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Question 5: Magnesium Sulphate for Acute Asthma in children.
Aniapravan, R, Pullattayil, A, Al Ansari, K, Powell, CVE
Paediatric respiratory reviews. 2020;:112-117
Abstract
Most children who present to the emergency department with acute asthma, respond well to inhaled β2-agonists (spacer or nebuliser), oxygen (if required) and systemic steroids. Guidelines across the world agree on this simple, straight forward evidenced based approach. In children with more severe asthma attacks and those who do not respond to initial treatment, the evidence base for the secondary level treatment is less clear. Many regimens exist for the next step. Intravenous Magnesium Sulphate (MgSO4) is now used frequently in these situations and some centres are starting to use nebulized MgSO4 as part of the initial maximal inhaled therapy options. This paper examines the role of MgSO4 in acute asthma in children. It focusses on how MgSO4 might work, what are the current recommendations for use and then what is the current evidence base to support its use. We have presented the evidence for the use of both nebulized and intravenous MgSO4. At the end of the paper we have suggested future directions for research in this area. Our aim is to present a synthesis of the current role of MgSO4 in the management of an acute asthma attack.
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Understanding reliever overuse in patients purchasing over-the-counter short-acting beta2 agonists: an Australian community pharmacy-based survey.
Azzi, EA, Kritikos, V, Peters, MJ, Price, DB, Srour, P, Cvetkovski, B, Bosnic-Anticevich, S
BMJ open. 2019;(8):e028995
Abstract
OBJECTIVES Overuse of asthma relievers is associated with significant adverse consequences. This study aimed to better understand the population purchasing and using short-acting beta agonists (SABA) over the counter (OTC); and compare the demographic, clinical and behavioural characteristics of those who overuse SABA with those who do not. DESIGN AND SETTING Real-world cross-sectional observational study in community pharmacy. PARTICIPANTS Of 412 participants ≥16 years requesting SABA OTC, 289 were SABA overusers (used SABA more than twice per week in the past 4 weeks). MAIN OUTCOME MEASURE Reliever use, Global Initiative for Asthma-defined control, healthcare utilisation, patterns of preventer use. RESULTS 70.1% of participants were classified as SABA overusers, that is, reporting SABA use more than twice a week within the last 4 weeks, 73.6% reported not using a preventer daily and only 81.6% reported a doctor diagnosis of asthma. SABA overusers were more likely to have moderate-severe nasal symptoms (80.8% vs 63.0%, p<0.001) and a diagnosis of depression (11.1% vs 5.7%, p<0.001), when compared with SABA non-overusers. A higher proportion of SABA overusers had uncontrolled asthma (59.0% vs 15.4%, p<0.001), were more likely to use oral corticosteroids to manage worsening asthma symptoms (26.2% vs 13.5%, p<0.01) and visit the doctor for their asthma in the past 12 months (74.5% vs 62.5%, p<0.01), when compared to SABA non-overusers. CONCLUSIONS This study uncovers a hidden population of people who can only be identified in pharmacy with suboptimal asthma, coexisting rhinitis, poor preventer adherence and, in some cases, no asthma diagnosis.
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β2-Agonist Induces Net Leg Glucose Uptake and Free Fatty Acid Release at Rest but Not During Exercise in Young Men.
Onslev, J, Jensen, J, Bangsbo, J, Wojtaszewski, J, Hostrup, M
The Journal of clinical endocrinology and metabolism. 2019;(3):647-657
Abstract
OBJECTIVE The role of selective β2-adrenergic stimulation in regulation of leg glucose uptake and free fatty acid (FFA) balance is inadequately explored in humans. The objective of this study was to investigate β2-adrenergic effects on net leg glucose uptake and clearance, as well as FFA balance at rest and during exercise. DESIGN The study was a randomized, placebo-controlled crossover trial where 10 healthy men received either infusion of β2-agonist terbutaline (0.2 to 0.4 mg) or placebo. Net leg glucose uptake and clearance and FFA balance were determined at rest and during 8 minutes of knee extensor exercise using Fick's principle. Vastus lateralis muscle biopsies were collected at rest and at cessation of exercise. The primary outcome measure was net leg glucose uptake. RESULTS At rest, net leg glucose uptake and clearance were 0.35 (±0.16) mmol/min and 41 (±17) mL/min (mean ± 95% CI) higher (P < 0.001) for terbutaline than placebo, corresponding to increases of 84% and 70%. During exercise, no treatment differences were observed in net leg glucose uptake, whereas clearance was 101 (±86) mL/min lower (P < 0.05) for terbutaline than placebo. At rest, terbutaline induced a net leg FFA release of 21 (±14) µmol/min, being different from placebo (P = 0.04). During exercise, net leg FFA uptake was not different between the treatments. CONCLUSIONS These observations indicate that β2-agonist alters net leg glucose uptake and clearance, as well as FFA balance in humans, which is associated with myocellular β2-adrenergic and insulin-dependent signaling. Furthermore, the study shows that exercise confounds the β2-adrenergic effect on net leg glucose uptake and FFA balance.
