AJCN. First published ahead of print May 30, 2012 as doi: 10.3945/ajcn.112.034207.
Oral magnesium supplementation in children with cystic fibrosis
improves clinical and functional variables: a double-blind,
randomized, placebo-controlled crossover trial1–3
Cle´sio Gontijo-Amaral, Elizabet V Guimarães, and Paulo Camargos
ABSTRACT
Background: Magnesium is one of the most important minerals in
the body. Although some studies reported that patients with cystic
fibrosis (CF) lack magnesium, no international study has assessed
the importance of oral magnesium supplementation in CF patients.
Objective: We prospectively investigated the long-term effect of
oral magnesium supplementation on respiratory muscle strength
by using manuvacuometry and the Shwachman-Kulczycki (SK)
score among children and adolescents with CF.
Design: This double-blind, randomized, placebo-controlled crossover study included 44 CF patients (aged 7–19 y; 20 males) who
were randomly assigned to receive magnesium (n = 22; 300 mg/d)
or placebo (n = 22) for 8 wk with a 4-wk washout period between
trials. All patients were undergoing conventional treatment of CF.
The experimental protocol included clinical evaluation, assessment
of urinary concentration of magnesium, and manuvacuometric measurements [maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP)]. MIP was the primary outcome.
Results: Urinary magnesium increased after the administration of
magnesium (change: 36.38 mg/d after magnesium compared with
0.72 mg/d after placebo; P , 0.001). Moreover, MIP and MEP significantly improved only after magnesium administration (change
in MIP: 11% predicted after magnesium compared with 0.5%
predicted after placebo; change in MEP: 11.9% predicted after
magnesium compared with 0.8% predicted after placebo; P , 0.001
for both). Magnesium administration had a beneficial effect on clinical
variables assessed by the SK score (change: 4.48 points after magnesium compared with 21.30 points after placebo; P , 0.001).
Conclusion: Oral magnesium supplementation helped improve both
the SK score and respiratory muscle strength in pediatric patients
with CF. This trial was registered at www.ufmg.br.bioetica/coep as
CAAEO 559.0.203.000-07.
Am J Clin Nutr doi: 10.3945/ajcn.
112.034207.
INTRODUCTION
Cystic fibrosis (CF)4 is a recessively inherited condition caused
by mutation of the CF transmembrane conductance regulator
(CFTR) and results in higher mortality in the white population.
Pulmonary and gastrointestinal manifestations influence the nutritional condition of patients, with the reverse also being true.
Nutrition-based treatments can contribute to a reduction in the
mortality and morbidity of CF (1, 2).
Patients with CF may have magnesium deficiency (3, 4), even
though a previous study did not find any reduction in serum
magnesium concentrations in these patients (5). Magnesium is an
intracellular ion, and there is only a small correlation between
serum and intracellular concentrations of magnesium, probably
because only 1% of the body’s magnesium store is found in the
blood (6). Serum magnesium tests measure short-term intake
variations, but they do not reflect the body’s magnesium store.
The magnesium concentrations in erythrocytes, mononuclear
cells, and granulocytes also do not reflect the body’s magnesium
store because magnesium is primarily concentrated in muscles
and bones (6, 7).
A promising new strategy in patients with CF could be increasing the magnesium concentration in the airway surface
liquid by aerolization of magnesium solutions or by oral intake of
magnesium supplements, which may facilitate the removal of
highly viscous mucus in chronic lung disease by activating endogenous DNase activity (8, 9).
Adults who received moderate physical training supplemented
with magnesium showed improved cardiorespiratory function
during a 30-min submaximal exercise test (10). These findings
suggest a potentially beneficial effect of magnesium supplementation on muscle metabolism. Supplemental magnesium
improves strength and muscle metabolism. However, it is unclear whether these observations are related to impaired nutritional status or to a pharmacologic effect (11).
1
From the Pediatrics Department, Diagnostic Support Action and Research Center (NUPAD), Faculty of Medicine, Federal University of Minas
Gerais (UFMG), Belo Horizonte, Brazil (CG-A, EVG, and PC), and the
Health Sciences Center, Postgraduate Program in Health Sciences, Federal
University of São João del-Rei, Divinópolis, Brazil (PC).
