http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–7 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2013.876620

REVIEW ARTICLE

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The use of intravenous and inhaled magnesium sulphate in management of children with bronchial asthma Waleed H. Albuali Pediatrics Department, College of Medicine, Dammam University, Dammam, Kingdom of Saudi Arabia

Abstract

Keywords

Background: Asthma is the most common chronic disease of childhood and the leading cause of childhood morbidity. When uncontrolled, asthma can place significant limits on daily life, and is sometimes fatal. The use of magnesium sulphate (MgSO4) is one of numerous treatment options available during acute severe asthma in children. The efficacy of intravenous, or inhaled MgSO4 has been demonstrated, while little is known about the actual clinical use of either intravenous (IV) or inhaling MgSO4. Objective: To assess the effectiveness of intravenous (IV) and/or inhaled MgSO4 on hospital admissions and pulmonary function in children with asthma. This systematic review assessed the best available evidence for the use of either intravenous or inhaled MgSO4 in children with acute asthma. Magnesium deficiency is a common electrolyte disorder in children with acute severe asthma. Several authors reported that IV magnesium was effective in the treatment of moderate to acute asthma in children but evidence for nebulised magnesium was insufficient. In addition, it is used in severe, progressed cases to prevent respiratory failure and/or admission to the intensive care unit. It has bronchodilating and anti-inflammatory effects and modulates ion transport and influences intracellular calcium concentration. Intravenous MgSO4 therapy helps in achieving earlier improvement in clinical signs and symptoms of asthma, e.g. respiratory function and significantly reduced hospital admission, in children with acute severe asthma. The role of nebulised MgSO4 in asthmatic children requires further investigation. Conclusion: According to the previous studies, the author recommends the use of intravenous MgSO4 as a safe and effective adjunct to conventional bronchodilator therapy in acute severe asthma in children.

Bronchial asthma, children, intravenous and inhaled magnesium sulphate

Introduction Asthma is a chronic inflammatory condition of lung airways characterised by bronchial hyper-responsiveness and reversible airflow obstruction leading to episodic airflow obstruction resulting in recurrent cough, wheeze or chest tightness, airway oedema, mucus secretion, smooth-muscle spasm (bronchospasm), shortness of breath (Paroxysmal dyspnoea) and chest tightness. In an asthma attack, the airways (passages to the lungs) narrow from muscle spasms and swellings (inflammation) [1,2]. The severity of an acute attack of asthma can be assessed by determination of the signs which are pulse rate, respiratory rate, amount of breathlessness (ability to talk and feed), use of accessory muscles of

Address for correspondence: Waleed H. Albuali, Pediatrics Department, College of Medicine, Dammam University, Dammam, Kingdom of Saudi Arabia. Fax: 00966-3-5800820-3030. E-mail: walbuali@ yahoo.com

History Received 7 November 2012 Accepted 15 December 2013 Published online 30 January 2014

respiration, extent and loudness of wheezing (which becomes less audible with increasingly severe airways obstruction), level of consciousness and presence of agitation (suggesting hypoxaemia) [3,4]. Asthma is one of the most common conditions among adults and children. Asthma is a common disease in childhood and an important health care problem worldwide. It is responsible for millions of lost school days every year. Children with asthma collectively have more days of restricted activity and hospitalisations annually. A recent analysis of childhood asthmatic deaths found that the major contributing factor for mortality was inadequate medical response [5]. There are numerous different triggers of asthma such as allergens, dust, gases, exercise, cold air, weather changes, cigarette smoke, infections and malformations of the bronchial system. Drug sensitivity, particularly aspirin products, may also induce hyper-reactive airways [6–9]. Bronchodilators, e.g. nebulised b2-agonists (e.g. albuterol); nebulised anticholinergic agent, and corticosteroids have been the primary drugs for the emergency room (ER) management of acute asthma. Some patients show inadequate response to the above therapy. In such situations other

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drugs which reverse airway obstruction would be of great benefit [10,11].