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Comparison between montelukast and tiotropium as add-on therapy to inhaled corticosteroids plus a long-acting β2-agonist in for patients with asthma.
Hoshino, M, Akitsu, K, Ohtawa, J
The Journal of asthma : official journal of the Association for the Care of Asthma. 2019;(9):995-1003
Abstract
Objective: Asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS) alone or with ICS plus a long-acting β2-agonist (LABA). The recommended alternative is the addition of either montelukast or tiotropium. The aim of this study was to compare the effects of montelukast and tiotropium on airway inflammation and remodeling in persistent asthma. Methods: Eighty-seven patients with asthma were treated with budesonide and formoterol (640/18 μg); then, the patients were randomly allocated to three groups to receive oral montelukast (10 mg/day), inhaled tiotropium (5 μg/day), or no add-on to the maintenance therapy for 48 weeks. Fractional exhaled nitric oxide (FeNO) and pulmonary function were measured, and quantitative computed tomography was performed. Results: Compared to the maintenance therapy, add-on montelukast significantly decreased FeNO (p < 0.05) and improved airflow obstruction (p < 0.05), whereas airway dimensions remained unchanged. Changes in FeNO were significantly correlated with changes in FEV1 (r = -0.71, p < 0.001). In contrast, the addition of tiotropium significantly decreased airway wall area corrected for body surface area (WA/BSA) (p < 0.05), decreased wall thickness (T/√BSA) (p < 0.05) and improved airflow obstruction (p < 0.05) with no change in FeNO. Changes in WA/BSA and T/√BSA were significantly correlated with the change in percentage predicted FEV1 (r = -0.84, p < 0.001 and r = -0.59, p < 0.01, respectively). Conclusions:Adding either montelukast or tiotropium to ICS/LABA may provide additive benefits with respect to the pulmonary function and airway inflammation or remodeling in patients with asthma.
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5.
Inhaled magnesium sulfate in the treatment of acute asthma in children.
Normansell, R, Knightly, R, Milan, SJ, Knopp-Sihota, JA, Rowe, BH, Powell, C
Paediatric respiratory reviews. 2018;:31-33
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Chronic β2 -adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men.
Hostrup, M, Onslev, J, Jacobson, GA, Wilson, R, Bangsbo, J
The Journal of physiology. 2018;(2):231-252
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Abstract
KEY POINTS While several studies have investigated the effects of exercise training in human skeletal muscle and the chronic effect of β2 -agonist treatment in rodent muscle, their effects on muscle proteome signature with related functional measures in humans are still incompletely understood. Herein we show that daily β2 -agonist treatment attenuates training-induced enhancements in exercise performance and maximal oxygen consumption, and alters muscle proteome signature and phenotype in trained young men. Daily β2 -agonist treatment abolished several of the training-induced enhancements in muscle oxidative capacity and caused a repression of muscle metabolic pathways; furthermore, β2 -agonist treatment induced a slow-to-fast twitch muscle phenotype transition. The present study indicates that chronic β2 -agonist treatment confounds the positive effect of high intensity training on exercise performance and oxidative capacity, which is of interest for the large proportion of persons using inhaled β2 -agonists on a daily basis, including athletes. ABSTRACT Although the effects of training have been studied for decades, data on muscle proteome signature remodelling induced by high intensity training in relation to functional changes in humans remains incomplete. Likewise, β2 -agonists are frequently used to counteract exercise-induced bronchoconstriction, but the effects β2 -agonist treatment on muscle remodelling and adaptations to training are unknown. In a placebo-controlled parallel study, we randomly assigned 21 trained men to 4 weeks of high intensity training with (HIT+β2 A) or without (HIT) daily inhalation of β2 -agonist (terbutaline, 4 mg dose-1 ). Of 486 proteins identified by mass-spectrometry proteomics of muscle biopsies sampled before and after the intervention, 32 and 85 were changing (false discovery rate (FDR) ≤5%) with the intervention in HIT and HIT+β2 A, respectively. Proteome signature changes were different in HIT and HIT+β2 A (P = 0.005), wherein β2 -agonist caused a repression of 25 proteins in HIT+β2 A compared to HIT, and an upregulation of 7 proteins compared to HIT. β2 -Agonist repressed or even downregulated training-induced enrichment of pathways related to oxidative phosphorylation and glycogen metabolism, but upregulated pathways related to histone trimethylation and the nucleosome. Muscle contractile phenotype changed differently in HIT and HIT+β2 A (P ≤ 0.001), with a fast-to-slow twitch transition in HIT and a slow-to-fast twitch transition in HIT+β2 A. β2 -Agonist attenuated training-induced enhancements in maximal oxygen consumption (P ≤ 0.01) and exercise performance (6.1 vs. 11.6%, P ≤ 0.05) in HIT+β2 A compared to HIT. These findings indicate that daily β2 -agonist treatment attenuates the beneficial effects of high intensity training on exercise performance and oxidative capacity, and causes remodelling of muscle proteome signature towards a fast-twitch phenotype.