2
CG-A is supported by the Diagnostic Support Action and Research
Center (NUPAD), Federal University of Minas Gerais (UFMG). PC is supported by the Brazilian research agencies Brazilian Council for Scientific
and Technological Development (CNPq; grant no. 303827/2009-2) and
Minas Gerais State Foundation for Research Support (FAPEMIG; grant
no. PPM-00230-10).
3
Address correspondence to C Gontijo do Amaral, Rua Pouso Alegre,
224/703, Floresta, CEP 31110-010, Belo Horizonte, Brazil. E-mail: [email protected].
4
Abbreviations used: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; MEP, maximal expiratory pressure; MIP, maximal inspiratory pressure; RDA, Recommended Dietary Allowance; SK,
Shwachman-Kulczycki.
Received January 5, 2012. Accepted for publication May 1, 2012.
doi: 10.3945/ajcn.112.034207.
Am J Clin Nutr doi: 10.3945/ajcn.112.034207. Printed in USA. Ó 2012 American Society for Nutrition
Copyright (C) 2012 by the American Society for Nutrition
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GONTIJO-AMARAL ET AL
Although the mechanism of action of magnesium in pulmonology is not fully understood, inhaled, intravenous, and oral
administration of magnesium has proven efficient in the treatment
of pulmonary pathology in both children and adults (12–15).
Over the past decade, interest in magnesium has increased with
biochemical studies on magnesium, its nutritional relevance, its
potential roles in human diseases, and particularly its association
with the pathogenesis of pulmonary disorders (16, 17).
Moreover, magnesium is a low-cost mineral, and no serious
side effects have been found after magnesium supplementation in
several studies.
We hypothesized that CF patients have low body magnesium
storage and that magnesium supplementation could improve
respiratory muscle strength. This study aimed to evaluate the
effects of oral magnesium supplementation on the respiratory
musculature.
SUBJECTS AND METHODS
Enrollment and follow-up for this crossover study were performed between January 2007 and December 2010. Forty-four
children and adolescents from a single center were included.
The patients were recruited and followed up at the university
hospital’s CF clinic (Federal University of Minas Gerais, Brazil).
Inclusion criteria were as follows: age of 7–19 y, 2 positive sweat
tests (60 mmol/L) according to the Gibson and Cook method
(18), and stable clinical condition (ie, no need for oral or IV
antibiotic treatment in the 4 wk before testing).
Smokers and patients receiving any treatment likely to affect
magnesium absorption or excretion, such as diuretics, digoxin, or
calcium-containing medications, were excluded from the study.
All children were undergoing conventional treatment of CF,
including respiratory medications, pancreatic enzyme, and supplementation of water-soluble and fat-soluble vitamins at Recommended Dietary Allowance (RDA) doses (2, 19).
After an initial screening and run-in period of 4 wk, the 44
patients were randomly assigned to the study treatments. Each
participant received 300 mg oral magnesium-glycine (n = 22) or
a placebo control (n = 22) once daily for 8 wk, with a washout
period of 4 wk between trials (Figure 1). Magnesium amino
acid chelate (taste free; lot number 251755) from Albion Laboratory was used. The magnesium dose used for each participant
ranged from 5 to 12 mg kg21 d21 according to the RDA. In
the initial phase of the study we evaluated the average weight of
the group to perform a stratified randomization. Thus, we arbitrarily chose the dose of 300 mg/d on the basis of the median
weight of the children and adolescents included in the study (40
kg · 7.5 mg/kg = 300 mg/d). Patient compliance with the prescribed magnesium therapeutic regimen was assessed in
a monthly follow-up by questionnaire.
Investigators and patients were blinded to randomization, drug
manipulation, and dispensing, which were performed independently from the recruitment and assessment of participants.
The magnesium and placebo powders were similar in appearance
and were prepackaged by a pharmacist in identical containers that
were coded according to a randomized sequence. Stratified
randomization was performed by using a computer-generated
table of random numbers, and participants were randomly
assigned to the intervention or placebo group. The randomization
code was revealed at the end of the study (20). The magnesium
powder was provided in a single-dose packet. The same researcher provided the packages containing either magnesium or
placebo at each appointment to ensure accuracy. Glycine was
used as a placebo, so the difference between the 2 groups was
only the presence or absence of magnesium. The magnesium and
placebo had a similar taste and appearance. Participant adherence
was evaluated at each appointment by checking the empty used
packages brought in by the parents or legally responsible member
of the family. If the patients used <80% of the monthly doses of
magnesium or placebo, they were excluded.
