SERUM MAGNESIUM LEVEL IN ACUTE EXACERBATION OF
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Dr. Ketan R. Kshirsagar1, Dr. S.A. Lomate2, Dr. S.C. Aundhakar3,Dr. Rahul Patil4,Dr. Varun
Jain1,Dr. Sumit Agarwal1,Dr.Nitin Patil1
1 Resident Doctor,2Professor, 3 Professor and Head of Department, 4Assistant Professor,
Department of Medicine , Krishna Institute of Medical Sciences , Karad, Maharashtra, India,
415110.Email – ketankshirsagar_kims@yahoo.com
Corresponding author: Dr. Ketan R. Kshirsagar
Abstract: To study, weather acute exacerbation of COPD is associated with changes in
serum magnesium levels.
Materials and Methods: The study includes 100 patients of COPD admitted as acute
exacerbations as defined by Anthonisen’s criteria, from Jan 2013 to Jun 2014. The same
cases served as controls when they attended outpatient department with stable COPD for
routine check-up one month after hospital discharge.
Results: A total number of 100 patients with COPD present as acute exacerbation were
included in this study. The incidence of hypomagnesaemia was present in 78% of patients
with acute exacerbation of COPD (cases) as compared to 1% patients with stable COPD
(control) with mean magnesium of 1.58±0.3 mg/dl in acute exacerbation of COPD(cases)as
compared to mean serum magnesium of 2.15±0.29 mg/dl in stable COPD(control). This
difference of mean values of serum magnesium in COPD exacerbation and stable COPD
patients was significant with p value < 0.001. In this study, there was significant correlation
present between hypomagnesaemia and GOLD staging in Stage II and stage III (p=0.001 and
p=0.006 respectively) with non-significant correlation between hypo-magnesium and stage I
and stage IV.
Conclusion: We conclude that, COPD exacerbation is associated with hypomagnesaemia.
We recommend monitoring of serum magnesium levels in COPD patients with acute
exacerbation.
Key words: COPD, Acute Exacerbation, Hypomagnesemia
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by
chronic obstruction of lung airflow that interferes with normal breathing and is not fully
reversible. COPD is not simply a “smoker's cough” but an under-diagnosed, life-threatening
lung disease1.Chronic obstructive pulmonary disease (COPD) is leading cause of morbidity
and mortality worldwide. Currently ranked as 5th leading cause of death worldwide and
predicted 3rd upto 2020, it represents an important public health challenge that is both
preventable and treatable. The burden of COPD is projected to increase in coming decades
due to continued exposure to COPD risk factors and the aging of the world’s population2.
According to WHO estimates, 65 million people have moderate to severe (COPD).
More than 3 million people died of COPD in 2005, which corresponds to 5% of all deaths
globally3.The worldwide increase in COPD prevalence renders disease exacerbation an
increasingly worrying phenomenon for clinicians, patients, healthcare organizations, and
society in general. As a result, there is a mounting interest not only in designing optimal
COPD treatment approaches but also in preventing its exacerbations.4-8Magnesium (Mg+2) is
an intracellular cation which is involved in the regulation of bronchial tone, mast cell
secretion, neuromuscular activity and respiratory muscle function9-10.
Hypomagnesaemia has been implicated in chronic asthma and it has been speculated
that allow intracellular magnesium concentration may promote airway hyper-responsiveness
in asthmatic patients11,12. Chronic obstructive pulmonary disease represents an overlap of
chronic bronchitis and emphysema.
Since magnesium is involved in muscle tone, therefore a decrease in magnesium in level in
COPD patients represents a factor which is detrimental to respiratory function as low
magnesium level induces muscle fatigue. A growing body of evidence suggests that Mg+2
deficiency contributes to exacerbations of asthma and, as a corollary, that Mg+2 is useful in
alleviating bronchospasm in these patients13-15. Although the precise mechanism of this action
is unknown, it has been suggested that Mg+2 plays a role in the maintenance of airway
patency via relaxation of bronchial smooth muscle16.COPD represents an overlap of chronic
bronchitis and emphysema, and patients with COPD have an element of asthmatic
bronchitis17.Bronchospasm is a contributing factor in their inability to clear secretions. This
may result in reduced pulmonary gas exchange with consequences such as decreased quality
of life and repeated hospitalization.18 Thus, Mg+2 may have a role in maintaining disease
stability in COPD patients. That notwithstanding, the relationship between serum Mg+2 levels
and outcome with regard to disease flares in COPD patients has not been, hitherto,
thoroughly explored. Low plasma magnesium concentration is a specific indicator of poor
magnesium status. So the aim of this study is to explore possible associations between COPD
exacerbation and serum magnesium levels.
