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TISSUE DOPPLER IMAGING IN THALASSEMIA MAJOR PATIENTS:
CORRELATION BETWEEN SYSTOLIC AND DIASTOLIC FUNCTION
WITH SERUM FERRITIN LEVEL
Syarif Rohimi1, Najib Advani1, Sudigdo Sastroasmoro1, Bambang
Madiyono1, Sukman Tulus Putra1, Mulyadi M Djer1, Fajar Subroto2
Abstract
Background Thalassemia is a major public health problem in Indonesia. Cardiac
diseases remain as the main cause of death in these patients due to iron overload.
Although the T2* magnetic resonance; imaging has been considered as the gold
standard for assessing cardiac iron overload but it has limited availability. The
tissue doppler imaging (TDI) echocardiography, a fairly new and easy method
that is suggested, can detect early abnormal myocardial iron overload.
Objective To assess myocardial systolic and diastolic function of thalassemic
patients using TDI and examine their correlation with serum ferritin level.
Methods A cross-sectional study was conducted from January to March 2011 at
the Harapan Kita Women and Children Hospital. We reformed clinical
examination, serum ferritin level, as well as conventional and tissue doppler
echocardiography on all subjects.
Results We included 34 regularly-tranfused patients, -of which 17 were boys. The
mean age of the subjects was 11.6 (SD 4.7 years, range 2.6 - 20 years). Mean
pulse rate and blood pressure were within normal range. Hemoglobin level at
inclusion ranged from 5.8 to 6 g/dL. Almost all patients did not receive regular
chelation therapy. Median serum ferritin level was 6275 ng/mL (range 2151 -
17,646 ng/mL). Conventional echocardiography showed normal systolic function,
but some diastolic dysfunctions were found including E wave abnormalites in 4
patients, A wave abnormalites in 3, and E/A ratio abnormalites found in 3. The
TDI showed decreased systolic function (Sa wave abnormality) in 9 patients and
diastolic dysfunctions (Ea wave abnormality in 11 patients and Aa wave
abnormaly in 2). No abnormality was found in Ea/Aa and E/Ea ratios. There was a
weak negative correlation between ferritin level and Sa wave and Ea wave
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respectively and a moderately negative correlation between ferritin level and Ea/
Aa ratio. There was no correlation between serum ferritin and Aa wave or E/La
ratio.
Conclusion TDI identifies a greater number of patients with systolic and diastolic
myocardial dysfunction than was revealed by conventional echocardiography.
There was a weak negative correlation between serum ferritin to Sa wave and Ea
wave, and a moderately negative correlation between ferritin and Ea/Aa ratio.
There was no correlation between scrum ferritin and Aa wave or E/Ea ratio.
[Paediatr Indones. 2012;52:187-93].
Keywords: tissue doppler imaging, echocardiography,-systolic function, diastolic
function, ferritin, beta-thalassemia major
Beta thalassemias are group of hereditary blood disorders characterized by
anomalies in the synthesis of the beta chains of hemoglobin resulting in various
phenotypes ranging from severe anemia to clinically asymptomatic individuals. In
Indonesia, thalassemia is one of the most common single gene disorders and
causes a major public health problem. Regular transfusion therapy and iron
chelation are reported to improve patients' quality of life, but their life expectancy
is limited by congestive heart failure associated with iron overload. Cardiac
disease remains the main cause of death in patients with iron overload.
Detection of early cardiac abnormality is difficult. The diagnosis of
myocardial iron overload is often delayed because cardiac iron deposition is
unpredictable. Also, symptoms and echocardiographic abnormalities arise late in
the course of the disease. Usually, patients have normal exercise capacity, with
systolic dysfunction occurring in the final state of disease.
Tissue doppler imaging (TDI) is a fairly new and an easy method to detect
abnormal myocardial iron overload in pediatric and adult patients with ^-
thalassemia. TDI has 88% sensitivity and 65% specificity compared to the gold
standard. MRI T2*. The MRI is not widely available, time-consuming, and
expensive, limiting its application in developing countries where thalassaemia is
most common. In clinical practice, serum ferritin has been used to assess
treatment effectiveness and is commonly used to assess the severity of iron
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overload. The aim of this study was to assess cardiac systolic and diastolic
functions using TDI and examine their correlation to serum ferritin in thalassemia
patients with iron overload.
Methods
We conducted a cross-sectional study from January to March 2011 at the
Harapan Kita Women and Children Hospital, Jakarta on children with beta
thalassemia. Subjects with > 10 unit RBC tranfusion and agreed to participate in
this study were enrolled and patients with congenital heart disease was excluded.
All subjects underwent clinical examination, serum ferritin measurements, as well
as conventional echocardiography and TDI according to the standardized
methods. Outcome assessed were cardiac dysfunction. On conventional
echocardiography, we measured left ventricular systolic function reflected by
fractional shortening (FS) and ejection fraction (EF) as well as left ventricular
diastolic function (the E wave, A wave, E/A ratio). The E wave reflected rapid
ventricular filling phase while the A wave was the atrial contraction. The TDI
measures myocardial systolic function (Sa wave), early myocardial diastolic
function (Ea wave), late myocardial distolic function (Aa wave), Ea/Aa ratio, and
E/Ea wave. TDI results was defined as abnormal if the Sa wave was
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patients, A wave abnormalites in 3, and E/A ratio abnormalites found in 3. The
TDI showed decreased systolic function (Sa wave abnormality) in 9 patients and
diastolic dysfunctions (Ea wave abnormality in 11 patients and Aa wave
abnormaly in 2), as are shown in Table 2.
Table 3 shows the distribution of TDI results. Pearson's correlation test
revealed a weak correlation between serum ferritin level and Sa wave (r = 0.360,
P = 0.036,). There was also a moderate correlation between serum ferritin level
and Ea (r = 0.434, P = 0.010). No correlation was observed between serum ferritin
level and Aa wave (r = -0.255, P = 0.146,), nor between serum ferritin level and
E/Ea ratio (r=-0.174, P = 0.349). There was a moderately positive correlation
between serum ferritin level and Ea/Aa ratio ( r=0.556, P=0.001).
Linear regression analysis between serum ferritin level and Sa wave
revealed an association (P= 0.036, r=0.36), with Sa increased 1 cm/sec for every
ferritin level increase of 42048 cm/sec (Y=-18.12 + 420.48 X + e). An Sa wave of
13% was influenced by increasing serum ferritin level (Figure 1).
Table 1. Subjects' characteristics
Characteristics Boys (n=17) Girls (n=17)
Age [years, median (range)]
Age at diagnosis [months, median (range)]
Age at first transfusion [months, median
(range)]
Body weight [kg, median (range)]
Body height [cm, median (range)]
Body surface area [m2, median (range)]
Hemoglobin level [g/dL, median (range)]
Heart rate [mean (SD)]
Systolic pressure [mmHg, mean (SD)]
Diastolic pressure [mmHg, mean (SD)]
Serum ferritin [ng/mL , median (range)]
Regular DFO administration, n
Irregular DFO administration, n
10.1 (2.8-18.1)
4(2-72)
4 (2-72)
24(14-45)
138(92-168)
0.85(0.58-1.53)
5.9 (6-6.2)
103(3)
100(7)
70(7)
6275(2151-
11,000)
0
17
13(5.3-20)
8 (3-54)
8 (3-54)
34(15-43)
127(100-152)
0.87 (0.68-1.35)
6,1 (5.8-6.1)
101 (2)
105(5)
65(5)
9822(2199-
17,646)
0
17
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DFO: desferoxamine
Table 2. Distribution of abnormalities based on echocardiography and TDI
findings
Echocardiography and TDINormal Abnormal
n % n %
Left ventricle systolic function FS 34 100 0 0
EF 34 100 0 0
Left ventricle diastolic function E 30 88 4 12
A 31 92 3 8
E/A ratio 31 85 3 8
Systolic myocardial function Sa wave 25 76 9 26
Diastolic myocardial function Ea wave 23 68 11 32
Aa wave 32 100 2 6
Ea/Aa ratio 34 100 0 0
E/Ea ratio 34 100 0 0
Notes: FS = fractional shortening; EF = ejection fraction
Table 3. Distribution of TDI results and serum ferritin levels
TDI parameterFerritin levels (ng/mL)
Number of
subjects
10000 n %
Sa wave 1 4 1 3 0 9 26
E wave 1 5 2 3 0 11 32
Aa wave 0 1 1 0 0 2 6
E/Ea ratio 0 0 0 0 0 0 0
Ea/Aa ratio 0 0 0 0 0 0 0
Linear regression analysis between serum ferritin level and Ea wave
revealed a correlation (P= 0.010, r=0.434), Ea increased 1 cm/sec for every
ferritin level increase of 429.965 ng/mL (Y = -47.98 + 429.97 X + e). An Ea wave
of 13% was influenced by increasing serum ferritin level (Figure 2).