FIGURE 1. Flowchart of study enrollment and design.
ORAL MAGNESIUM IN CHILDREN WITH CYSTIC FIBROSIS
The experimental protocol included clinical evaluation and
assessment of urinary magnesium and strength of respiratory
musculature. All of these assessments were performed at the
beginning of the trial as well as after 60 d of magnesium or
placebo administration during both trial periods. Maximal
inspiratory and expiratory pressures (MIPs and MEPs, respectively) were measured as indexes of respiratory muscle
strength. The primary outcome was MIP, and secondary outcomes were MEP and respiratory disease severity assessed by the
Shwachman-Kulczycki (SK) score.
Written informed consent was obtained from each participant
and/or his or her parents before the study. The research committee
approved both the informed consent and the experimental
protocol in accordance with the Brazilian Ministry of Health/
Brazilian National Committee on Ethics in Research, resolution
no. 196/1996. All procedures were conducted in accordance with
the Helsinki Declaration of 1975 as revised in 1983.
Maximal respiratory pressures
The measurement of maximal respiratory pressures generated
at the mouth is an accepted noninvasive clinical method for
evaluating the strength of respiratory muscles (21, 22). The MIP
reflects the strength of the diaphragm and other inspiratory
muscles, whereas the MEP reflects the strength of the abdominal
muscles and other expiratory muscles. The detection of a change
in respiratory muscle strength can be useful in identifying improvement or progression of the disease (23). MIP and MEP were
measured by using an analogic manuvacuometer (Imebrás), with
operating intervals of 0–300 cm H2O. All of the tests were
performed according to American Thoracic Society/European
Respiratory Society statements (23) by the same member of the
research team. Inspiratory and expiratory muscle strength was
measured before and immediately after each treatment period by
using maximal static pressures produced at the mouth. MIP was
measured at residual volume, and MEP was measured at total
lung capacity with the subject seated in a hard-backed chair
while wearing a nose clip and keeping a mouthpiece held firmly
between the lips. Because of the volitional character of the test,
the researcher carefully instructed and encouraged motivation of
children and adolescents during the test, eliciting maximal effort
for each maneuver (24). Each pressure attempted was measured
at 1-min intervals at least 3 times until there was <10% difference between the 2 highest values. The maximal MIP and MEP
values were described and analyzed as percent-predicted values
for the study subjects. The predicted values were based on those
reported by Wilson et al (25).
Clinical assessment
The SK score was calculated by 2 pediatric pulmonologists
with expertise in CF. The pediatric pulmonologists were blinded
to each other and to subject treatment and order of treatment. The
SK score is divided into 4 domains: general activity, physical
examination, nutrition, and radiologic findings. Each of these
domains has 5 possible subscores based on the degree of impairment. The scores of the 4 domains are summed to obtain the
final score, from which the condition of the patient is categorized
as excellent (86–100 points), good (71–85 points), average
(56–70 points), poor (41–55 points), or severe (40 points) (26).
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Anthropometric measurements
Anthropometric measurements included weight, height, and
BMI. They were performed according to the WHO recommendations (27) by the same member of the research team. Weight
(in kg) was measured by using an anthropometric platform scale
(Filizola SA), and height (in cm) was measured by using a stadiometer attached to the same scale. BMI was calculated as
weight divided by height squared. Values of weight, height, and
BMI were standardized by age and sex according to the WHO
growth curve (28) and expressed as z scores.
Urinary concentration of magnesium
The urinary concentration of magnesium was assessed in all
patients before and after each study period. Concentrations were
determined by using the VITROS magnesium slide method with
the Mg Slides and Chemistry Products Calibrator Kit 1 in
VITROS 250/350/950/5, the 1 FS (shading coefficient) and 4600
Chemistry Systems, and the 5600 Integrated System (Johnson &
Johnson).
