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Texte intégral de l'article
 
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Effect of MgSO 4 on FEV 1 in stable severe asthma patients with chronic airflow limitation


Magnesium Research. Volume 22, Numéro 4, 256-61, December 2009, Original article

DOI : 10.1684/mrh.2009.0184

Summary  

Auteur(s) : Alinda MG Zandsteeg, Petra Hirmann, Henk R Pasma, Jan-Peter Yska, Anneke ten Brinke , Department of Pulmonary Diseases, Department of Hospital Pharmacy, Medical Centre Leeuwarden, Henri Dunantweg 2, Leeuwarden, The Netherlands.

Illustrations

ARTICLE

Auteur(s) : Alinda MG Zandsteeg1, Petra Hirmann1, Henk R Pasma1, Jan-Peter Yska2, Anneke ten Brinke1

1Department of Pulmonary Diseases
2Department of Hospital Pharmacy, Medical Centre Leeuwarden, Henri Dunantweg 2, Leeuwarden, The Netherlands

Most patients with asthma have mild to moderate disease that can be easily controlled with standard treatment and preservation of lung function. However a subset of patients develops irreversible airway obstruction [1], with prevalences varying from 16% in mild to 49% in severe asthma [2, 3]. Persistent airflow limitation seems important, since the level of FEV1 has been shown to predict both asthma-related [4] and overall [5] mortality.

The mechanism underlying persistent airflow limitation in asthma is still unknown, but is supposed to be related to structural adaptations in the airways [6]. In addition to other inflammatory and structural changes, airway smooth muscle (ASM) mass seems to be highly important in airway remodeling and subsequent airflow limitation [7], and the benefit of current asthma treatments may (in part) be due to their actions on ASM.

Already in 1912 magnesium has been recognized as a powerful smooth muscle relaxant [8], probably acting by opposing the contractile effect of calcium [9, 10]. For this reason magnesium is used as the drug of choice in eclampsia [11] and has been investigated in a variety of diseases such as acute myocardial infarction and stroke.

In acute exacerbations of asthma, the therapeutic effect of magnesium has been well established [12]. Studies in acute asthma attacks have shown that intravenous (iv) and inhaled magnesium sulphate (MgSO4) improve lung function and reduce the number of hospitalizations, particularly in patients with the lowest levels of FEV1 [13, 14].

Whether the bronchodilating features of magnesium are also beneficial in patients with severe asthma and chronic airflow limitation has not been investigated yet, but this hypothesis is supported by the following observation in a 54 yr woman with oral corticosteroid dependent asthma and persistent airflow limitation. In summer 2007 her symptoms and lung function gradually deteriorated until very low levels of exercise tolerance and a FEV1 of 0.69 L (25% predicted) (figure 1). Despite extensive anti-asthma treatment, including high doses of iv corticosteroids and bronchodilators, clinical improvement was not achieved. Ultimately, we decided to try MgSO4 therapy, aiming at ASM relaxation, and started with an iv loading dose of 4 g MgSO4 and continued 1 g/h iv therapy for 24 hours with serum magnesium level control, according to a protocol used for treatment of eclampsia in our hospital, followed by nebulisations (2.5 mL isotonic MgSO4 6.4%) 3 times/day for 3 weeks. A remarkable increase in FEV1 was demonstrated up to 1.66 L (60% predicted) on just the second day of treatment, accompanied by a decrease in symptoms. This effect lasted for about 2 months until FEV1 gradually declined to the baseline value.

This observation suggested that ASM relaxation by magnesium might also occur in asthma patients with chronic airway obstruction. Therefore, the aim of the present study was to investigate whether inhaled MgSO4, administered according to a dosing scheme shown to be effective in acute asthma, induces bronchodilation in stable, severe asthma patients with persistent airflow limitation.

Materials and methods

Patients

We recruited non-smoking (< 10 packyears) patients with stable severe asthma [15] and a postbronchodilator FEV1 < 75% predicted. Patients with an exacerbation < 4 weeks prior to study were excluded. The protocol was approved by the Hospital Ethics Committee of Medical Centre Leeuwarden and all participants gave informed consent.

Study design

In this randomized, double-blind, placebo-controlled, cross-over trial, baseline FEV1 was measured before and 30 min after inhalation of 400 mcg salbutamol and 80 mcg ipratropiumbromide. If postbronchodilator FEV1 was ≤ 75% predicted, patients were randomly allocated into 2 groups and received either 2.5 mL MgSO4 6.4% solution (160 mg per dose) or 2.5 mL placebo solution (NaCl 0.9%) by jet nebulisation (Micro Mist Small Volume Nebulizer; Hudson Respiratory Care Inc., Salt Lake City, USA) 3 times at 30 minute intervals [16] (figure 2). The osmolarity of the solution was calculated to be 260 mOsm/L. The change in FEV1 from postbronchodilator baseline value to 30 min after the last nebulisation was chosen as primary outcome. For safety reasons, FEV1 was recorded before each nebulisation and before departure. The procedure was repeated after 1-3 weeks with the alternative inhalation solution.

Methods

Lung function was measured by a handheld spirometer (Microlab 3300) [17]. Nitric oxide (NO) in exhaled air was measured by a handheld NO-analyser (Niox Mino, Accuramed, Nossegem, The Netherlands) [18].