In addition, linear regression analysis between serum ferritin level and
Ea/Aa wave revealed a correlation (P= 0.001, r=0.556), with Ea/Aa ratio
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increased 1 unit for every ferritin level increase of 13,517 ng/mL (Y= -25,090 +
13,517 X + e). A 30% decrease of Ea/Aa ratio was influenced by serum ferritin
level (Figure 3).
Figure 1. Correlation between serum ferritin and Sa wave Ferritin
Figure 2. Correlation between serum ferritin and Ea wave
Figure 3. Correlation between serum ferritin and Ea/Aa ratio Discussion
Discussion
There is no passive excretory mechanism of iron. In thalassemia patients,
iron is easily accumulated by repeated blood transfusions. Free iron,
nontransferrin-bound iron (NTBI), and labile plasma iron in the circulation, as
well as the labile iron pools within cells, are responsible for iron toxicity. Labile
unbound iron is able to redox cycle between Fe2+ and Fe3 + , thereby generating
reactive oxygen species (ROS), leading to lipid peroxidation and organelle
damage. Ultimately this damage causes degeneration, fibrosis, cell death and
dysfunction. In hemochromatosis cases, microscopic examination revealed large
amounts of iron in muscle cells and histiocytes. Focal degeneration and fibrosis
were extensive. Myocardial fibers varied in size and in iron content. In some, as
much as two-thirds of the cell appeared filled with iron. The hearts were dilated as
well as hypertrophied, in some to more than twice the expected weight.
Quantifying myocardial iron content is difficult. The diagnosis of
myocardial iron overload is often delayed because cardiac iron deposition is
unpredictable. Symptoms and echocardiographic abnormalities arise late in the
course of the disease.
In clinical practice, serum ferritin has been commonly used to assess the
severity of iron overload and the effectiveness of treatment. Serum ferritin does
not correlate with myocardial iron load. Advantages of serum ferritin
measurement are that it is easy to assess, inexpensive, amenable to serial
measurements for monitoring chelation therapy, and correlates positively to
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morbidity and mortality. However, serum ferritin measurements are not always
reliable, since ferritin is an acute phase reactant and serum levels may be
influenced by factors such as inflammatory disorders, liver disease and
malignancy.
Echocardiography studies have shown cardiovascular prognosis in p thalassemia
patients to be excellent if serum ferritin is < 2500 ng/mL. Serum ferritin < 2500
ng/mL has been considered to be a safe level.
A limitation in this study is that echocardiography and TDI were
performed by only one person, possibly leading to a selective bias. However, this
study should be viewed as preliminary study of TDI's correlation to the degree of
it on overload in pediatric patients with P thalassemia.
In our study, subjects's characteristics were similar to those in other studies
(Table l).19'21 Indonesian subjects' characteristics were common to those found
in subjects from other developing countries. The few differences in characteristics
may have been due to the number of subjects, age distribution, compliance to
chelation therapy or serum ferritin level.
In our study, conventional echocatdiography showed no abnormalities in
LV systolic function with normal fraction shottening (FS) and ejection fraction
(EF). Kremastinos found that P-thalassemia was not a pure iron storage disease
and the pathophysiology of cardiac dysfunction was poorly understood and
multifactorial in etiology. Systolic dysfunction was. not correlated with serum
ferritin and occured in a" late stage of the disease. Chronic iron myocardial
deposition does not affect left ventricular relaxation. Engle et al. first reported in
1964 the co-existence of pericarditis and fatal arrhythmias with heart failure in p-
thalassemia major patients. Pericarditis usually coincided to some degree with
myocarditis, as both are inflammatory heart diseases, usually with an
immunological background. Patients with transfusion-dependent P-thalassemia
are at risk of acquiring viral infections such as hepatitis B and C, as well as IIIV.
The increased frequency of infections associated with p-thalassemia seems to be
related to abnormalities of the immune system. Multiple transfusions represent a
repetitive antigenic stimulus, together with iron chelation therapy itself. Once
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systolic function of the left ventricle becomes impaired, survival is reduced,
suggesting it to occur at a very late stage in the disease process.
Diastolic LV dysfunction measurements included E wave > 0.70 m/sec in
4 subjects, A wave < 0.30 m/sec in 3 subjects and E/A ratio < 2 in 3 subjects
(Table 2), findings which were similar to those of other studies. Diastolic
dysfunction proceeded systolic dysfunction. Early restrictive diastolic function
occurred and correlated to severe serum ferritin level.
TDI is a relatively new and an easy method with 88% sensitivity and 65%
specificity compared to MRI T2* for earlier detection of abnormal myocardial
iron overload.10 TDI is superior and reproduceable in detecting myocardial
dysfunction. Silvilairat et al. evaluated TDI in 31 patients with normal LVFS and
found that diastolic myocardial dysfunction was absent in all patients with serum
ferritin < 2500 ng/ mL, but was present in all patients with setum ferritin > 5000
ng/mL.11 We found that TDI revealed systolic myocardial dysfunction (Sa wave)
in 26% of those subjects in which conventional echocardiography did not show
any abnormalities. TDI also showed decreasing left ventricular myocardial
diastolic function (Ea wave) in 32% of subjects and decreasing atrial contraction
(Aa wave) in 6% of subjects. No abnormalities were found in Ea/Aa and E/Ea
ratios of all subjects. There was a weak negative correlation between ferritin and
Sa wave and Ea wave, but a moderately negative correlation between ferritin and
Ea/Aa ratio (Figures 1-3). There was no correlation between serum ferritin and Aa
wave or E/Ea ratio.
Using TDI, we observed that diastolic dysfunction was more pronounced
than systolic dysfunction. Iron deposition in the heart may be patchy and not
uniform. Iron is known to accumulate in the ventticular septum, as well as the free
wall of the ventricles, with a tendency to be more concentrated in the epicardial
layers.27 Clinical and experimental studies have shown that iron is deposited
within myocytes rather than within the interstitium. Wall motion abnormalities
may represent an early sign of cardiac disease despite preserved global function.
The regional abnormalities are related to iron overload and are easily detectable
with TDI. The regional wall motion in patients with thalassaemia and iron
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overload is altered in the absence of global dysfunction. It is possible that at an
early stage iron is predominantly deposited in the septum while at a later stage
other areas become affected.
Long-term prospective studies of echocardiographic assessment for
systolic and diastolic ventricular function in larger numbers of pediatric patients
with P-thalassemia is warranted. TDI should be a routine part oi the
echocardiographic assessment of pediatric patients with p-thalassemia. In
conclusion, TDI revealed a greater number of patients with systolic and diastolic
myocardial dysfunction than was revealed by conventional echocardiography.
There was a weak negative correlation between serum ferritin and Sa wave and Ea
wave, and a moderately negative correlation between ferritin and Ea/Aa ratio.
There was no correlation between serum ferritin to Aa wave or E/Ea ratio.
References
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EFFICACY OF SALBUTAMOL-IPRATROPIUM BROMIDE
NEBULIZATION COMPARED TO SALBUTAMOL ALONE IN
CHILDREN WITH MILD TO MODERATE ASTHMA ATTACKS
Matahari Harumdini, Bambang Supriyatno, Rini Sekartini
Abstract
Background The efficacy of salbutamol-ipratropium bromide nebulization in
children with moderate asthma attacks remains unclear, and studies on patients
with mild attacks have been relatively few, especially in Indonesia. However, it is
common practice for this drug combination to be given to patients with mild-
moderate asthma attacks.