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Protection against severe hypokalemia but impaired cardiac repolarization after intense rowing exercise in healthy humans receiving salbutamol.
Atanasovska, T, Smith, R, Graff, C, Tran, CT, Melgaard, J, Kanters, JK, Petersen, AC, Tobin, A, Kjeldsen, KP, McKenna, MJ
Journal of applied physiology (Bethesda, Md. : 1985). 2018;(2):624-633
Abstract
Intense exercise induces pronounced hyperkalemia, followed by transient hypokalemia in recovery. We investigated whether the β2 agonist salbutamol attenuated the exercise hyperkalemia and exacerbated the postexercise hypokalemia, and whether hypokalemia was associated with impaired cardiac repolarization (QT hysteresis). Eleven healthy adults participated in a randomized, counterbalanced, double-blind trial receiving either 1,000 µg salbutamol (SAL) or placebo (PLAC) by inhalation. Arterial plasma potassium concentration ([K+]a) was measured at rest, during 3 min of intense rowing exercise, and during 60 min of recovery. QT hysteresis was calculated from ECG ( n = 8). [K+]a increased above baseline during exercise (rest, 3.72 ± 0.7 vs. end-exercise, 6.81 ± 1.4 mM, P < 0.001, mean ± SD) and decreased rapidly during early recovery to below baseline; restoration was incomplete at 60 min postexercise ( P < 0.05). [K+]a was less during SAL than PLAC (4.39 ± 0.13 vs. 4.73 ± 0.19 mM, pooled across all times, P = 0.001, treatment main effect). [K+]a was lower after SAL than PLAC, from 2 min preexercise until 2.5 min during exercise, and at 50 and 60 min postexercise ( P < 0.05). The postexercise decline in [K+]a was correlated with QT hysteresis ( r = 0.343, n = 112, pooled data, P = 0.001). Therefore, the decrease in [K+]a from end-exercise by ~4 mM was associated with reduced QT hysteresis by ~75 ms. Although salbutamol lowered [K+]a during exercise, no additive hypokalemic effects occurred in early recovery, suggesting there may be a protective mechanism against severe or prolonged hypokalemia after exercise when treated by salbutamol. This is important because postexercise hypokalemia impaired cardiac repolarization, which could potentially trigger arrhythmias and sudden cardiac death in susceptible individuals with preexisting hypokalemia and/or heart disease. NEW & NOTEWORTHY Intense rowing exercise induced a marked increase in arterial potassium, followed by a pronounced decline to hypokalemic levels. The β2 agonist salbutamol lowered potassium during exercise and late recovery but not during early postexercise, suggesting a protective effect against severe hypokalemia. The decreased potassium in recovery was associated with impaired cardiac QT hysteresis, suggesting a link between postexercise potassium and the heart, with implications for increased risk of cardiac arrhythmias and, potentially, sudden cardiac death.
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Hypertrophic effect of inhaled beta2 -agonist with and without concurrent exercise training: A randomized controlled trial.
Jessen, S, Onslev, J, Lemminger, A, Backer, V, Bangsbo, J, Hostrup, M
Scandinavian journal of medicine & science in sports. 2018;(10):2114-2122
Abstract
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.