MATERIALS AND METHODS
:
Study Design:
This is hospital based CASE- CONTROL Study.A total 100 cases and 100 controls
were enrolled in the study from Tertiary Care Centre, after meeting inclusion and exclusion
criteria.
Source of data:
Study was conducted in the department of Internal Medicine, at Tertiary care centre,
Karad, prospectively over a period of one and half years from Jan 2013 to Jun 2014.
Inclusion Criteria:
Case group
The case group included subjects who presented with an exacerbation of COPD
requiring hospitalization in the department of internal medicine.
Control group
The same cases served as controls when they attended outpatient department with
stable COPD for routine check-up one month after hospital discharge.
Patient’s characteristics
The patients in case and control groups were diagnosed as having COPD based on
dynamic pulmonary function test results (ratio of 1-sec forced expiratory volume, FEV1/
forced vital capacity, FVC<70), according to the European Respiratory Society Task Force
recommendations. The patients in case group were diagnosed as having acute exacerbation
based on the criteria of Anthonisen et al, i.e. either presence of shortness of breath, or severe
cough with or without increased sputum volume. After obtaining detailed history, meticulous
examination, baseline investigations and staging of COPD the cases and controls were
subjected to blood tests to determine serum levels of Magnesium.
Exclusion criteria
A.Patients with following associated conditions which can be a separate risk factor for
electrolyte imbalance were excluded.
1. Gastrointestinal disease: Malabsorption syndrome, ulcer disease, pancreatitis and
severe diarrhoea.
2. Pregnancy and lactation.
3. Hormonal disease :diabetes mellitus , hypothyroidism, hyperthyroidism
4. Renal failure.
5. Drugs: thiazide diuretics, loop diuretics.
6. Malignancy
7. Alcoholism.
B. Patients with pulmonary embolism and pneumothorax
C. Patients with acute exacerbation of bronchiectasis.
1. Method of determination of serum magnesium level.
SPECTROPHOTOMETRY
The calmagite reacts with the magnesium present in the sample, in an alkaline
medium. The reaction results in the formation of a colored complex that can be measured by
spectrometry. The concentration of magnesium in the sample is directly proportional to the
color of the complex. EGTA-I included in reagent to remove calcium interference.
2. Pulmonary Function Test
Recorder and Medicare system Chandigarh computerised Spirometry.
Statistical Analysis:
Descriptive statistics such as mean, SD and percentage were used. Comparison between
groups was done by unpaired t test for continuous variable and chi-square test for categorical
variable. Correlation between variables was done by Pearson’s correlation coefficient (r). For
association between variables was done by chi-square test or Fisher’s exact test for small
sample was used. A p-value less than 0.05 were considered for significant.
RESULTS:
In this study group of 100 patients, maximum number of patients of acute
exacerbation were seen in age group of 61-70 years i.e. (45 patients) 45%, followed by age
group of 71-80 years 26% and age group of 51-60 years 21%, 6% and 2% patients were
present in age groups of below 50 years and above 80 years respectively. In this study, mean
age of patients was 66.44 ± 8.19 years with minimum age 45 years and maximum 82 years.
In this study, 74 patients were males and 26 patients were females, with male-female
ratio 2.85:1. 71% of COPD patients were chronic smokers, 29 % patients were non-smokers
among the patients studied. In this study, 1% patients were in stage I, 45% patients were in
stage II, 40% patients were in stage III and 14% patients were in stage IV.
In this study, 72% of patients of COPD exacerbations had hypomagnesaemia (i.e.
serum Mg+2 < 1.7 mg/dl) and 28% patients of COPD exacerbations had normomagnesaemia
(i.e. serum Mg+2 > 1.7 mg/dl).In this study, 1% patient of stable COPD (control) had
hypomagnesaemia (i.e. serum Mg+2 < 1.7 mg/dl) and 99% patients of stable COPD had
normomagnesaemia. (i.e. serum Mg+2 >1.7 mg/dl).
Table No.1:Comparison of serum magnesium level between stable COPD
patients(control) and exacerbation of COPD patients(cases).