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Magnesium in health Magnesium is the fourth most abundant mineral in the human body and is essential to good health. Magnesium is needed for more than 300 biochemical reactions in the body. Magnesium takes part in many metabolic processes in the human body, including energy metabolism, protein and nucleic acid synthesis, cell cycle, the binding of substances to the plasma membrane, and maintenance of cytoskeletal and mitochondrial integrity. It regulates the blood sugar level, keeps the heart rhythm and immune system and keeps bones strong. Magnesium is also an important coenzyme for various enzyme activities, helping maintain cellular homeostasis. Magnesium is also present in the muscles (25%), and in other cell types and body fluids. It has the ability to relax our muscles. This explains how magnesium deficiency can trigger muscle tension, muscle spasms, muscle cramps and muscle fatigue. Our nerves also depend upon magnesium to avoid becoming overexcited [12–14]. Magnesium is necessary for the maintaining of serum potassium and intracellular calcium levels due to its effect on the renal tubule. In the heart, magnesium acts as a calcium channel blocker. It also activates sodium–potassium ATPase in the cell membrane to promote resting polarisation and produce arrhythmias. Magnesium prevents premature labour by inhibiting myometrial contractions. In the central nervous system (CNS), magnesium prevents or controls seizures by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end-plate by the motor nerve impulse. It also has a depressant effect on the CNS [13,15]. MgSO4 is being used more frequently in patients with severe airflow limitation, in conjunction with aggressive treatment (e.g. systemic corticosteroids, b2-agonists and ipratropium bromide), and in patients who often required prolonged ED care or hospitalization. Moreover, MgSO4 effectiveness relies on early recognition and administration during a severe attack; widespread use of other effective asthma therapies would therefore not be expected to reduce the need for MgSO4 [16].

Objective Magnesium has been evaluated in both the intravenous (IV) and nebulised dosage form which may have a different role in children. The author therefore aimed to undertake a systematic review of both IV and nebulised magnesium sulphate (MgSO4) to determine: (a) The effectiveness of IV and nebulised MgSO4 in children with acute severe asthma. (b) Whether either should be standard first-line treatment for children presenting to the emergency department with acute severe asthma. (c) The effect of IV or nebulised MgSO4 upon length of hospital stay and use of high-dependency or intensive care. (d) IV or nebulised MgSO4 will improve patient’s assessment of their breathlessness.

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Asthma and magnesium deficiency Magnesium deficiency is a common electrolyte disorder in patients with acute asthma. There are some data suggesting lower levels of Mg2+ and increased Ca2+/Mg2+ ratios in asthmatic patients compared with non-asthmatics. In 1912, Trendelenburg [17] first recognised the potential bronchodilator effect of magnesium. He observed bronchial smoothmuscle relaxation in cows, after magnesium administration. In 1936, Rosello and Pla [18] also demonstrated a bronchodilator effect of magnesium in asthmatic patients. Magnesium (Mg) has been shown to relax bronchial smooth muscle in vitro [19] and to bronchodilate asthmatic airways in vivo [20]. Mg deficiency may then lead to an increased excitability of bronchial smooth muscle with a consequent bronchoconstriction, airway hyper-reactivity and self-reported wheezing [21]. In addition, magnesium supplementation has relaxant effect on vascular and bronchial tones in animals and asthmatic children [19,22]. De Valk and Kok [23], found that intracellular Mg2+ content is reduced in patients with acute asthma, with exacerbation-induced bronchoconstriction. Haury [24] stated that magnesium deficiency is a common electrolyte disorder in patients with acute asthma and hypomagnesaemia results in an increase in bronchi smooth muscles excitability and their contraction. He also found that the half of patients with asthma exacerbations had low serum magnesium levels. Sinert et al. [25] also showed a strong positive correlation between bronchial reactivity, as assessed by the metacholine provocation test, and the intracellular magnesium concentration.

