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
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5/8
|
|
|
Age, yr*
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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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