Parameter
stable
COPD
(Control)
COPD
Mean
95% CI of
Exacerbation
t-value p-value
difference difference
(Case)
serum
magnesium
level
(mg/dl)
2.15 ± 0.29
1.58 ± 0.3
0.57
0.49 – 0.65
13.49
P<0.0001
The incidence of hypomagnesaemia was present in 78% of patients with acute
exacerbation of COPD (case) as compared to 1% patients with Stable COPD (control), with
the mean serum magnesium of 1.58 ± 0.3 mg/dl in acute exacerbation of COPD (case) as
compared to mean serum magnesium of 2.15 ± 0.29 mg/dl in Stable COPD (control). This
difference of mean values of serum magnesium in COPD exacerbation and stable COPD
patients was significant with p value of < 0.0001.
Table No.2:Pearson’s Correlation coefficient (r) of serum magnesium level of
exacerbation of COPD patients with serum magnesium level in stable COPD patients.
Serum magnesium level of
p-value
exacerbation (r)
Parameters
Serum
magnesiumlevel
stability
of 0.439
Remarks
P<0.0001
Highly
significant
Correlation serum magnesium levels with acute exacerbation of COPD
and stable COPD patients
SERUM_Mg_ExA_mg_dl
3.0
2.5
2.0
1.5
1.0
1.50
1.75
2.00
2.25
2.50
SERUM_Mg_stable_mg_dl
2.75
3.00
The correlation of serum magnesium levels in exacerbation patients (i.e.
hypomagnesaemia in exacerbation) and serum magnesium level stable COPD patients (i.e.
normomagnesaemia in stable COPD patients) was highly significant by Pearson’s Correlation
coefficient (r)
Table No.3:Baseline parameters
Normomagnesaemia
in
Baseline
parameters
Hypo-magnesaemia
(n=72)
Normomagnesaemia
p-value
(n=28)
Remarks
Age in years
66.54 ± 8.32
66.18 ± 8.0
P = 0.84
NS
Male / Female
55 /17
19 / 9
P=0.53
NS
53 /19
18 / 10
P=0.49
NS
Smoker
smoker
/
Non-
cases
with
hypomagnesaemia
and
There was no significant correlation present between hypomagnesaemia and
parameters like Age, Gender and Habit.
Table No.4:Association
Normomagnesaemia
of
stages
of
COPD
with
hypomagnesaemia
Stage I
Hypomagnesaemia
(n=72) (%)
0
Normomagnesemia
(n=28) (%)
1 (3.6%)
Stage II
25 (34.7%)
20 (71.4%)
P=0.001 HS
Stage III
35 (48.6%)
5 (17.9%)
P=0.006 HS
Stage IV
12 (16.7%)
2 (7.1%)
P=0.34 NS
Stages of COPD
χ2 = 13.18, df=2, p=0.001
and
P value
P=0.28 NS
significantly association
In the study, there was significant correlation between hypomagnesaemia and GOLD staging
in stage II and stage III (p=0.001 and p=0.006 respectively), with non-significant correlation
between hypomagnesaemia and stage I and stage IV.
DISCUSSION
There is growing awareness of serum magnesium level in pulmonary diseases. Much
of the impetus for recognition of magnesium as both risk factor and potential therapeutic
agent in patients with COPD comes from relatively well established role of magnesium in the
treatment of acute asthma19. Magnesium disturbance is a well-known abnormality seen in
patients with pulmonary disease20,21,22,23 .Results from literature described frequency of
hypomagnesaemia in 10-60% among hospital treated patients, especially in patient who were
medically treated in intensive care units according to study by Mir Sadaqat Hassan Zafar24
and ColardynF.25
Since magnesium is involved in muscle tone, therefore a decrease in magnesium level
in COPD represents a factor which decreases respiratory muscle function and induces muscle
fatigue. COPD represents an overlap of chronic bronchitis and emphysema and patients of
COPD have an element of hyper responsive airways. Bronchospasm is contributory factor in
their inability to clear secretions and thus reduces pulmonary gas exchange with
consequences such as decrease quality of life and repeated admissions.
In this study, the age distribution of patients was between 40-82 years. The mean age
of the patients in our study was 66.44±8.19 years. The maximum numbers of patients were in
the age group of 60-69 years (45%), followed by age group of 71-80 years (26%) and age
group of 51-60 years (21%). As compared to study by J P Singh26distribution of patients were
between 40-76 years with mean age 60±6.5 years and the maximum numbers of patients were
in the age group of 60-69 years (48%). As compare to by S. Rajjab27mean age of the patients
was 62.3±8.2 years.
There were males predominant in this study, out of 100 patients, 74 were males and
26 were females with male-female ratio 2.85:1.
