthma deaths in a dose-response manner. Beta2 agonists increase the severity of asthma through enhanced bronchial hyperresponsiveness and reduced lung function. Also, it has been shown that overreliance on SABA delays recognition of a potentially life-threatening asthma attack. We believe that overreliance on SABA in asthma is also an important public health issue. The fact that SABA use in GINA is not supported by a randomized trial but by an anonymous paper; makes us guess that we use SABA just because we are used to do so. In 2019 GINA strategy introduces one of the most important changes in the management of Asthma in the past 30 years, highlighting anti-inflammatory reliever therapy. A combination of low dose ICS/fast action bronchodilator will not only treat symptoms, but more importantly the underlying inflammation, protecting patients from preventable asthma attacks. After 50 years of a SABA centric approach in asthma management, it is time to leave behind a treatment based just on the bronchodilation and tackle the inflammation.

Evaluation and management of the critically ill adult asthmatic in the emergency department setting.

INTRODUCTION: Asthma is a common reason for presentation to the Emergency Department and is associated with significant morbidity and mortality. While patients may have a relatively benign course, there is a subset of patients who present in a critical state and require emergent management. OBJECTIVE: This narrative review provides evidence-based recommendations for the assessment and management of patients with severe asthma. DISCUSSION: It is important to consider a broad differential diagnosis for the cause and potential mimics of asthma exacerbation. Once the diagnosis is determined, the majority of the assessment is based upon the clinical examination. First line therapies for severe exacerbations include inhaled short-acting beta agonists, inhaled anticholinergics, intravenous steroids, and magnesium. Additional therapies for refractory cases include parenteral epinephrine or terbutaline, helium­oxygen mixture, and consideration of ketamine. Intravenous fluids should be administered, as many of these patients are dehydrated and at risk for hypotension if they receive positive pressure ventilatory support. Noninvasive positive pressure ventilation may prevent the need for endotracheal intubation. If mechanical ventilation is required, it is important to avoid breath stacking by setting a low respiratory rate and allowing permissive hypercapnia. Patients with severe asthma exacerbations will require intensive care unit admission. CONCLUSIONS: This review provides evidence-based recommendations for the assessment and management of severe asthma with a focus on the emergency clinician.

Recent advances in the design of RAR α and RAR ß agonists as orally bioavailable drugs. A review.

Retinoic acid receptors (RARs) α, ß, and γ are members of the nuclear receptor superfamily. Compounds which bind to and activate the RARs are termed retinoids which regulate a wide variety of biological processes such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation, and apoptosis, as well as their disorders. Although many synthetic selective RARα, RARß, and RARγ agonists have been designed and prepared, these have generally been lipophilic acids without good drug-like properties and with low oral bioavailability. Recently this has been changing and drug design approaches to highly potent and selective RARα and RARß agonists with low lipophilicity that are orally bioavailable and less toxic have been developed, that have a range of potential therapeutic uses. This review covers these new advances.

Switching from long-acting beta-agonist and inhaled corticosteroid to long-acting beta-agonist and long-acting muscarinic antagonist for chronic obstructive pulmonary disease: a case report of inhaled corticosteroid withdrawal.

Chronic obstructive pulmonary disease (COPD) is a medical condition characterised by persistent respiratory symptoms and airflow limitation. For the long-term management of COPD, inhaled therapies are the main approach to maintenance treatment. In order to improve treatment efficacy and tolerability for patients with COPD, recent clinical trials have focused on the withdrawal of inhaled corticosteroids (ICSs), the use of which has been associated with adverse outcomes, including pneumonia. In this case report, a patient with Global Initiative for Chronic Obstructive Lung Disease grade 3 COPD was switched from a combined inhaled therapy of a long-acting beta-agonist (LABA) and ICS to a combination of a LABA and a long-acting muscarinic antagonist (tiotropium/olodaterol) during hospitalisation for an acute exacerbation of COPD in April 2016. He was subsequently maintained in a stable condition, and was able to live and travel independently. This case report of successful ICS withdrawal suggests that, for moderate-to-severe COPD, if it is assessed individually, dual therapy of LABA and long-acting muscarinic antagonist can be highly effective and well-tolerated. Treatment compliance and lifestyle modifications have been shown to be critical in optimising treatment outcomes.

The determination of ß-agonist residues in bovine tissues using liquid chromatography-tandem mass spectrometry.