Objective To compare the efficacy of salbutamol-ipratropium bromide
nebulization to salbutamol alone in children with mild to moderate asthma attacks.
Methods This single-blind, randomized clinical trial was held in the Department
of Child Health at Cipto Mangunkusumo Hospital, the Tebet Community Health
Center, and the MH Thamrin Salemba Hospital on children aged 5-18 years with
mild to moderate asthma attack. We randomized subjects to receive either 2.5 mg
salbutamol plus 0.5 mg ipratropium bromide (experimental group) or 2.5 mg
salbutamol alone (control group). Nebulization was given twice, with a 20 minute
interval between treatments. We assessed clinical scores, vital signs, oxygen
saturations, and peak flow rates (PFRs) at baseline, and every 20 minutes up to
120 minutes post-nebulization.
Results A total of 46 patients were randomized to either the experimental or the
control group. Subjects had similar baseline measurements. At 20 minutes post-
nebulization, the percentage increase of PFR was 19% higher in the experimental
group (P=0.01,95% CI 1.8 to 47.2). The proportion of PFR reversibility was 27%
higher in the experimental group, although this result was statistically
insignificant (P=0.06, 95% CI 0.03 to 0.52). There were no significant differences
in clinical scores, oxygen saturations, respiratory rates, or hospitalization rates
between the two groups. Side effects also did not differ significantly. Conclusion
Salbutamol-ipratropium bromide nebulization improved PFR measurements better
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than salbutamol alone. However other clinical parameters were not significantly
different between the two groups. [Paediatr Indones. 2012;52:200-8].
Keywords: children, mild to moderate asthma attack, ipratropium bromide,
salbutamol
Asthma is global health problem in children, and is increasing in
prevalence, even though the pathogenesis, pathophysiology, and management of
asthma is well understood. The National Health Interview Survey in the United
States reported an asthma prevalence of 7.5% in 1995.1 In Indonesia, Rahajoe
et.al. reported asthma prevalence to be 6.7%.2
Controversies in asthma management may increase morbidity and
mortality of patients. The addition of ipratropium bromide for patients with
asthma attacks has been controversial. Beta2- agonists are potent bronchodilators,
but multiple or large doses may cause adrenergic side effects. However,
ipratropium bromide is an anticholinergic bronchodilator with a slower onset,
longer duration of action, and less adrenergic side effects compared to those of
beta2-agonists. Previous studies have shown that a combination of salbutamol and
ipratropium in patients with severe asthma attacks improve lung function and
clinical score, while lowering emergency department (ED) admission duration and
hospital admission rates. Other studies have also reported salbutamol-ipratropium
bromide superiority in patients with moderate attacks, while studies on its use in
patients with mild asthma attacks have been few. Salbutamol-ipratropium
nebulization has commonly been given to patients with mild to moderate asthma
attacks, although only one Indonesian study to date has been published on this
subject.
We aimed to compare the efficacy of salbutamol-ipratropium nebulization
with salbutamol alone in pediatric patients with mild to moderate asthma attacks.
We measured and compared clinical scores, peak flow rates, oxygen saturations,
respiratory rates, and hospital admission rates of the two groups.
Methods
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This study was designed as a single-blind, randomized, clinical trial
performed from September 2010-March 2011 at the Community Health Center of
Tebet District, and the EDs of Cipto Mangunkusomo Hospital and MH Thamrin
Salemba Hospital. We compared the effects of nebulization with salbutamol-
ipratropium combination to those of salbutamol alone.
Patients aged 5-18 years who visited the ED with mild to moderate asthma
attacks, classified according to Schuh's asthma clinical score, were eligible for
enrollment. We excluded patients with signs of respiratory failure, need of
intensive care management, heart abnormality, pneumonia or other respiratory
disorders altering lung function, ocular disorder altering intraocular pressure or
pupillar response (as diagnosed by history-taking and physical examination),
hypersensitivity to ipratropium or salbutamol, and those who had received
ipratropium bromide treatment within the 36 hour;: prior to enrollment. Subjects'
parents provided informed consent.
We consecutively assigned subjects to receive either salbutamol-
ipratropium bromide (experimental group) or salbutamol alone (control group),
according to a drug sequence table generated by block randomizations of six. This
table was kept by the principal investigator (PI) to keep the subjects blinded to
their allocated group.
Subjects were given either 2.5 mg salbutamol with 0.5 mg ipratropium
bromide (Combivent) or 2.5 mg saibutamol (Ventolin) nebulization in 3-5 ml
saline. Subjects were given two doses by ultrasonic nebulizer (Omron NE-C29)
via face mask, with a 20 minute interval between treatments. The duration of each
nebulizer treatment was about 10 minutes. At enrollment, subjects' baseline data
was collected including demographic characteristics (age, sex, and nutritional
status), asthma history, treatment history, asthma comorbidities (allergic rhinitis
or sinusitis), duration of current symptoms, and asthma severity. We also
measured baseline clinical parameters, including Schuh's clinical scores, vital
signs, PFRs by mini peak flow meter (Breath-Taker, Australia, reproducibility
8.4%, SD 27 L/m), and oxygen saturation by pulse oxymetry (Oxy3, OneMed).
Clinical response was assessed every 20 minutes, until 2 hours post-nebulization,
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including the same parameters measured at baseline. For patients with moderate
attacks, we planned to also measure blood gas analysis (BGA) twice, at baseline
and at 2 hours after treatment, though most patients declined. PFR was measured
by forced expiration maneuver (patient twice performed forced expiration after
maximal inspiration with at least a 5-second interval between forced expiration).
Only the best value was recorded. Patients with inadequate clinical response after
2 hours post-treatment were admitted to the hospital.
If the principal investigator (PI) was absent when an asthma attack patient
came to ED, the clinical score at baseline was measured by a research assistant or
by trained ED attending physicians. When a subject enrolled, the PI was called by
phone for study group random allocation instructions. By the time the second
nebulization was finished, the PI would have arrived at the ED to continue data
measurements. Prior to the study, interrater reliability for baseline clinical scoring
WHS assessed by comparing the Pi's ratings to those of a research assistant on 6
patients. Individual severity scores were summed and divided into three severity
groups as follows: mild (total score 1-3), moderate (total score 4-6) or severe
(total score 7-9) (Table 1). Interrater reliability was measured using these severity
subgroups, with Kappa = 0.6.
The primary outcome was nebulization efficacy, measured by several
parameters including decreased clinical score, increased PFR, increased oxygen
saturation, decreased respiratory rate, and decreased percentage of hospital
admission. PFR was measured as the percentage increase from baseline. PFR
reversibility was defined as a PFR increase >12% from baseline. The proportion
of patients with PFR reversibility in each group was also recorded. Secondary
outcomes were blood gas values before and after treatment, and side effects of
medications.
The required sample size was determined by a formula of mean difference
of two independent groups, with oc=5% and power of 80%. Since a previous
study showed that the standard deviation of mean change in clinical asthma score
between the saibutamol-ipratropium and salbutamol groups was 1.5,9 the
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clinically significant difference was set at 1.5. Therefore, 16 patients per study
group, or a total of 32 patients, were needed for this study.
Differences in clinical scores, PFRs, oxygen saturation, and respiratory
rates between groups were analyzed by independent t-test, or Mann-Whitney test
if the data had an abnormal distribution. Differences in PFR reversibility, hospital
admission, and side effects were analyzed by Chi-square test or Fisher's exact test.
We performed intention-to-treat analyses and considered P
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(n=30), we found mean difference of 15,8% at 20 minutes (95% CI 1,05 to 30,31;
P=0,05; Table 4). In moderate subjects alone (n=10), we found more than 50%
mean difference at the beginning and final observation, but statistical analysis
could not be performed (Table 4).