Statistical analyses
On the basis of our previous pilot study (data not published),
a sample size of 19 patients was determined for each group, with
consideration of appropriate calculations for randomized clinical
trials and the possibility of a type II error. With an SD of 6.46 base
units of MIP (percent predicted) used as the primary outcome, we
calculated that 19 subjects in each group would be required for
85% power at the 5% level of significance. Descriptive statistics
were assessed accordingly.
Student’s t test was used to compare age, weight, and BMI in
both groups. The Mann-Whitney U test was used to compare
height. Chi-square and Fisher’s exact tests were used to analyze
sex and race, respectively. Because the urinary concentrations of
magnesium were normally distributed, a single paired Student’s
t test was used.
Normality was tested for all outcomes. Because a crossover
design was used and the results were not normally distributed, the
Wilcoxon signed-rank test was used. All data were entered before
the treatment codes were revealed and were analyzed by using the
Statistical Package for Social Sciences (version 17 for Windows;
SPSS); P values ,0.05 were considered significant. Data are
presented as means 6 SDs (29).
RESULTS
Forty-four patients screened for participation in this study met
the study criteria. There were no dropouts. No carryover effect
was seen in the groups that started with either magnesium or
placebo. Although it is impossible to accurately test for the
presence of a carryover effect (ie, whether the effect of treatment
“carries over” and affects results while the patient is receiving
placebo) in a traditional 2 · 2 crossover design (2 groups, 2
periods) such as this one, we have tested the effects of sequence
and period-by-treatment interaction, which are possible indicators of a carryover effect. The effects of sequence and period-by-treatment interaction were not significant for any
outcomes (P . 0.05 for all outcomes, ANOVA). No adverse
effects of magnesium toxicity such as vomiting, double vision,
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GONTIJO-AMARAL ET AL
TABLE 1
Characteristics of the patients with cystic fibrosis1
Characteristics
Age (y)
Sex (M:F)
Race (white:black)
Weight (kg)
z Score
Height (m)
z Score
BMI (kg/m2)
z Score
FEV1 (% predicted)
PI [n (%)]
1
2
3
4
5
6
All (n = 44)
Magnesium group
(n = 22)
Placebo control group
(n = 22)
P
value
12.86 6 3.722
20:24
39:5
39.63 6 12.81
21.13 6 1.37
1.46 6 0.17
21.10 6 1.34
17.95 6 2.52
21.15 6 1.37
75 6 23
7/44 (15.9)
12.68 6 3.73
10:12
19:3
39.22 6 12.86
21.08 6 1.3
1.46 6 0.18
21.0 6 1.25
17.68 6 2.24
21.09 6 1.31
69 6 25
3/22 (13.6)
13.05 6 3.79
10:12
20:2
40.04 6 13.04
21.18 6 1.47
1.47 6 0.18
21.20 6 1.44
18.21 6 2.69
21.20 6 1.46
80 6 18
4/22 (18.2)
0.753
1.004
1.005
0.833
0.606
0.946
0.296
0.493
0.436
0.266
1.005
FEV1, forced expiratory volume in 1 s; PI, children and adolescents with pancreatic insufficiency.
Mean 6 SD (all such values).
Student’s t test.
Chi-square test.
Fisher’s exact test.
Mann-Whitney U test.
feeling of warmth, flushing, or hypotension were reported from
patients in either group.
Random assignment resulted in a well-balanced equivalent
distribution of patients with respect to age, sex, race (selfreported), weight, height, BMI, forced expiratory volume in 1 s,
and pancreatic insufficiency at baseline. These results are shown
in Table 1. Both groups showed appropriate compliance.
Urinary concentrations of magnesium and SK score data at
baseline and at the end of follow-up for both groups are shown in
Table 2.
As shown in Figure 2, after the intervention period MIP
showed an 11 6 7.8% predicted increase (from 98.3 6 29.7% to
109.3 6 31.8% predicted) in the magnesium group, with a slight
0.5 6 6.3% predicted increase (from 99.2 6 28.6 to 99.7 6
29.3% predicted) in the placebo group. MEP also showed an
11.9 6 7.7% predicted increase (from 97.5 6 27.8 to 109.4 6
27.3% predicted) after magnesium administration and a slight
0.8 6 6.5% predicted increase (from 97.4 6 26.6% to 98.2 6
27.3% predicted) after placebo administration. The differences
between the intervention and placebo periods were significant
(P , 0.001 for both MIP and MEP).