Efficacy of intravenous MgSO4 in treatment of asthmatic children The beneficial effect of intravenous MgSO4 for the treatment of asthma was first reported by Getal [26] of a case 60 years ago. Then, in 1989, Skobeloff et al. [27] confirmed the benefits of MgSO4 for acute asthma exacerbations. Several studies analysed the effectiveness of intravenous MgSO4 in children with acute severe asthma episodes. They showed that MgSO4 was effective for its use both in emergency departments and intensive care units and improved clinical asthma score, e.g. peak expiratory flow rate (PEFR), oxygen saturation, forced expiratory volume in 1 s, and forced vital capacity for those children as well as a decrease in hospital admissions was also found [28–30]. In addition, the metaanalysis by Alter and colleagues [31] reported that intravenous MgSO4 as an adjunct therapy improved spirometry airway function in acute bronchospasm. Other studies [32–34] showed that intravenous MgSO4 improves pulmonary function and decreases hospital admission rates in patients presenting to the emergency department (ED) with severe exacerbations of asthma. There is also a higher decrease in pulse rate and a larger increase in oxygen saturation in intravenous MgSO4 group as compared to controls. Benefits of magnesium treatment in children were also suggested by Kowal et al. [35], who showed that IV magnesium-treated children group with severe asthma have some benefits, such as lung function improvement, but it does not reduce hospital admissions rates.

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More recent study reported that magnesium is used infrequently in Canadian pediatric EDs in acute asthma requiring hospitalisation. Many of these children also do not receive frequent albuterol and ipratropium, or early corticosteroids. Significant variability in the use of these interventions was detected [36]. Bloch et al. [37] in their randomised double-blind study found that intravenous MgSO4 decreased admission rate and resulted in a significant improvement in forced expiratory volume in one second (FEV1) in the severe group of asthmatic children. Ciarallo et al. [38] reported that using a higher dose of MgSO4 resulted in a faster and longer improvement in pulmonary function, and a higher discharge rate in children who did not respond to b2-agonists. Intravenous MgSO4 showed early and significant improvement as compared to the placebo group and nebulised salbutamol. The results obtained by Rowe et al. [39] did not support the use of MgSO4 alone, but indicated that intravenous MgSO4 as adjunct to standard treatment was beneficial in severe acute asthma patients, both in terms of pulmonary functions and hospital admission rate. Other studies found that a single dose of intravenous MgSO4 is safe and effective in those patients with acute severe asthma who have had a poor response to initial therapy [37,40]. Cheuk et al. [41] reported that intravenous MgSO4 provides an additional benefit in acute, moderate and severe asthma by reducing hospitalisation in these patients with a decrease of absolute risk. A very recent study [42] confirmed this results which reported that IV infusion of MgSO4 during the first hour of the patient’s admission with acute severe asthma to the hospital was associated with a significant decrease in the number of children requiring mechanical ventilation support. In 2009, Øymar and Halvorsen [43] endorsed the use of intravenous MgSO4 for severe asthma exacerbations in children, after using inhaled b2-adrenergics and corticosteroids. This study has recommended to the use of MgSO4 in paediatric care. Intravenous MgSO4 is useful as an adjunctive treatment in severe asthma with failed response to nebulised salbutamol but, its routine use for acute asthma is not recommended [44]. Li [45] suggested that children with moderate-to-severe asthma exacerbations might be treated with high dose of intravenous MgSO4. Very recent study reported that IV infusion of MgSO4 during the first hour of hospitalisation in patients with acute severe asthma significantly reduced the percentage of children who required mechanical ventilation support [42].