Table 1. Schuh's clinical asthma score 9
Score Accessory muscle score Wheeze score Dyspnea score
0 No retractions No wheeze and
moving air well
Dyspnea absent
1 Intercostal retractions End-expiratory
wheezes
Normal activity and speech;
minimal dyspnea
2 Intercostal and
suprasternal retractions
Panexpiratory +
inspiratory wheezes
Decreased activity; 5-8 word
sentences; moderate dyspnea
3 Nasal flaring Wheezes audible
without stethoscope
Concentrate on breathing;
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Mean initial respiratory rate, x/min (SD)
Mean initial heart rate, x/min (SD)
97 (96-99)
28.76 (6.24)
102.19(12.54)
98 (96-99)
29.42(7.11)
103.74(20.03)
Table 3. Comparative median/mean decreases in clinical score
SubjectsTime at
evaluation
Decrease in clinical score
P 95% CIControl (n= 23)
median (range)
Experimental
(n=23) median
(range)
Mild tomoderate
attack
20 minutes40 minutes
60 minutes
120 minutes
2(1-4)2(1-5)
2(1-5)
2 (1-5)
2(1-4)3(1-6)
3(1-6)
3(1-6)
0.5600.775
0.524
0.414
-0.40 to 0.57-0.55 to 0.81
-0.42 to 1.12
-0.34 to 1.29
Control (n=7)
mean (SD)
Experimental
(n= 7) mean (SD)
Moderate
attacks only
20 minutes
40 minutes
60 minutes
120 minutes
2.14 (0.90)
3.57 (0.98)
3.71 (0.95)
3.71 (0.95)
2.43 (0.98)
4.14 (1.07)
4.86 (1.07)
5.29 (0.76)
Statistical analysis was not
performed due to
inadequate number of
subjects
We observed a higher proportion of subjects with PFR reversibility in the
experimental group (17/19 subjects) than in the control group (13/21 subjects) at
20 minutes. The difference between groups was 0.27 (95% CI0.026 to 0.524;
P=0.069). At 40 to 120 minutes, there were similarly no significant differences in
proportions of subjects with PFR reversibility (Table 5). In subjects with mild
attacks alone (n= 30), there was also no difference between groups (Table 5),
while in subjects with moderate attacks alone (n= 10), reversibility tended to be
higher in the experimental group, but the sample size was too small to analyze
(Table 5).
Before intervention, all subjects had oxygen saturation >95%, therefore,
oxygen therapy was not needed. There were no differences in oxygen saturation
between the two groups. We also found no significant difference in the decrease
of respiratory rates between the two groups (Table 6) In moderate asthma attack
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subjects alone (n= 14), there was a greater decrease in respiratory rates in the
experimental group. These differences were 4 x/minutes at 20 and 40 minutes, and
6x/minutes at 60 and 120 minutes, which were clinically quite apparent (Table 6)
but statistical analyses were not performed due to lack of subjects.
Two patients with moderate asthma attack from the control group
responded inadequately at 120 minutes, requiring hospital admission. These 2
subjects were given ipratropium bromide nebulization and intravenous steroids.
They were analyzed in the control group, since we used intention-to-treat in the
experimental group (0/23 subjects), but this analyses. The number of hospital
admissions was difference was not statistically significant (P = 0.489) higher in
the control group (2/23 subjects) than (Table 7).
Table 4. Comparative median FFR percentage increase
SubjectsTime at
evaluation
Control (n=21) %
increase, (range)
Experimental
(n=19) % increase,
(range)
P* 95% CI
Mild to 20 minutes 14.28(0-100) 33.33 (8.33-200) 0.012 1.80 to 47.18
moderate attack 40 minutes 25(7.14-100) 50 (8.33-200) 0.114 1.61 to 54.17
60 minutes 25(11.1-100) 50 (8.33-300) 0.115 4.46 to 83.59
120 minutes 25(11.1-100) 50 (8.33-200) 0.115 4.46 to 83.61
Control (n=16) %
increase, (range)
Experimental (n=14)
% increase, (range)P* 95% CI
Mild attacks 20 minutes 13,39(0-57,14) 29,16(8,33-100) 0.058 1.05 to 30.31
only 40 minutes 22,5(7,14-60) 50(8,33-100) 0.234 -2.5 to 40.96
60 minutes 25(11,11-100) 50 (8,33-200) 0.531 -10.56 to 49.46
120 minutes 25(11,11-100) 50 (8,33-200) 0.531 -10.56 to 49.46
Control (n=5) %
increase, (range)
Experimental (n=5)
% increase, (range)
Moderate attacks
only
20 minutes
40 minutes
16,7(0-100)
50(16,7-100)
66,7 (20-200)
100 (20-200)
Statistical analyses was not
performed due to lack of
subjects60 minutes 50(16,7-100) 166,7(60-300)
120 minutes 50(i6,7-100) 166,7(60-300)
*Mann-Whitney test. CI was measured by formula using mean v&;us
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Table 5. Comparative proportions of PFR reversibility (defined as PFR increase
>12% from baseline)
Reversibility 5tControl
(n=21)
Experimental
(n= 19)P* 95% CI
Mild to moderate 20 minutes 13 17 0.069q
0.026 to 0.524
attacks 40 minutes 19 17 1q
-0.409 to 0.431
60 minutes 20 17 0.596q
-0.107 to 0.223
120 minutes 20 17 0.596q
-0.107 to 0.223
Control ExperimentalP
. (n=16) (n= 14)
Mild attacks only 20 minutes 10 12 0,226a Not measured
40 minutes 14 12 1b
60 minutes 15 12 0,586b
120 minutes 15 12 0,586b
Control Experimental
(n=5) (n=5)
Moderate attacks 20 minutes 5 5 Statistical analysis was not
performed due to lack of
subjects
only 40 minutes
60 minutes
5
5
5
5120 minutes 5 5
a Chi-square test b Fisher's exact test
Table 6. Comparative median respiratory rate decrease
Time at
Evaluation
Control
(n=23)
Experimental
(n= 23)P* 95% CI
Mild to
moderate
attacks
20 minutes
40 minutes
60 minutes
120 minutes
4 (2-18)
6 (4-20)
6 (4-20)
6 (4-20)
4 (0-8)
8 (1-16)
8 (1-16)
8 (1-16)
0,907
0,585
0,602
0,602
-2,86; 1,12
-2,19; 2,79
-2,40; 3,19
-2,41; 3,18
Control
(n=7)
Experimental
(n= 7)
Moderate
attacks only
20 minutes
40 minutes
60 minutes
4 (4-16)
6 (4-16)
6 (4-18)
8 (4-8)
10 (8-12)
12 (8-12)
Statistical analysis was
not performed due to lack
of subjects
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120 minutes 6 (4-18) 12 (8-12)
* Mann-Whitney test; CI measured by formula using mean value
Table 7. Comparative proportion cf hospitalization
Control (n=23) Experimental (n= 23)
Hospitalization
No hospitalization
2
21
0
23
P=0.488 ( Fisher's exact test)
Of 14 patients with moderate attacks, only 2 consented to BGA
examination. The first patient agreed to arterial puncture after the intervention,
and the second patient agreed before the intervention. In both subjects, we found
decreased pressure of oxygen in arterial blood (Pa02) (33.6 and 31 mmHg,
respectively) and low HC03 (21 and 19 mmol/L, respectively), while pH, Pa02
and oxygen saturation were still normal.
We found the side effect of mouth mucosal dryness to be of similar
proportions in both groups. The unilateral decrease of light pupillar response was
found in 2 patients from the experimental group at 20 minutes, but spontaneously
resolved at 40 minutes. The proportion of subjects with tachycardia was highest at
20 minutes, but did not differ between groups. Tachycardia resolved with time.
Discussion
This study had some limitations. In this single-blinded study, investigators
were not blinded, but subjects were. Ideally, the study should be double-blinded,
since we used a subjective parameter of efficacy (clinical score).
However, the other efficacy parameters (PFR, oxygen saturation,
respiratory rate, and proportion of hospital admission) were objectively measured.