DISCUSSION
Our results showed that after 2 mo, children and adolescents
with CF who were receiving conventional therapy for CF and oral
magnesium supplementation achieved a significant improvement
in the functional status of the respiratory musculature, as assessed
by manuvacuometry. Significant clinical improvements, shown
by means of the SK score, were also observed.
To the best of our knowledge, the current study is the first
performed in pediatric CF subjects to investigate the effects of
oral magnesium administered on a regular basis. Up to the time
of the study outline, there was a lack of data that could be used
as parameters for improved planning in CF pediatric subjects
in terms of effective doses of magnesium, length of treatment
period, and possible side effects. Some of the available data
were based on studies performed in adult patients and in those
with other respiratory diseases (10, 14). Other data were
obtained from updated reviews of the physiologic, clinical, and
analytic aspects of the use of magnesium in different diseases
(6).
Assessment of age, weight, height, race, and sex indicated that
our population was homogeneous. Moreover, the characteristics
of our population were similar to those of CF children in other
studies. Even after random assignment, the 2 groups retained
similar demographic characteristics without any statistically
significant differences.
The assessment of serum magnesium concentrations is not an
accurate reflection of the magnesium status of muscle, bone, and
other tissues. There is a poor correlation between serum and
intracellular magnesium concentrations, most probably because
only 1% of total body magnesium reserves can be found in whole
blood (6). We therefore decided to analyze the urinary
TABLE 2
Urinary concentration of magnesium and SK score data at baseline and at the end of follow-up for both groups1
Magnesium group (n = 44)
Urinary magnesium (mg/d)
SK score
Placebo control group (n = 44)
Baseline
After follow-up
Change
Baseline
After follow-up
Change
39.69 6 9.46
80.05 6 10.65
76.08 6 16.09
84.52 6 9.62
36.38 6 11.29
4.48 6 5.28
39.94 6 9.89
80.55 6 10.82
40.66 6 9.92
79.25 6 10.68
0.72 6 3.21
21.30 6 3.63
1
All values are means 6 SDs. Student’s t test for urinary magnesium and Wilcoxon signed-rank test for SK score were used (comparison of the 2 change
values): P , 0.001 for both tests. SK, Shwachman-Kulczycki.
ORAL MAGNESIUM IN CHILDREN WITH CYSTIC FIBROSIS
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FIGURE 2. Functional assessment of respiratory musculature: baseline, posttreatment, and change comparison in maximal respiratory pressure values (MIP
and MEP) assessed by manuvacuometry in both groups (n = 44). P values for change comparison in MIP and MEP between magnesium and placebo
treatments were calculated by using Wilcoxon’s signed-rank test (P , 0.001 for both). Shaded bars, magnesium group; open bars, placebo control group;
*95% CIs. MEP, maximal expiratory pressure; MIP, maximal inspiratory pressure; Post, after treatment.
concentration of magnesium before and after each period of
magnesium or placebo administration (30).
Many factors may be responsible for magnesium deficiency in
CF patients. First, current dietary surveys show that the average
magnesium intake in Western countries is often below the RDA
(280 and 350 mg/d for women and men, respectively) (31).
Second, gastrointestinal malabsorption, a common symptom of
CF, may cause hypomagnesemia (32). Third, certain antibiotics
and chemotherapeutic agents such as amphotericin B, cyclosporine, aminoglycosides, and tobramycin used by CF patients
also induce hypomagnesemia (33). Magnesium supplementation
is therefore a promising strategy for improving clinical symptoms
and respiratory musculature strength in CF patients, as was
shown by this trial.
Interestingly, only those patients who received oral magnesium
in the study period presented with better clinical symptoms as
assessed by the SK score. In a study by Stollar et al (34), the SK
score was reported to be a useful and simple tool for monitoring
the severity of CF.
The proposed action of magnesium in CF patients is not
completely understood. ATP regulates the opening and closing of
the CFTR Cl channel, and magnesium plays a role in many crucial
enzyme systems, especially those involving ATP metabolism (35).