Efficacy of nebulised (inhaled) MgSO4 in treatment of asthmatic children There are also some data suggesting a protective nature of MgSO4 inhalations in asthmatics. Chande and Skoner [46] studied the effect of nebulised MgSO4 in animals in reversing bronchoconstriction induced by methacholine. They found that MgSO4 has a minimal bronchodilatory effect. Nannini and colleagues [47] were also studied effect of nebulised magnesium in sodium metabisulfite (MBS) induced bronchoconstriction in subjects, and concluded that inhaled MgSO4 had protective effect. Mangat and colleagues [48] also found that

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nebulised MgSO4 (3 ml 3.2% solution) had significant bronchodilatory effect similar to nebulised salbutamol. Inhaled MgSO4 has also been investigated in asthma children between 5 and 17 years of age. Nebulised MgSO4 was found to provide short-term bronchodilation [49,50]. A recent study has been shown that inhaled MgSO4 is beneficial for the control of acute asthma in adults and children [51]. Some previous studies [52,53] used inhaled MgSO4 in the treatment of children with acute asthma. They found that the therapy with nebulised isotonic MgSO4 with or without b2-agonist can be safely administered at a variety of doses to children with acute moderate-to-severe asthma. They also reported that nebulisation by isotonic MgSO4 solution with salbutamol provide early and better response as compared to conventional approach (e.g. salbutamol plus normal saline) in acute exacerbation of asthma in children. In addition, Hughes et al. [54] found significantly greater improvement in FEV1 with nebulised salbutamol plus isotonic MgSO4 solution than salbutamol plus normal saline. But Blitz et al. [55] reported that the administration of nebulised MgSO4 in combination with b2-agonists (usually salbutamol), improved pulmonary function but did not reduce the number of hospital admissions.

Inefficient effects of either IV or inhaled MgSO4 in treatment of asthmatic children Some studies [56,57] reported that the addition of nebulised magnesium to conventional treatment had no significant effect in acute severe asthma in childhood. Other studies using meta-analysis found a trend toward less hospitalisation with nebulised MgSO4 [58,59] and other disagreed [60]. The results obtained by Mohammed and Goodacre [61] also showed that nebulised magnesium has no benefit in the treatment of children with acute asthma in the emergency department and has no significant effect on hospital admission. Green and Rothrock [62] stated that the intravenous MgSO4 is failed to decrease the emergency treatment duration or need for hospitalisation. Some investigators reported that MgSO4 do not appear to be effective in patients with chronic asthma. The study by Hill and Britton [63] and Rodrigoe and Rodrigo [64] showed that neither IV nor inhaled MgSO4 was useful in patients with chronic asthma. Bernstein and colleagues [65] also concluded that IV magnesium was not effective as a bronchodilator in chronic stable asthmatic. Other studies [66,67] found also that the routine administration of high-dose magnesium to moderate-to-severely ill children with asthma, as an adjunct to initial treatment with albuterol and corticosteroids, was not efficacious. In Asia, the study conducted by Boonyavorakul and colleagues [68] concluded that MgSO4 as an adjunctive therapy did not improve either admission rate or severity score in patients with acute severe asthma. The study of Aggarwal et al. [69] suggested that there is no therapeutic benefit of adding MgSO4 to salbutamol nebulisation in the treatment of patients with acute severe or life threatening asthma. Intravenous MgSO4 has also failed to show benefit in several large, prospective studies for patients presenting to the emergency department with acute asthma [70–72].