Also, the PFR could net be measured in 6 patients, but the remaining sample size
was still adequate for most statistical analyses. In addition, we planned to measure
BGA in all subjects with moderate attacks, but most subjects refused the arterial
puncture. Since Carruthers et al. showed that respiratory failure was unlikely in
patients with oxygen saturation >92%, BGA was not necessary unless otherwise
clinically indicated.
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In our study, interrater reliability could only be measured between the Pi
and a research assistant on 6 patients, due to limitations of time and sample size.
Our Kappa was 0.6 (0.6-0.8 was considered sufficient). The same clinical score
was used by previous studies with Kappa values ranging from 0.6 to 0.9, similar
to that of our study.
The required minimal sample size was 32 subjects, but at the end of the study, we
had more subjects to be analyzed. We attempted to subgroup analyses for different
attack severities. However, a subanalysis could only be performed on subjects
with mild attacks due to insufficient number of subjects with moderate attacks.
Therefore, we analyzed data of mild and moderate attack subjects as a whole,
while trying to demonstrate clinical differences in each subgroup. The low
number of asthma attack patients at our public facilities may be due to increasing
numbers of private health centers with nebulization facilities as well as better
maintenance treatment for asthma patients.
Demographic and clinical parameters that may influence the clinical
response to nebulization treatment were assessed at baseline, and found to be
similar in the two groups. We observed an insignificant difference in clinical
scored throughout che study between the two groups (median difference of 1
point). Similarly, Rayner et al. reported that ipratropium bromide given after
beta2-agonist resulted in a reduced synergistic effect. Furthermore, Kumaratne et
al.11 reported that in young subjects (4 months-6 years) assumed to have a
predominant bronchospasm on peripheral small bronchi, ipratropium bromide was
less effective.
In our analysis of subjects with moderate attacks alone, we found a greater
decrease in clinical score in the experimental group than in the control group
(mean difference 1.58 points), though further statistical analyses could not be
performed due to insufficient subjects. Previous studies by Schuh et al. Sharma et
at. Kartininingsih et al. and Qureshi et al. also demonstrated a larger decrease in
clinical score in their experimental groups. Those studies included children of
younger age and greater numbers of subjects with moderately severe attacks. Our
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study included mostly subjects with mild asthma attacks, in which less cholinergic
activity occurs. On the other hand, in subjects with moderate attacks, we found a
larger difference in the decrease in clinical scores. This difference might have
been more profound if the number of subjects with moderate attacks was larger.
The Global Initiative for Asthma (GINA) recommends lung function tests to
confirm diagnoses and to evaluate asthma severity, as well as asthma attack
severity. Lung function tests generally comprise spirometry and peak flow meter
examinations. We chose to use peak flow meters due to their greater availability.
The reference data for predicting PFR values for age, sex, and body mass index in
patients aged 5-18 years in Indonesia was insufficient, so we gauged PFR
response to be the percentage of increase from baseline, and the proportion of
patients with PFR increase of J> 12% from baseline (PFR reversibility).
We found a 19% difference (95%CI 1.80to47.18; P=0.012) in PFR
between the groups at 20 minutes. Beyond 20 minutes, we also found differences
of 25%, but they were not significant. However, the increasing confidence interval
suggested relevant differences beyond 20 minutes. This result was consistent with
previous studies9'20 which showed more profound differences of lung function
parameters at the end of the observations, due to the slower onset of ipratropium
bromide compared to that of salbutamol. Similarly, in a meta-analysis on subjects
with moderate to severe attacks, Rodrigo et al. found a difference of 12.4% in
forced expiratory volume at 1 minute (FEVj) measured by spirometry. Sharma et
al. also found a higher PFR increase percentage in the experimental group at 30
minutes to 4 hours after nebulization, in a study on subjects with moderate
attacks.
In subjects with moderate attacks alone, we found a larger difference in
PFR improvement (>50%) at 20 to 120 minutes, but statistical analyses could not
be performed. Schuh et al. reported that differences in FEV increased as attack
severity increased. Nonetheless, a significant difference in PFR increase was
reported by Rayner et al. who gave ipratropium bromide sequentially after
salbutamol, and Qureshi et al.8 who completed PFR measurements in only 40% of
their subjects.
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We also found a greater proportion of PFR reversibility at 20 minutes in
the experimental group. The difference in proportion was only 27% (95%CI 0.026
to 0.524; P=0.069), in contrast to previous studies which showed better efficacy at
the end of the observation periods. Our study included mostly patients with mild
attacks and less bronchoconstriction, thus the synergistic effect of ipratropium-
salbutamol was observed at just 20 minutes. At the subsequent rime points, the
proportion of reversibility did not further increase because maximal
bronchodilatation had already occurred at 20 minutes.
Kartininingsih et al. and Qureshi et al. found significant differences in
oxygen saturation between their groups, in subjects with moderate to severe
attacks. In contrast, most of our subjects had mild attacks with high oxygen
saturation (96-99%) at baseline, thus clinical improvement could not be shown.
Ducharme et al. also reported no significant difference in oxygen saturation in
subjects with mild to moderate attacks.
We observed no significant difference in decreased respiratory rates
between the two groups. However, in moderate attack subjects alone, we only
found a tendency of difference between the groups. Studies by Sharma et al. and
Qureshi et al. reported a greater decrease in respiratory rate in the experimental
groups, in subjects with moderate attacks and subjects with severe attacks,
respectively. Our contrasting results may be due to the smaller number of subjects
with moderate attacks in our study.
Many previous studies on subjects with moderate to severe attacks
reported lower hospital admission rates in the ipratropium bromide group. The
difference in admission rates between groups was greatest in the most severe
cases. We found a small difference in hospital admissions (2/23 in the control
group vs 0/23 in the experimental group), but it was not statistically significant
(P=0.489). Most of our subjects had mild attacks, and as such were less likely to
be hospitalized. Furthermore, our sample size was too small to detect any
differences in hospitalization rates.
An asthma attack patient may initially hyperventilate to increase oxygen
uptake, thus decreasing carbon dioxide levels. If the obstruction continues, the
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ventilation-perfusion mismatch can no longer be overcome by hyperventilation,
thus resulting in hypoxemia and hypercapnia. Carruthers et al. reported that the
respiratory failure rate was only 4-2% among patients with oxygen saturation >
92%. In contrast, in patients with oxygen saturation
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We thank Boebringer Ingelheim for supporting the study, as well as EM Dadi
Suvoko, MD, Partini R Trihono, MD, Antonius H. Pudjiadi, MD, and Waldi
Nurhamzah, MD, for their valuable advices. We also thank our research assistant,
Hari Nugroho, MD and all staff of the Respirology Division of the Department of
Child Health at Cipto Mangunkusumo Hospital, the Cipto Mangunkusumo
Hospital ED, the MH Thamrin Salemba Hospital ED, and the Community Health
Center of Tebet District.
References
1. Akinbami LJ, Schoendorf KC. Trends in childhood asthma: prevalence, healthcare utilization, and mortality. Pediatrics. 2002;110:315-22.
2. Rahajoe N, Supriyatno B, Setyanto DB. Pedoman nasional asma anak. Jakarta:UKK Respirologi PP Ikatan Dokter Anak Indonesia; 2004. p. 3-4.
3. Lotvall J. Bronchodilators. In: O'Byrne P, Thomson N, editors. Manual ofasthma management. 2nd ed. London: WB. Saunders; 2001. p. 237-60.
4. Pedersen S. Management of acute asthma in children. In: O'Byrne P ThomsonN, editors. Manual of asthma management. 2nd ed. London: W.B. Saunders;
2001. p. 237-60.
5. Liu A, Spahn J, Leung D. Childhood asthma. In: Behrman6. Pederscn S, Bisgaard H. Clinical pharmacology and therapeutics. In:
Silverman M, editor. Childhood asthma and other wheezing disorders. 2nd ed.
London: Arnold; 2002. p. 247-76.