Moreover, magnesium acts as a cofactor in the enzymatic
degradation of DNA by rhDNase I, so a minimum concentration
of magnesium is required to obtain optimal rhDNase I activity
(36). The addition of magnesium to sputum samples that cannot
be degraded by rhDNase I enables these samples to be degraded
by that enzyme (36). Sanders et al (8) showed that the effect of
magnesium on rhDNase I is mediated through actin and that
oral intake of magnesium enhances its concentration in the
sputum of CF patients. The failure of rhDNase I may therefore
be overcome by combining rhDNase with oral magnesium
supplements.
In the analyses of the functional status of the respiratory
musculature, our findings were similar to those reported that used
the SK score because, at the end of the follow-up period, we
observed significant improvement in MIP and MEP values. MIP
reflects the strength of the diaphragm and other inspiratory
muscles, whereas MEP reflects the strength of the abdominal
muscles and other expiratory muscles (23). Magnesium plays an
important role in muscle tissue (6). The skeletal muscle cells
contain long complex fibers made up of the proteins actin and
myosin. These proteins work together to promote contraction and
relaxation of muscle fibers. Magnesium helps to provide these
contractile fibers the energy they require to function (6).
In addition, maximal voluntary ventilation is a test of the
overall function of the respiratory system (24). The respiratory
system exists in an oxygenated milieu and is continuously exposed to both endogenous and exogenous oxidants and irritants
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GONTIJO-AMARAL ET AL
(16). A variety of diet-dependent defenses have evolved to protect
the lungs. These comprise vitamins, proteins, polyphenols, fatty
acids, and cofactors (16, 37). Magnesium has a variety of functions,
including acting as a cofactor for sodium and potassium ATPase,
which is responsible for maintaining muscle membrane potential
and action potential propagation. Magnesium deficiencies can
result in muscle weakness and cramping (6).
Inflammation is a major pathophysiologic feature of the lung
disease in CF, and the abnormal CFTR function is probably also
involved in this inflammatory process (38). Recently, oxidative
stress has been increasingly recognized as one of the major factors
contributing to the chronic inflammatory process in CF (39).
Magnesium is closely related to the immune system in both
nonspecific and specific immune responses (ie, innate and acquired immune responses) (40). Furthermore, magnesium is also
a cofactor in .300 enzymatic reactions, and its deficiency is
linked to inflammation and oxidative stress (41). For example,
it is a cofactor for glucose-6-phosphate dehydrogenase and
6-phosphogluconate dehydrogenase, 2 pentose-cycle enzymes
that catalyze the production of NADPH from NADP+. Thus,
a deficiency of dietary magnesium reduces glutathione reductase
activity and results in radical-induced protein oxidation and
marked lesions in tissues such as the skeletal muscles, brain,
kidneys, and lungs (42).
In conclusion, our double-blind, randomized, crossover study
showed that children and adolescents with CF who receive
conventional treatment in combination with oral magnesium
supplementation achieve significant improvement in functional
status of the respiratory musculature and better clinical results.
Further large-scale studies should include other well-established
pulmonary function tests to further assess the potential role of
magnesium supplementation in the management of CF in children and adolescents.
We thank Fernando Henrique Pereira for statistical advice; Ricardo A
Corrêa, Luciano A Péret Filho, Danielle SR Vieira, Antônio F Ribeiro,
and Mônica LC Wayhs for reviewing the previous version of the manuscript;
Albion Laboratory for providing magnesium; and Amphora for drug manipulation. We also thank the 44 study participants and their families for their
dedication and contribution to the research.
The authors’ responsibilities were as follows—CG-A, PC, and EVG:
designed the research (ie, project conception, development of overall research
plan, and study oversight); CG-A: undertook data collection, wrote the manuscript, and has primary responsibility for the final content of the manuscript;
and EVG: supervised the research. All authors assisted in the interpretation of
analyses and revision of the manuscript and read and approved the final manuscript. The supporting research agencies had no influence in study design; in
the collection, analysis, and interpretation of data; in the writing of the report;
or in the decision to submit the manuscript for publication. The authors had
no personal or financial conflicts of interest.
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