Efficacy of Salbutamol

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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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46/49

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

1. Ngo NT, Cao XT, Kneen R, Wills B, Nguyen VM, Nguyen TQ, et al. Acutemanagement of dengue shock syndrome: a randomized double-blind

comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis.

2001;32:204-13.

2. Soegijanto S, Budivanto, Kartika, Taufik, Amor. Update management ofdengue complication in pediatric. Indonesian J Trop Infect Dis. 2011;2:1-11.

3. Catharina S, Tatty E. S, Eric CM, Robert J D, et al. Risk factors for mortalityin dengue shock syndrome (DSS). Media Medika Indonesiana. 2009;43:213-9.

4. Agaral R, Kapoor S, Nagar R, Misra A, Tandon R, Mathur A, et al. A clinicalstudy of the patients with dengue hemorrhagic fever during the epidemic of

1996 at Lucknow, India. Southeast Asian J Trop Med Public Health.

1999;30:735 40.

5. World Health Organization (WHO) Regional Office for South-East Asia.Guidelines for treatment of dengue fever/ dengue hemorrhagic fever in small

hospitals. New Delhi: WHO Regional Officer for South East Asia; 1999.

6. Alkrinawi S, Chernick V. Pleural fluid in hospitalized pediatric patients. ClinPediatr. 1996;35:5-9.

7. Syahrial R, Sukonco K, Iwan E. Radiologi diagnostik. Jakarta: GayaBaru;1998. p. 115-8.

8. Sathupan P Khongphattanayothin A, Srisai J, Srikaew K. The role of vascularendothelial growth factor leading to vascular leakage in children wi4i dengue

virus infection. Ann Trop Paediatr. 2007;27:179-84.

9. Vaughn DW Green S, Kalayanarooj S, Innis BL, Nimmannitya S,Suntayakorn S, et al. Dengue in the early febrile phase: viremia and antibody

responses. J Infect Dis. 1997;176:322-30.


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10.Committee of Epidemic Diseases. Surveillance for dengue fever/denguehemorrhagic fever in Singapore. Epidemiological News Bulletin (Singapore).

2002;28:25-30.

11.World Health Organization (WHO). Guidelines for case reporting andmanagement. Dengue fever and fengue hemorrhagic fever. New Delhi: WHO

Regional Office for South-East Asia; 1999.

12.Supriatna MS. Perbedaan gangguan fungsi hati pada demam berdarah dengue[master's thesis]. [Semarang]: Diponegoro University; 2004.

13.Setiati TE. Pengelolaan syok pada demam berdarah dengue anak. In:Sutaryo.Hagung P Mulatsih S, editors. Tatalaksana syok dan perdarahan pada

demam berdarah dengue. Yogyakarta: Medika FK UGM; 2004. p. 75-86.

14.Rigau-Perez JG, Clark GG, Guhler DJ, Reiter R Sander EJ, Vorndam AV.Dengue and dengue haemorrhagic fever. Lancet. 1998;352:971-7.

15.Setiati TE. Faktor hemostasis dan faktor kebocoran vaskular sebagai faktordiskriminan untuk memprediksi syok pada DBD [dissertation]. [Semarang]:

Diponegoro University; 2004.

16.Pramuljo HS. Peran pencirraan pada demam berdarah dengue. In: Harun SR,Safari HI, editors. Naskah lengkap pelatihan bag! pelatih dokter spesialis anak

dan dokter spesialrs ptnyakit dalam. Jakarta: BP FKUI; 2000. p. 63-72.

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