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Intracellular interactions of umeclidinium and vilanterol in human airway smooth muscle.
Shaikh, N, Johnson, M, Hall, DA, Chung, KF, Riley, JH, Worsley, S, Bhavsar, PK
International journal of chronic obstructive pulmonary disease. 2017;:1903-1913
Abstract
BACKGROUND Intracellular mechanisms of action of umeclidinium (UMEC), a long-acting muscarinic receptor antagonist, and vilanterol (VI), a long-acting β2-adrenoceptor (β2R) agonist, were investigated in target cells: human airway smooth-muscle cells (ASMCs). MATERIALS AND METHODS ASMCs from tracheas of healthy lung-transplant donors were treated with VI, UMEC, UMEC and VI combined, or control compounds (salmeterol, propranolol, ICI 118.551, or methacholine [MCh]). Cyclic adenosine monophosphate (cAMP) was measured using an enzyme-linked immunosorbent assay, intracellular free calcium ([Ca2+]i) using a fluorescence assay, and regulator of G-protein signaling 2 (RGS2) messenger RNA using real-time quantitative polymerase chain reaction. RESULTS VI and salmeterol (10-12-10-6 M) induced cAMP production from ASMCs in a concentration-dependent manner, which was greater for VI at all concentrations. β2R antagonism by propranolol or ICI 118.551 (10-12-10-4 M) resulted in concentration-dependent inhibition of VI-induced cAMP production, and ICI 118.551 was more potent. MCh (5×10-6 M, 30 minutes) attenuated VI-induced cAMP production (P<0.05), whereas pretreatment with UMEC (10-8 M, 1 hour) restored the magnitude of VI-induced cAMP production. ASMC stimulation with MCh (10-11-5×10-6 M) resulted in a concentration-dependent increase in [Ca2+]i, which was attenuated with UMEC pretreatment. Reduction of MCh-induced [Ca2+]i release was greater with UMEC + VI versus UMEC. UMEC enhanced VI-induced RGS2 messenger RNA expression. CONCLUSION These data indicate that UMEC reverses cholinergic inhibition of VI-induced cAMP production, and is a more potent muscarinic receptor antagonist when in combination with VI versus either alone.
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Beta2-adrenergic stimulation increases energy expenditure at rest, but not during submaximal exercise in active overweight men.
Onslev, J, Jacobson, G, Narkowicz, C, Backer, V, Kalsen, A, Kreiberg, M, Jessen, S, Bangsbo, J, Hostrup, M
European journal of applied physiology. 2017;(9):1907-1915
Abstract
PURPOSE β2-Agonists have been proposed as weight-loss treatment, because they elevate energy expenditure. However, it is unknown what effect β2-agonists have on energy expenditure in overweight individuals. Furthermore, the influence of β2-agonist R- and S-enantiomer ratio for the increased energy expenditure is insufficiently explored. METHODS Nineteen males were included in the study of which 14 completed. Subjects were 31.6 (±3.5) years [mean (±95% CI)] and had a fat percentage of 22.7 (±2.1)%. On separate days, subjects received either placebo or inhaled racemic (rac-) formoterol (2 × 27 µg). After an overnight fast, energy expenditure and substrate oxidation were estimated by indirect calorimetry at rest and during submaximal exercise. Plasma (R,R)- and (S,S)-formoterol enantiomer levels were measured by ultra-performance liquid chromatograph-mass spectrometry. RESULTS At rest, energy expenditure and fat oxidation were 12% (P ≤ 0.001) and 38% (P = 0.006) higher for rac-formoterol than placebo. Systemic (R,R):(S,S) formoterol ratio was correlated with change in energy expenditure at rest in response to rac-formoterol (r = 0.63, P = 0.028), whereas no association was observed between fat percentage and rac-formoterol-induced change in energy expenditure. During exercise, energy expenditure was not different between treatments, although carbohydrate oxidation was 15% higher (P = 0.021) for rac-formoterol than placebo. Rac-formoterol-induced shift in substrate choice from rest to exercise was related to plasma ln-rac-formoterol concentrations (r = 0.75, P = 0.005). CONCLUSION Selective β2-adrenoceptor agonism effectively increases metabolic rate and fat oxidation in overweight individuals. The potential for weight loss induced by β2-agonists may be greater for R-enantiopure formulations.