We aimed to develop a rapid, simple and reproducible method based on LC-tandem mass spectrometry (LC-MS/MS) to analyze ß-agonist residues (clenbuterol, zilpaterol, ractopamine and isoxsuprine) in bovine tissues. The method was validated in accordance with the European Council Decision 2002/657/EC. The samples were homogenized, and then 10 mL of an acetate buffer was added to a 5-g sample. The sample was then centrifuged at 12,000 rpm and filtered. Sodium hydroxide (2 m) was added to adjust pH of the sample that was centrifuged again. The extract was filtered through a solid-phase extraction column. The residue was re-dissolved in 250 µL acetonitrile and then subjected to LC-MS/MS. The separation was done on a C18 column. The mobile phase consisted of 0.1% formic acid in deionized water and 0.1% formic acid in methanol. The mean recoveries of ß-agonists were in the range of 84.3%-119.1% with relative standard deviations (%RSDs) of 0.683%-4.05%. Decision limits and detection capabilities of the analytes ranged from 0.0960 to 4.9349 µg/kg and from 0.0983 to 5.0715, respectively. This method was used to detect four ß-agonists in 100 bovine muscle, 100 liver and 100 kidney tissues from a slaughterhouse. No residue was found above the maximum residue limit level.

Discovery and lead optimisation of a potent, selective and orally bioavailable RARß agonist for the potential treatment of nerve injury.

Oxadiazole replacement of an amide linkage in an RARα agonist template 1, followed by lead optimisation, has produced a highly potent and selective RARß agonist 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (10) with good oral bioavailability in the rat and dog. This molecule increases neurite outgrowth in vitro and induces sensory axon regrowth in vivo in a rodent model of avulsion and crush injury, and thus has the potential for the treatment of nerve injury.

Effectiveness of fluticasone furoate/vilanterol versus fluticasone propionate/salmeterol on asthma control in the Salford Lung Study.

OBJECTIVE: The Asthma Salford Lung Study demonstrated the effectiveness of initiating once-daily fluticasone furoate/vilanterol (FF/VI) versus continuing usual care in asthma patients in UK primary care [ 1 ]. Here, we report a secondary analysis in a subset of patients with fluticasone propionate/salmeterol (FP/Salm) as their baseline intended maintenance therapy, to evaluate the relative effectiveness of initiating FF/VI versus continuing FP/Salm. METHODS: Adults with symptomatic asthma were randomised to initiate FF/VI 100[200]/25 µg or continue FP/Salm. The Asthma Control Test (ACT), Asthma Quality of Life Questionnaire (AQLQ), Work Productivity and Activity Impairment Asthma questionnaire, severe exacerbations, salbutamol inhaler prescriptions and serious adverse events (SAEs) were recorded throughout the 12-month treatment period. RESULTS: One thousand two hundred and sixty-four patients (FF/VI 646; FP/Salm 618) were included in this subset analysis; 978 had baseline ACT score <20 and were included in the primary effectiveness analysis (PEA) population. At week 24, odds of patients being ACT responders (total score ≥20 and/or improvement from baseline ≥3) were significantly higher with FF/VI versus FP/Salm (71% vs. 56%; odds ratio 2.03 [95% CI: 1.53, 2.68]; p < 0.001 [PEA]). Significant benefit with FF/VI versus FP/Salm was also observed for AQLQ responders, activity impairment due to asthma, exacerbation rates, and salbutamol inhalers prescribed. No significant between-group differences were observed for impairment while working or work absenteeism due to asthma. CONCLUSIONS: For patients in primary care, initiating FF/VI was significantly better than continuing with FP/Salm for improving asthma control and quality of life, and reducing asthma exacerbations, with no notable difference in SAEs. ClinicalTrials.gov: NCT01706198.

Pharmacogenetics of inhaled long-acting beta2-agonists in asthma: A systematic review.

BACKGROUND: Long-acting beta2-agonists (LABA) are recommended in asthma therapy; however, not all asthma patients respond well to LABA. We performed a systematic review on genetic variants associated with LABA response in patients with asthma. METHODS: Articles published until April 2017 were searched by two authors using PubMed and EMBASE. Pharmacogenetic studies in patients with asthma and LABA response as an outcome were included. RESULTS: In total, 33 studies were included in this systematic review; eight focused on children (n = 6051). Nineteen studies were clinical trials, while 14 were observational studies. Studies used different outcomes to define LABA response, for example, lung function measurements (FEV1 , PEF, MMEF, FVC), exacerbations, quality of life, and asthma symptoms. Most studies (n = 30) focused on the ADRB2 gene, encoding the beta2-adrenergic receptor. Thirty studies (n = 14 874) addressed ADRB2 rs1042713, 7 ADRB2 rs1042714 (n = 1629), and 3 ADRB2 rs1800888 (n = 1892). The association of ADRB2 rs1042713 and rs1800888 with LABA response heterogeneity was successfully replicated. Other variants were only studied in three studies but not replicated. One study focused on the ADCY9 gene. Five studies and a meta-analysis found an increased risk of exacerbations in pediatrics using LABA carrying one or two A alleles (OR 1.52 [1.17; 1.99]). These results were not confirmed in adults. CONCLUSIONS: ADRB2 rs1042713 variant is most consistently associated with response to LABA in children but not adults. To assess the clinical value of ADRB2 rs1042713 in children with asthma using LABA, a randomized clinical trial with well-defined outcomes is needed.