Analysis

On the basis of an SD of 0.4 L for FEV1, we calculated that 12 patients would be needed to detect an effect size of 0.3 L, with 80% power at a two-sided α of 0.05. The within-group differences between the 2 time points were explored using two-tailed paired t-tests or Wilcoxon rank tests. The between-group changes were explored using ANOVA with treatment (magnesium or placebo) as between-patient factor and baseline value of the measurement as covariate. All analyses were performed using the Statistical Package of the Social Sciences (SPSS-12.0).

Results

All 13 included patients (table 1) used high doses of ICS (1,600-7,200 mcg/day beclomethason) and 31% used daily oral steroids. Serum magnesium concentrations at baseline were all in the normal range. No significant differences in baseline values were seen between the 2 visits.

The inhalations were well tolerated in all patients. After magnesium nebulisations no change was observed in FEV1 (56.2 ± 16.8 to 55.4 ± 17.4% predicted [p = 0.5]) (figure 3). In addition, no effect on the Borg score (0.5 (0-6) to 0.5 (0-5) [p = 0.1]) was found. The changes in FEV1, and Borg score were not significant between the treatment arms (p ≥ 0.09).
Table 1 Baseline characteristics of patients with severe asthma and persistent airflow limitation.

n = 13

Female/male gender, n

5/8

Age, yr*

56.6 ± 14.9

Age (mean) at asthma onset, yr

33

(0-65)

Positive atopic status, %

46

Smoking, packyears

0

(0-9)

Postbronchodilator FEV1, % predicted*

58.2 ± 15.4

Reversibility FEV1, % change

6.5

(- 3 to 16)

Exhaled NO, parts per billion

22.5

(8-166)

Serum Mg level, mmol/L

0.84

(0.63-0.98)

Discussion

In the present study, short-term treatment with nebulised MgSO4, administered according to a dosing scheme shown to be effective in acute severe asthma, did not improve FEV1 in patients with stable severe asthma and persistent airflow limitation. This might imply that mechanisms independent of ASM relaxation contribute to the process of irreversible airway obstruction. However, the remarkable improvement in FEV1 observed after magnesium administration in the reported case suggests that, in some patients with severe asthma, part of the so-called fixed airway obstruction might be responsive to the ASM relaxing effect of magnesium, and supports further exploration of the use of magnesium in these patients.

This study is the first to investigate the effect of inhaled MgSO4 on FEV1 in stable asthma patients with persistent airflow limitation. The importance of magnesium in severe asthma has been demonstrated in studies in acute exacerbations, showing that additional treatment with intravenous [14, 19, 20] or inhaled MgSO4 [13, 16] improved lung function, particularly in patients with the lowest levels of FEV1. Data on the effects of magnesium in stable asthma are limited. In mild asthma, iv magnesium appeared to be a weak bronchodilator [21, 22], whereas inhaled magnesium showed no bronchodilating effect [23]. In the present study the first step have been taken to address the potentially beneficial effect of magnesium on lung function in chronic severe asthma.

It might be doubted whether inhaled magnesium reaches the airways of patients with severe obstruction, however, the finding that magnesium inhalation was beneficial in patients with acute severe bronchoconstriction [16], suggests an adequate airway deposition. In the present study, we aimed to assess the additional bronchodilating potency of nebulised magnesium after salbutamol and ipratropium inhalation. However, it might be interesting to extend our findings and investigate whether administration of magnesium and salbutamol in the same nebuliser solution leads to better results, possibly by magnesium potentiating the effects of β2-agonists on adenyl-cyclase [24].

The mechanism whereby magnesium may carry out its favourable effect on lung function is supposed to be mainly related to inhibition of calcium-induced ASM contraction by the blocking of calcium ion flux [9, 10, 25]. Persistent airflow limitation in stable asthma is presumed to be due to structural changes in the airways [6, 26], with ASM as an important component [27]. Although this so-called airway remodelling has been regarded as an irreversible process, this might account for the difference in response to magnesium in patients with stable versus acute bronchoconstriction. Yet, interesting questions are raised as to whether and how distinct components of remodelling can be reversed [28], probably related to dose or duration of treatment [6]. Indeed, the remarkable improvement in FEV1 observed after high dose magnesium in the reported case might be due to restoration of depleted intracellular magnesium levels. This case suggests that more intensive treatment might be needed and supports the hypothesis that (components of) airway remodeling in asthma may still respond to specific therapies.

The search for the bronchodilating potency of magnesium in patients with asthma and persistent airflow limitation is of clinical importance. Patients with severe asthma experience considerable morbidity and consume a large amount of health care resources. They are seriously in need of new therapies with good risk-benefit ratios. In line with previous studies highlighting the potential usefulness of targeting ASM in asthma treatment [29, 30], additional magnesium treatment might be an attractive candidate.

In the present study we investigated the ASM relaxing and bronchodilating potency of inhaled magnesium in chronic severe asthma patients with persistent airflow limitation. Although the investigated magnesium dose and formulation did not improve lung function in our study, the reported case suggests a possible heterogeneity in response, probably related to the intensity and duration of treatment. Therefore, the bronchodilating features of magnesium in patients with chronic severe asthma deserve further exploration with respect to optimal administration routes and dose schemes.

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