7. Restrepo RD. Use of inhaled anticholinergic agents in obstructive airwaydisease. Respir Care. 2007;52:833-51.
8. Qureshi F, Pestian J, Davis P, Zaritsky A. Effect of nebulized ipratropium onthe hospitalization rates of children with asthma. N Engl J Med.
1998;339:1030-5.
9. Schuh S, Johnson DW, Callahan S, Canny G, Levison H. Efficacy of frequentnebulized ipratropium bromide added to frequent high-dose albuterol therapy
in severe childhood asthma. J Pediatr. 1995;126:639-45.
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10.Zorc JJ, Pusic MV, Ogborn CJ, Lebet R, Duggan AK. Ipratropium bromideadded to asthma treatment in the pediatric emergency department. Pediatrics.
1999; 103:748-52.
11.Rodrigo G], Castro-Rodriguez J A. Anticholinergics in the treatment ofchildren and adults with acute asthma: a systematic review with meta-analysis.
Thorax. 2005;60:740-6.
12.Storr J, Lenney W Nebulised ipratropium and salbutamol in asthma. Arch DisChild. 1986;61:602-3.
13.Ducharme FM, Davis GM. Randomized controlled trial of ipratropiumbromide and frequent low dose"; of salbutamol in the management of mild and
moderate acute pediatric asthma. J Pediatr. 1998;133:479-85.
14.Kartininingsih L, Setiawati L, Makmuri M. Comparison of clinical efficacyand safety between salbutamol-ipratropium :bulization compared to
salbutamol alone in asthma attacks bromide nebulization and salbutamol alone
in children with asthmatic attack. Paediatr Indones. 2006;46:241-5.
15.Carruthers DM, Harrison BD. Arterial blood gas analysis or oxygen saturationin the assessment of acute asthma/ Thorax. 1995;50:186-8.
16.Rayner RJ, Cartlidge PH, Upton CJ. Salbutamol and ipratropium in acuteasthma. Arch Dis Child. 1987;62:840-1.
17.Kumaratne M, Gunawardane G. Addition of ipratropium to nebulizedalbuterol in children with acute asthma presenting to a pediatric office. Clin
Pediatr (Phita). 2003;42:127-32.
18.Sharma A, Madaan A. Nebulized salbutamol vs salbutamol and ipratropiumcombination in asthma. Indian J Pediatr. 2004;71:121-4.
19.Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGeraid M, etal. Global strategy for asthma management and prevention: GINA executive
summary. Eur Respir J. 2008;31:143-78.
20.Qureshi F, Zaritsky A, Lakkis H. Efficacy of nebulized ipratropium inseverely asthmatic children. Ann Emerg Med. 1997;29:205-11.
21.Rodriguez-Roisin R. Acute severe asthma: pathopaysiology and pathobiologyof gas exchange abnormalities. Eur Respir J. 1997;10:1359-71.
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22.Rodrigo GJ, Rodriquez Verde M, Peregalli V, Rodrigo C. Effects of short-term 28% and 100% oxygen on PaC02 and peak expiratory flow rate in acute
asthma: a randomized trial Chest. 2003;124:1312-7.
23.Meert KL, Clark J, Sarnaik AE Metabolic acidosis as an underlyingmechanism of respiratory distress in children with severe acute asthma.
Pediatr Crit Care Med. 2007;8:519-23.
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EFFICACY OF SYNBIOTIC AND PROBIOTIC TREATMENTS ON
ACUTE WATERY DIARRHEA IN CHILDREN
Ani Isti Rokhmawati, Wahyu Damayanti, Madarina Julia
Abstract
Background In developing countries, acute watery diarrhea is a common cause of
morbidity and mortality in children. Giving synbiotics or probiotics may decrease
the severity of diarrhea. Objective To compare the efficacy of synbiotics and
probiotics in decreasing the frequency of diarrhea, shortening the duration, and
increasing patient body weight.
Methods This was a double-blind, randomized clinical trial.to compare the effects
of synbiotic vs probiotic treatment in children aged 6-59 months with acute
watery diarrhea. This study was performed from October to December 2010 in
two hospitals in Central Java. Subjects received either synbiotics or probiotics
twice daily for five days. The measured outcomes were duration of diarrhea, daily
frequency of diarrhea, and increase in body weight.
Results There was no significant difference in the mean duration of the diarrhea
in the synbiotic and probiotic groups, 3.92 days (SD 0.79) vs 3.80 days (SD 0.82),
(P=0.35), respectively. Nor did we observe a significant difference in the mean
increase in body weight in the synbiotic and probiotic groups, 150 g (SD 49.7) vs
160 g (SD 48.9), (P= 0.67), respectively.
Conclusion We observed no significant differences in-efficacy of synbiotic and
probiotic treatment for management of acute watery diarrhea. [Paediatr Indones.
2012;52:209-12].
Keywords: Acute watery diarrhea, synbiotic, probiotic
Acute watery diarrhea is a common cause of morbidity and mortality in
children. Dehydration, as its main complication, causes the death of 5 to 10
million children in the world annually. The main treatments for managing acute
watery diarrhea are rehydration, prevention of further dehydration, and dietetic
treatment. The goal of dietetic treatment is to improve the microbial ecosystem of
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the gut. Effects of probiotics in the gastrointestinal tract are improvement of
lactose absorption, normalization of gut microflora, clearance of pathological
microorganisms, and improvement cf humoral immunity by increasing IgA
secretion. Intake of probiotics (living microorganisms), and synbiotics (consisting
of a mixture of living microorganisms and oligosaccharides) has been
demonstrated to modify the composition of the gut microflora, restore the
microbial balance, hence, providing potential health benefits.
Previous studies have assessed the efficacy of probiotics compared to
placebo, as well as synbiotics compared to placebo, in the management of acute
watery diarrhea. Both reported significant benefits. However, there has been little
data on which of the two, probiotics or synbiotics, is more effective for treating
acute watery diarrhea in children.
We conducted this study to compare the effects of synbiotics and
probiotics in decreasing the frequency of diarrhea, shortening the duration of
diarrhea, and increasing body weight during illness.
Methods
We conducted this study in the pediatric ward of Soeradji Tirtonegoro
Hospital, Klaten, and Muntilan Hospital, Magelang, from October to December
2010. The study design was a randomized, double-blind clinical trial. Subjects
were children aged 6-59 months with acute water/ diarrhea admitted at the two
hospitals. Acute watery diarrhea was defined as watery stools occurring more than
three times per day and lasting for at least seven days. We excluded subjects with
bloody diarrhea and diarrhea with severe complications, such as severe
dehydration, metabolic acidosis, or seizures. Parents of subjects provided written
informed consent. This study was approved by the Health and Medical Ethics
Committee of the Gadjah Mada University Medical Faculty.
The required number of subjects (176) was determined by hypothesis test,
based on the means of the two populations. Subjects were consecutively allocated
into the two treatment groups using a random number table. Only the appointed
pharmacist had access to the subjects' allocated intervention, while subjects and
physicians were blinded to the information (see study profile in Figure 1).
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Before the study, subjects were examined to determine their level of
dehydration, based on WHO guidelines. Subjects suffering from dehydration were
rehydrated before weighing. The synbiotic and piobiotic sachets were
administered twice daily for five days by nurses. Patient compliance was
recorded.
The physician evaluated the level of dehydration and frequency of diarrhea
every two hours in the first six hours after admission, followed by evaluation
every twelve hours. We evaluated the duration of diarrhea from acute watery
diarrhea, as well as the increase in body weight during illness. Duration of
diarrhea was defined as the time taken for diarrheal frequency tc decrease to less
than three times per day. If subjects were discharged in less than five days, we
asked parents to have their children weighed at the outpatient clinic on day five
after admission.
Figure 1. Study profile
Results
Of the 207 children recruited, 176 subjects completed the study. There
were 88 subjects in each of the two groups. Baseline characteristics of subjects are
shown in Table 1. The results of this study are shown in Table 2. There was no
significant difference in the duration of the diarrhea (P~ 0.35), the daily frequency
of diarrhea, or the increase in body weight (P=0.67). We observed potential side
effects of giving synbiotics and probiotics, like bloating and flatulence. Three
patients suffered from bloating in synbiotic group. No other gastrointestinal
adverse effects were observed during the study.