Comparison of a rapid albuterol pathway with a standard pathway for the treatment of children with a moderate to severe asthma exacerbation in the emergency department.

OBJECTIVE: The objective of this study was to determine if a rapid albuterol delivery pathway with a breath-enhanced nebulizer can reduce emergency department (ED) length of stay (LOS), while maintaining admission rates and side effects, when compared to a traditional asthma pathway with a standard jet nebulizer. METHODS: Children aged 3-18 presenting to a large urban pediatric ED for asthma were enrolled if they were determined by pediatric asthma score to have a moderate to severe exacerbation. Subjects were randomized to either a standard treatment arm where they received up to 2 continuous albuterol nebulizations, or a rapid albuterol arm where they received up to 4 rapid albuterol treatments with a breath-enhanced nebulizer, depending on severity scoring. The primary endpoint was ED LOS from enrollment until disposition decision. Asthma scores, albuterol dose, side effects, and return visits were also recorded. RESULTS: A total of 50 subjects were enrolled (25 in each arm). The study LOS was shorter in the rapid albuterol group (118 vs. 163 minutes, p = 0.0002). When total ED LOS was analyzed, the difference was no longer statistically significant (192 vs. 203 minutes, p = 0.65). There were no statistically significant differences with respect to admission rates, asthma score changes, side effects, or return visits. CONCLUSION: A rapid albuterol treatment pathway that utilizes a breath-enhanced nebulizer is an effective alternative to traditional pathways that utilize continuous nebulizations for children with moderate to severe asthma exacerbations in the ED.

Hypertrophic effect of inhaled beta2 -agonist with and without concurrent exercise training: A randomized controlled trial.

Due to a high prevalence of asthma and exercise-induced bronchoconstriction in elite athletes, there is a high use of beta2 -adrenoceptor agonists (beta2 -agonists) in the athletic population. While anabolic in rodents, no study has been able to detect hypertrophy in humans after chronic beta2 -agonist inhalation. We investigated whether inhaled beta2 -agonist, terbutaline, alters body composition and metabolic rate with and without concurrent exercise training in healthy young men. Sixty-seven participants completed a 4-week intervention of daily terbutaline (8 × 0.5 mg) or placebo treatment without concurrent training (habitual; n = 23), with resistance (n = 23) or endurance (n = 21) training 3 times weekly. Before and after the interventions, participant's body composition was determined by dual-energy X-ray absorptiometry and resting metabolic rate and substrate oxidation by indirect calorimetry. Terbutaline increased lean body mass by 1.03 kg (95% CI 0.29-1.76; P < .05) and 1.04 kg (95% CI 0.16-1.93; P < .05) compared to placebo in the habitual and resistance training group, respectively, but had no effect compared to placebo in the endurance training group [-0.56 kg (95% CI -1.74-0.62; P > .05)]. Fat mass, bone mineral content, and resting metabolic rate did not change differently between treatments with the intervention. Daily inhalation of terbutaline in near-therapeutic doses induces skeletal muscle growth. This observation should be a concern for antidoping authorities.

Controversies in Management of Hyperkalemia.

BACKGROUND: Hyperkalemia is a common electrolyte disorder that can result in morbidity and mortality if not managed appropriately. OBJECTIVES: This review evaluates the classic treatments of hyperkalemia and discusses controversies and new medications for management. DISCUSSION: Potassium (K+) plays a key role in determining the transmembrane potentials of "excitable membranes" present in nerve and muscle cells. K+ is the predominant intracellular cation, and clinical deterioration typically ensues when patients develop sufficiently marked elevation in extracellular fluid concentrations of K+ (hyperkalemia). Hyperkalemia is usually detected via serum clinical laboratory measurement. The most severe effect of hyperkalemia includes various cardiac dysrhythmias, which may result in cardiac arrest and death. Treatment includes measures to "stabilize" cardiac membranes, to shift K+ from extracellular to intracellular stores, and to promote K+ excretion. Calcium gluconate 10% dosed 10 mL intravenously should be provided for membrane stabilization, unless the patient is in cardiac arrest, in which case 10 mL calcium chloride is warranted. Beta-agonists and intravenous insulin should be given, and some experts recommend the use of synthetic short-acting insulins rather than regular insulin. Dextrose should also be administered, as indicated by initial and serial serum glucose measurements. Dialysis is the most efficient means to enable removal of excess K+. Loop and thiazide diuretics can also be useful. Sodium polystyrene sulfonate is not efficacious. New medications to promote gastrointestinal K+ excretion, which include patiromer and sodium zirconium cyclosilicate, hold promise. CONCLUSIONS: Hyperkalemia can be deadly, and treatment requires specific measures including membrane stabilization, cellular shift, and excretion.