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Mechanism of action of MgSO4 as a drug for asthma Various mechanisms might have contributed to a larger improvement in pulmonary function in our study group using adjunct intravenous MgSO4: (i) Calcium channel block in smooth muscle: in smooth muscle, magnesium decreases intracellular calcium by blocking Ca2+ entry (regulated by Ca/Mg-dependent membrane ATPase) and modulates prostaglandin and G-protein mediated vascular smooth-muscle relaxation and by activating sodium–calcium pumps causing airway smooth muscle relaxation [73–75]. (ii) Inhibition of calcium’s interaction with myosin results in muscle cell relaxation: Magnesium deficiency in asthmatic patients, intracellular calcium flows into the airway smooth muscle cells resulting in the muscles’ contractility by enhancing myosin phosphorylation catalysed by Myosin kinase (regulated by magnesium) increase in the muscles’ contractility, activation of secretory system in the mast cells and mucus producing cells. Thus, hypomagnesaemia results, then, in an increase in bronchi smooth muscles excitability and their contraction [13,76]. (iii) Magnesium (Mg) prevents acetylcholine and histamine release from cholinergic motor nerve terminals to the axon terminal: Mg depresses muscle fibre excitability and promotes a bronchodilating effect. Some researchers found that laboratory animals severely deficient in magnesium had much higher blood levels of histamine when exposed to substances that trigger allergies than animals getting sufficient magnesium. Thus, hypomagnesaemia results, then, in an increase in bronchi smooth muscles excitability and their contraction [75,77,78]. (iv) Magnesium has an anti-inflammatory action via stabilisation of T lymphocytes, inhibition of mast cell degranulation, and decreased superoxide production in neutrophils probably leads to sustained improvement in pulmonary function leading to a reduction in inflammatory mediators [36]. Magnesium also exerts anti-inflammatory effect by decreasing the release of leukotriene and histamine from mast cells; therefore it may be useful in controlling inflammation in asthma exacerbations [75]. (v) Magnesium stimulates nitric oxide and prostacyclin synthesis, which might reduce asthma severity [75]. (vi) Magnesium inhibits the calcium release from the sarcoplasmic reticulum: magnesium’s pharmacological action is based upon its ability to inhibit the release of calcium from vesicles in the resulting sarcoplasmic reticulum [79].

Discussion This is a systematic review of the literature to date to assess the effectiveness of IV and nebulised MgSO4 upon hospital admissions and pulmonary function in children with asthma. Several reviews studied the use of intravenous MgSO4 in children with acute asthma. Most of them referred that intravenous MgSO4 can provide additional bronchodilation when given in conjunction with standard bronchodilating agents and helps in achieving earlier improvement in clinical signs and symptoms of asthma, but little of them showed small improvements in measurements of lung function of asthmatic children. IV administration of MgSO4 was also shown to be safe and highly effective in those studies where vital signs and side effects were recorded. For example,

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MgSO4 treatment improves pulmonary function and decrease in hospital admission and did not change pulse or respiratory rates but the minor change in systolic blood pressure was clinically insignificant. The findings of other studies stated that the IV administration of MgSO4 during the first hour of the patient’s admission to the hospital was associated with a significant decrease in the number of children requiring mechanical ventilation support and shorten hospital length-of-stay Other reports with MgSO4 used nebulised form of this drug in children with asthma in whom no beneficial effect was demonstrated. But, insufficient data exist to draw reliable conclusions regarding the role of nebulised MgSO4 in children [80]. Thus, the implications of this review are that intravenous MgSO4 appeared to be an effective treatment for children with acute, moderate-to-severe asthma, while the evidence for inhaled MgSO4 is less convincing. Owing to its bronchodilating and anti-inflammatory effects, magnesium is an encouraging adjuvant therapy for paediatric patients who do not respond to conventional treatment in acute severe exacerbations. Finally, intravenous MgSO4 has been recommended in pediatric care and the role of nebulised MgSO4 in children requires further investigation.

Safety and advantages of intravenous MgSO4 MgSO4 is generally a safe drug to administer [79]. There were some minor side effects reported associated with MgSO4 administration, such as epigastric or facial warmth, flushing, pain and numbness at the infusion site, dry mouth and malaise. There are other advantages of using intravenous MgSO4 as a drug for treatment of acute severe asthma, which are: (i) It is a drug approved by the National Administration of Medicines, Food and Technology of Argentina (ANMAT) for its use in children, as stated in resolution N; 0798 [43]. (ii) It is safe, effective and available for use in treatment of acute asthma. (iii) It has low cost, widespread availability and low incidence of side effects. (iv) Magnesium has a clear role in the emergency management of a number of conditions. (v) Magnesium should be available for immediate use in all emergency departments. (vi) It should be used as first-line therapy in eclampsia and torsade de pointes ventricular tachycardia. (vii) It has a clearly defined role as a second-line therapy in acute severe bronchial asthma. (viii) Hypomagnesaemia should be considered in patients with biventricular failure presenting with malignant arrhythmias. (ix) Intravenous MgSO4 has been proposed as an effective and safe adjunct in treatment of acute asthma due to its low cost, widespread availability and low incidence of side effects. (x) The delivered dose of nebulised MgSO4 would probably be lower than with the IV route. So, the patient requiring some respiratory effort to maximise its effectiveness. (xi) The IV route provides direct access to the venous system, allowing the delivery of high drug concentrations. (xii) The addition of nebulised magnesium to conventional treatment had no significant effect in acute severe asthma in childhood. (xiii) Magnesium is an encouraging adjuvant therapy for paediatric patients who do not respond to conventional treatment in acute severe because it has anti-