Discussion
We conducted this study to compare the effects of synbiotics and
probiotics in decreasing the frequency of diarrhea, shortening the duration of
diarrhea, and increasing body weight during illness. We found no significant
differences between the two groups for mean daily frequency of diarrhea, mean
duration of diarrhea or mean increase in body weight.
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We observed side effects, such as bloating and flatulence, from both
synbiotic and probiotic treatment. Three patients in the synbiotic group suffered
from bloating. Fermentation of the substrate (prebiotics) produces hydrogen,
which may cause bloating, flatulence, and diarrhea. But it is difficult to
differentiate if these effects ate due the diarrhea itself or due to the additional
substrates (prebiotics).
Table 1. Baseline characteristics of subjects Characteristics
Characteristics Synbiotic group (n=88) Probiotic group (n=88)
Mean age, months SD
Gender
Males, n (%)
Females, n (%)
Socio-economic status1
Low, n (%)
High, n (%)
Nutritional status2
Undernourished, n (%)
Well-nourished, n (%)
27.69 13.73
51 (58)
37 (42)
21 (24)
67 (76)
31 (35)
57 (65)
23.69 14.74
41 (47)
47 (53)
41 (76)
47 (34)
34 (38)
54 (52)
1 Determination of socio-economic status was based on the ratio of meal
expenditure to monthly family income. In Central Java in 2009, high socio-
economic status was defined as a ratio of < 51.8%, while low socio-economic
status was defined as a ratio of > 51.8%.
2 Nutritional status was categorized by body weight for height z-score, based on
the WHO 2006 growth standard. Obesity was defined as a 7-score of > 2 SD;
well-nourished was defined as a z-score of -2 SD to +2 SD; wasting was defined
as a z-score of -2 SD to -3 SD; while severe wasting was defined as a z score of 34 weeks. They were singletons and received breast milk or
breast milk and formula combination either directly or by bottle, spoon, or
nasogastric catheter. Subjects who got breastmilk combined with formula milk
and/or additional food or only formula milk were classified as not exclusively
breastfed. Subjects' parents provided written informed consent. Subjects were
excluded if they suffered from complications during labor, infections during their
time in the hospital nursery, or had contraindications for breastfeeding or
congenital anomalies. The required number of subjects was 181, based on a=5%
and power 80%. Subjects were recruited by consecutive sampling and assigned to
either the exclusively breastfed group or the non-exclusively breastfed group
At the time of hospital discharge, mothers were given diaries to record
their breastfeeding practices and their child's illnesses. They were asked to visit
the Outpatient Clinic of the Department of Child Health, Sanglah Hospital,
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Denpasar, on a monthly basis. During each visit, mothers filled questionnaires on
the episodes of acute respiratory infections in their child, as well as the continuity
of their breastfeeding practice. Parents were requested to take their infants
immediately to the Pediatric Outpatient Clinic if their infants were ill. Sick infants
were then examined by eligible pediatric residents. If the parents and infants were
unable to attend the monthly clinic visit, a research assistant would call or make a
home visit on a suggested day. Questionnaires would then be filled at the subject's
residence.
We used Chi square and logistic regression tests to analyze the data. A P
value of < 0.05 was considered to be statistically significant. This study was
approved by the Ethics Committee of the Udayana University Medical School/
Sanglah Hospital. Denpasar.
Table 1. Baseline characteristics of subjects
Characteristics months 4
(n = 91)
CharacteristicsExclusively breastfed
for 4 months (n = 90)
Not exclusively
breastfed for 4
months (n = 91)
Infant characteristics
Male gender, n (%) 46(51) 44 (48)
Small for gestational age, n (%) 43 (48) 36 (39)
Family characteristics
Mean maternal age, years (SD) 25.57(4.71) 26.02 (4.75)
Parity, n (%)
First parity 51 (57) 41 (45)
Multiparity 39 (43) 50 (55)
Maternal nutritional status, n (%)
Undernourished 17(19) 19(21)
Well-nourished 67 (74) 65(71)
Overweight 6(7) 6(7)
Obese 0(0) 1(1)
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Mean monthly family income, Rupiah (SD) * 1,390,000 (688,464) 1,350,000 (580,684)
Family size, n (%)
< 4 people 51 (57) 39 (43)
Combination contraception, n (%)
Yes 1(1) 12(13)
Smoke exposure, n (%)
Yes 55(61) 66 (73)
Ethnicity, n (%)
Balinese 63 (70) 61 (67)
Javanese 19(21) 23 (25)
Others 8(9) 7(8)DPT immunization, n (%)
Yes 87 (97) 91 (100)
Family history of atopy, n (%)
Yes 32 (35) . 38 (42)
Results
One hundred eighty-six subjects fulfilled our inclusion criteria. Three
subjects were lost to follow up and two dropped out the study due to change of
residence and death. Hence, 181 subjects completed the study. The baselinecharacteristics for each group are shown in Table 1.
In unadjusted analysis, infants who were exclusively breastfed for four
months were at lower risk for having acute respiratory infection than those who
were not exclusively breastfed for four months (RR 0.07; 95% CI 0.03 to 0.14)
(Table 2).
Table 3 shows the risk of acute respiratory infection after adjustments for
gestational age, parity, maternal nutritional status, family size, smoke exposure,
and family history of atopy. We found that infants who were exclusively breastfed
for four months had a lower risk of acute respiratory infection compared to those
who were not exclusively breastfed for four months (Adjusted RR 0.06; 95% CI
0.03 to 0.13).
Table 2. Risk of acute respiratory infection (ARI)
Incidence of
ARIRR 95% Cl P value
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Exclusively breastfed (n= 90 )
Not exclusively breastfed (n=91)
23
76
0.07 0.033 to 0.140 0.0001
Table 3. RR for ARI adjusted for size for gestational age, parity, maternal
nutritional status, family size, smoke exposure, and history of atopy
Adjusted RR 95% CI P value
Exclusively breastfsd 0.06 0.03 toy. 13 0.001
Size for gestational age
Small gestational age 0.84 0.39 to 1.79 0.649
Parity
First parity 0.59 0.23 to 1.46 0.254
Maternal nutritional status
Under-nourished 1.60 0.79 to 3.22 0.186
Familv size
< 4 people 2.01 0.79 to 5.10 0.140
Smoke exposure
Yes 1.14 0.52 to 2.50 0.739
Family history of atopy
Yes 0.96 0.45 to 2.07 0.923
Discussion
There have been few Indonesian studies on the relationship between
exclusive breastfeeding and acute respiratory infection, particularly in low birth
weight infants. Most studies used normal weight, newborn infants as subjects. In
previous studies, infants given formula milk for four months were reportedly at
greater risk for acute respiratory infections compared to those who were
exclusively breastfed. Another study reported that shorter duration of
breastfeeding increased the risk of acute respiratory infections.
We found that exclusively breastfed low birth weight infants had a lower
risk of acute respiratory infection compared to those who were not exclusively
breastfed for the first four months of life.
It is thought that bioactive components in breast milk protect against acute
respiratory infections. Passive protection from breast milk affects the immune
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system's response by various mechanisms, such as the immune system's
maturation, anti-inflammation, immunomodulation, and antimicrobial activity.
Immune components found in breast milk, such as secretory
immunoglobulin A (slgA) and interferon, protect low birth weight infants from
infection. Also, skin to skin contact during breastfeeding stimulates the production
of specific antibodies from mothers against infection.
Secretory Ig A is- one of three main classes of immunoglobulins found in
colostrum and breast milk Secretory Ig A concentration in breast milk of mothers
with low birth weight infants is higher than in mothers with normal birth weight
infants.' Secretory Ig A can activate the complement system through alternative
pathway and in cooperation with macrophages can also phagocytize various
microorganisms. Secretory Ig A also plays an important role in the defense against
syncytial virus, and macroglobulin-like substance can inhibit influenza and
parainfluenza viruses.