In this study, 72 patients were having a habit of tobacco smoking more than 10 years,
which state that tobacco smoking was main etiological factor for COPD. This is in
concordance with study by Jindal SK28 which states that smoking is commonest etiological
factor for COPD. Rest of the non-smokers especially female indoor pollution secondary to
use of biomass and coals as their main source of energy for cooking, heating and other
household needs was etiological factor for COPD. Above observations were as accordance to
studies done earlier by Dennis RJ , Maldondo D29 risk for obstructive airway disease among
women and Abbey DE30 stating long term particulate and other air pollutants and lung
function in non-smokers.
In our study the maximum numbers of patients with exacerbation were having
predominant stage II and stage III according to GOLD staging criteria for COPD3.
Studies
This study
JP Singh26
S. Rajjab27
Percentage of patients in 83.3%
stage II and stage III
88%
92.3%
In this study, about 83.3% of the patients with hypomagnesaemia were having stage II
and stage III disease and 16.7% were in stage IV. In JP Singh76/26 study 88% of
hypomagnesaemia patients were having stage II and stage III, while S. Rjjab27 study 92.3%
of hypomagnesaemia patients were in stage II and stage III.In our study, there was significant
correlation was present between hypomagnesaemia and GOLD staging II and stage III
(p=0.001 and p =0.0006 respectively), with non-significant correlation between
hypomagnesaemia and stage I.
As compared to study by JP Singh26 88% of the patients with hypomagnesemia were
having stage II and stage III disease (15/17) as compared to 54.6% with normal magnesium
level in stage II and III. In the study by S. Rajjab27 , hypomagnesaemia group 34.6% were
having stage III, 57.7% stage II and 7.7% were having stage I disease,as compared to patients
with normal magnesium levels 3.9% were having stage III, 47.1% were having stage II and
49% were having stage I disease according to GOLD criterion for staging of COPD. This
explains that there is significant correlation between serum magnesium level and staging of
COPD. In our study, it was showed that there was no significant correlation between
hypomagnesaemia and stage IV, and none other studies, studied stage IV and serum
magnesium level correlation, so need further study for staging and hypomagnesaemia
correlation.
Table No.5: Comparison of studies
Study
In this study
Serum Mg+2
in 1.58± 0.3
exacerbation(mg/dl)
Serum Mg+2
in 2.15±0.29
stable patient(mg/dl)
S.Aziz
study31
1.87
S.
Rajjab JP
Singh
27
26
study
study
1.88±0.67
1.7±0.86
2.21
2.3±0.36
2.15±0.3
The mean serum magnesium of patients with acute exacerbation of COPD was
1.58± 0.3 mg/dl (0.6494mmol/l) and serum magnesium in patient with stable COPD was
2.15±0.29 mg/dl (0.8836 mmol/L) with mean difference 0.57 mg/dl and p value <0.0001.
This showed significant correlation between hypomagnesaemia and COPD exacerbation.
This observation was accordance with studies conducted by Hany S. Aziz31, S. Rajjab27 and
JP Singh26.
Prevalence of hypomagnesaemia at one month of follow up was 1%. Our patient did
not receive any replacement therapy for reduced serum magnesium level. This can be
explained by either correction of hypoxia, treatment of infection or avoidance of drugs
precipitating hypomagnesaemia would correct hypomagnesaemia.
The frequent use of methylxanthines, β2- agonist inhalers and β2-agonist oral
preparation has been described as a cause of Magnesium depletion and hypomagnesaemia.
Hypomagnesaemia in patients with acute pulmonary disease has also been related to a result
of severe infections, inappropriate secretion of anti-diuretic hormone (ADH), antibiotic
administration (aminoglycosides) etc. as stated by Krusten R21 and Colardyn F25.
In this study, there was no significant correlation of serum magnesium level with
habits, age and gender of patients this is in accordance with studies by S. Rajjab27 and JP
Singh26.
The potential mechanism for the direct relaxing effects of magnesium on bronchial
smooth muscles include calcium channel blocking properties, inhibition of cholinergic
Neuro-Muscular Junction transmission with decreased sensibility to the depolarising action of
acetylcholine , stabilization of mast cells and T lymphocytes and stimulation of nitric oxide
and prostacycline32,33 .
In the study by Bhatt SP34, Mohan A serum magnesium is one of the Predictor of in
hospital mortality and morbidity in patients with acute exacerbation of chronic obstructive
pulmonary disease. In the study by Bhatt SP2, Khandelwal P serum magnesium is an
independent predictor of frequent readmissions due to acute exacerbation of chronic
obstructive pulmonary disease.
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