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inflammatory action and has the ability to counteract the effects of calcium on airways. (xiv) Intravenous MgSO4 seems to be beneficial in the treatment of moderate-to-severe asthma in children than inhaled one. (xv) Choosing the best MgSO4 nebuliser system, that would be effective over the entire age range, is difficult. (xvi) Output rate and a larger particle size distribution, which would be inappropriate for smaller children.

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Summary Magnesium deficiency is a common electrolyte disorder in patients with acute asthma. There are some data suggesting lower levels of Mg2+ and increased Ca2+/Mg2+ ratios in asthmatic patients compared with non-asthmatics. MgSO4 seems to be beneficial in the treatment of moderate-to-severe asthma in children. It has both anti-inflammatory and bronchodilator action. This is unlike most of the other drugs used in acute severe asthma which have predominantly either bronchodilator or anti-inflammatory action. It is low cost and a safe drug to administer as there were no life-threatening side effects noted in any of the trials, but there have been minor side effects reported, such as epigastric or facial warmth, flushing, pain and numbness at the infusion site, dry mouth, malaise and hypotension. Evidence suggests that intravenous MgSO4 is beneficial in acute asthma, while the evidence for inhaled MgSO4 is less convincing. For patients with the most severe airflow obstruction, intravenous MgSO4 appears to provide important clinical benefits, including a lower rate of hospital admission from the emergency department. Magnesium has been used in hospitals to help relieve the symptoms of life-threatening, drug-resistant asthma attacks and to diminish the effects of the asthma drugs used. The role of nebulised MgSO4 is less clear, with pooled analysis failing to provide clear evidence of benefit. Thus, the efficiency of inhaled MgSO4 is still being discussed.

Conclusion The author found good evidence when using the intravenous MgSO4 method in treatment of childhood asthma because: (i) it allows delivery of exact amount of MgSO4, (ii) it is safe and effective in treatment of acute severe asthma and improves respiratory function in children and a potential reduction in hospital admissions, (iii) it achieves early improvement in clinical asthma score. At the same time, the author, according to the previous studies, found that the current recommendations do not support using the inhaled MgSO4 method as a management of children with mild or moderate asthma because: (i) it can deliver a lower or high percentage of drug by delivery device which is then associated with an increased risk of death, (ii) insufficient data are available to draw reliable conclusions regarding the role of inhaled MgSO4 in children. Finally, the author recommends to use of intravenous MgSO4 as a safe and effective adjunct to conventional bronchodilator therapy in acute severe asthma in children.

Further studies are necessary to test (1) The clinical effects of higher dose of intravenous MgSO4; (2) the optimal dose and duration of either inhaling or

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intravenous MgSO4 in treatment of asthma in children; (3) the efficacy of inhaled MgSO4 in various clinical setting; (4) the long-term effect of injected or inhaled MgSO4 on clinical symptoms, bronchial reactivity, lung function and allergeninduced skin responses in children with moderate, persistent or severe asthma; (5) a good inhaler technique to maintain the appropriate amount of inhaling MgSO4; (6) the effects of MgSO4 on very young children

Declaration of interest The author reports no conflicts of interest. The author alone is responsible for the content and writing of the article.

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The use of intravenous and inhaled magnesium sulphate in management of children with bronchial asthma.

Asthma is the most common chronic disease of childhood and the leading cause of childhood morbidity. When uncontrolled, asthma can place significant l...
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