The relatively short duration of follow-up was a limitation of this study.
The effects of exclusive breastfeeding were studied only until the infants were
four months of age. The recommended minimum duration of exclusive
breastfeeding for low birth weight infants is four months. Further research with a
longer duration of breastfeeding is needed to determine the long-term effect of
breastfeeding on acute respiratory infections.
In conclusion, in low birth weight infants, subjects who were exclusively
breastfed for the first four months of life had reduced risk of acute respiratory
infection compared to subjects who were not exclusively breastfed.
Acknowledgment
We would like to express our highest gratitude to I Gde Raka Widiana,
MD for his help in constructing the methodology and statistical analyses in this
study.
References
1. Pojda J, Kelley L. Low Birth Weight. ACC/SCN Nutrition Policy Paper.2000;2:18-28.
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2. Indonesian Ministry of Health. Peningkatan pemberian ASI sampai tahun2005. In: Utoro R. editor. Strategi nasional program for appropriate
technology in health. 1st ed. Jakarta: Depkes; 2005. p. 1-12.
3. Dinas Kesehatan Propinsi Bali. Data cakupan ASI tahun 2008. Dinaskesehatan Propinsi Bali: Denpasar; 2008.
4. Raisler J, Alexander C, O'Campo E Breastfeeding and infant illness: a dose-response relationship? Am J Public Health. 1999;89:25-30.
5. Chantry CJ, Howard CR, Auinger E Full breastfeeding duration andassociated decrease in respiratory tract infection in US children. Pediatrics.
2006;117:425-32.
6. Bachrach VRG, Schwarz E, Bachrach LR. Breastfeeding and the risk ofhospitalization for respiratory disease in infancy. Arch Pediatr Adolesc Med.
2003;157:237-43.
7. Duitjs L, Jaddoe V, Hofman A, Moll H. Prolonged and exclusivebreastfeeding reduces the risk of infectious disease in infancy. Pediatrics.
2010;126:18-25.
8. Alarcon ML, Villapando S, Arturo F. Breastfeeding lowers the frequency andduration of acute respiratory infection and diarrhea in infants under six months
of age. J Nutri 1996;127:436-42.
9. Maria AQ, Kelly Y], Amanda S. Breastfeeding hospitalization for diarrhealand respiratory infection the United Kingdom millennium cohort study.
Pediatrics? 2007;119:837-42.
10.Kelly DC. Early nutrition and the development of immune function in theneonate. Proc Nutr Soc. 2000;59:177-85.
11.Gross SJ, Buckley RH, Wakil SS, McAllister DC, David RJ, Faix RG.Elevated IgA concentration in milk produced by mothers delivered ot preterm
infants. J Pediatr. 1981;99.389-93.
12.Ryan E Kawaoka Y. cc2-macroglobulinis the major neutralizing inhibitor ofinfluenza. Am J Epidemiol. 1993;119:516-25.
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THE RELATIONSHIP BETWEEN PLEURAL EFFUSION INDEX AND
MORTALITY IN CHILDREN WITH DENGUE SHOCK SYNDROME
Novrianti Hawarini1, Muhammad Sholeh Kosim
1, M Supriatna
1, Yusrina
Istanti1, Eddy Sudijanto
2
Abstract
Background Dengue shock syndrome (DSS) mortality rate is still high. The
extenf of plasma effusion in dengue shock syndrome can be identified in the right
lateral decubitus position on chest x-ray, and quantified by the pleural effusion
index (PEI). It is thought that PEI value can be used to predict DSS mortality in
children. Pleural effusion in DSS patients can cause respiratory failure and death.
Objective To determine the relationship between PEI'and ' mortality in children
with DSS.
Methods This cross-sectional, retrospective study was held in the Dr. Kariadi
Hospital, Semarang, Indonesia. Data was taken from medical records of pediatricintensive care unit (PICU) patients with DSS from January 2009 to January 2011.
DSS diagnosis was confirmed by clinical and radiological manifestations. PEI
diagnosis was established by the presence of tluid in the pleural cavity on
pulmonary radiological examinations. X-rays were interpreted by the radiologist
on duty at the time. Chi square and logistic regression tests were used to analyze
the data. Results There were 48 subjects with DSS, consisting of 18 males (37.5
%), and 30 females (62.5%). Twenty-nine subjects (60.4%) survived and 19
(39.6%) died. One patient (2.1%) had.PEI 30% on their x-rays The
mortality rate of DSS with PEI 15-30% was 11.8% (95% CI 0.021 to 0.564;
P30% was 65.4 % (95% CI 3,581 to 99,642; P < 0.005).
Conclusion PEI > 15% was a risk factor for mortality in children with DSS.
[Paediatr Indones. 2012;52:239-42],
Keywords: pleural effusion index, mortality in dengue shock syndrome
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manifestations. PEI was assessed from lateral decubitus position on chest x-rays
and calculated by the formula A/B x 100% (Figure l).
Radiological examination results were reviewed by the on-duty
radiologist. We analyzed data using Chi square and logistic regression analyses
with SPSS software version 17.0.
Results
There were 48 PICU cases of DSS from January 2009 to Januari 2011,
consisting of 18 males (37.5%) and 30 females (62.5%). Twenty-nine subjects
survived (60.4%), and 19 died (39.6%), as shown in Table 1. Table 2 shows the
PEI groupings based on x-ray findings.
The relationship of PEI to death was observed in PEI values of greater
than 15%, with a statistically significant association in the two highest PEI
categories, 15-30% and > 30% (Table 3).
Discussion
This study was conducted to determine the relationship of plasma leakage
severity, as measured by PEI, to mortality in DSS patients.
Subjects' genders in our study were 37.5% male and 62.5% female. A
1987 Singaporean study reported a higher number of cases of men than women
with a ratio of 1.9 : 1, while a 1993 That study reported girls to be two times more
frequently hospitalized due to dengue. In a 1990 Indonesian study, cited from
Supriatna MS, there was no significant difference between males and females in
the number of DHF cases and shock events.
From a total of 48 DSS patients, 19 died (39.6%) and 29 lived (60.4%).
Nationally, DHF mortality rate was reported to be low (2.5% in 1997) and
remains to be below 3%.13 In Semarang in 2004, there were 1621 dengue cases
with an incidence rate of 11.8 per 10,000 population and a case fatality rate of
0.43%. DSS mortality in the Dr. Kariadi Hospital PICU decreased from 12% in
2002 to 10.8% in 2004.
Figure 1. Pleural effusion index calculation8
Table 1. Characteristics of subjects
Characteristics n = 48 %
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Sex
Male
Female
Mortality status
Survived
Died
18
30
29
19
37.5
62.5
60.4
39.6
DSS is defined as DHF with signs of circulatory failure, including narrow
pulse pressure (20 mm Hg), hypotension, or frank shock. The prognosis in DHF/
DSS depends on prevention or early recognition and treatment for shock. In
hospitals with experience in treating DSS, the case fatality rate in DHF may be as
low as 0.2%. Once shock has set in, the fatality rate may be much higher (12% to
44%).M Table 2. PEI groupings based on chest x-ray findings
PEI N = 48 %
30%
1
4
17
26
2.1
8.3
35.4
54.2
Table 3. Relationship of mortality rates to PEI
PEI Death n (%) OR 95% CI P
15-30%
>30%
2(11.8)
17(65.4)
0.110
18,889
0.021 to 0.564
3,581 to 99,642
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A limitation of our study was that we could not use a Kappa test for
radiologists' assessment-of x-ray findings, since this was a retrospective study.
Our study revealed a significant relationship between mortality rate from
DSS and PEI. In conclusion, PEI > 15% was a risk factor for mortality in children
with DSS.
References
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10.Committee of Epidemic Diseases. Surveillance for dengue fever/denguehemorrhagic fever in Singapore. Epidemiological News Bulletin (Singapore).
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Regional Office for South-East Asia; 1999.
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demam berdarah dengue. Yogyakarta: Medika FK UGM; 2004. p. 75-86.
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Diponegoro University; 2004.
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