a b s t r a c t

Objectives: The aim of this study was to determine whether plasma levels of amino-terminal Brain natriuretic peptide could differentiate between heart failure and lung disease among infants with acute bronchiolitis. Methods: Sixty-eight infants (age range, 1-26 months; median age, 5.9 +- 5.0 months) who presented with respiratory distress underwent physical examination, plasma BNP measurement, and echocardiography within 24 hours after ad- mission. Nineteen (28%) patients had congenital heart disease. The control group was consisted of 30 healthy infants. Results: Although mean plasma BNP levels were 118.9 +- 219.5 pg/mL in patients with isolated bronchiolitis (n = 49), it was 841.2 +- 1475.8 pg/mL in patients with congenital heart disease (n = 19). Plasma BNP levels were significantly higher in infants with congenital heart disease (P = .001).

Conclusion: It was shown that plasma BNP levels were affected much more in cardiac disease rather than lung disease. Among infants with respiratory distress, plasma BNP measurements can differentiate congenital heart disease and lung disease and can be used to monitor the effects of treatment for infants with heart failure.

Response to reviewers: The comments were taken for consideration. The patient groups control BNP levels were attached to the results. As it was a clinical study and multiple factors (respiratory score, respiratory rate, treatment, etc) may effect on BNP levels, the tables could not be decreased to 1 table.

(C) 2015

Many cardiac Disease states (ventricular septal defect [VSD], patent ductus arteriosus, coarctation of aorta, cardiomyopathy, etc) can mimic the more common illnesses of childhood, such as bronchiol- itis, reactive airway disease, and sepsis [1]. Acute bronchiolitis, one of the most common diseases of this group, is most commonly seen in children aged younger than 2 years. Acute bronchiolitis, which is characterized by cough, wheezing, tachypnea, retractions on the chest, and prolonged expiration, is because of small airway obstruction caused by viral agents [2].

Although echocardiography (ECO) is a good diagnostic tool for the diagnosis of congenital heart disease and ventricular dysfunction, it is not available in every clinic [3]. Because of that, a sensitive, reachable marker to aid in the recognition of heart disease and lung disease in children will be useful [1].

Recently, brain natriuretic peptide levels were found to be reliable test for the diagnosis of underlying cardiovascular disease in infants with respiratory distress [3]. Nowadays, the usage of BNP and N-terminal ProBNP (NT-proBNP) in children with congenital heart diseases is increasing gradually [4-9]. It seems to be reliable to use

? Conflict of interest: The authors do not have any conflict of interest.

* Corresponding author at: 225 Sok. No.: 59 Kat: 3 D: 6, Karesi Balikesir. Tel.: +90

5055407144.

E-mail address: [email protected] (U. Karadas).

Natriuretic peptides as a marker in children with congenital heart disease [10].

Brain natriuretic peptides especially induce natriuresis, diuresis, and vasodilatation and secreted mainly by cardiac myocytes in response to ventricular volume increase and pressure [11]. Brain natriuretic peptide is first secreted as a preprohormone with 134 amino acids and then converts to proBNP, which consists of 108 amino acids [12]. Pro-brain natriuretic peptide consists of inactive NT-proBNP and active BNP [12]. Active form of BNP is released after the N-terminal part of the proBNP is cut off [12].

In this prospective study, we sought to evaluate the effect of BNP as a marker to differentiate cardiac- or lung-related respiratory distress in patients who were hospitalized with acute bronchiolitis in infancy.

Materials and methods

This study was performed at Izmir Tepecik Hospital Pediatrics Department between August 2012 and August 2013. Hospitalized 68 patients with respiratory distress accompanying acute bronchiolitis were enrolled to the study. Nineteen (28%) patients had congenital heart disease (9 patients had VSD, 4 patients had Atrial septal defect and VSD, and 2 patients had VSD and patent ductus arteriosus) and cardiomyopathy (4 patients had dilated cardiomyopathy).

http://dx.doi.org/10.1016/j.ajem.2015.02.005

0735-6757/(C) 2015

698 T. Sahingozlu et al. / American Journal of Emergency Medicine 33 (2015) 697-700

Local ethical committee approved the study. Informed consents were taken from the parents. Thirty patients who admitted to hospital because of minor orthopedic and urologic problems and whose respira- tory and cardiovascular examinations were normal were enrolled to the study as control group.

The acute bronchiolitis was diagnosed with history and physical examination [2], and anterior posterior lung x-ray was performed to all of the patients. Except chronic lung disease and heart disease, the pa- tients with chronic illnesses such as immune deficiency, renal failure, cerebral palsy, etc, and the patients with severe pneumonic infiltrations in lung x-ray were excluded. Respiratory scoring was performed accord- ing to the patients’ general appearance, respiration rate, heart rate, and retractions on the chest wall to evaluate the severity of the disease [2]. According to the respiratory scores, the patients between 0 and 3 points were classified as mild, 4 and 8 points as moderate, and 9 and above as severe bronchiolitis. The oxygen saturations at room air, heart rates, and respiration rates are recorded.

The blood samples of both patient and control group were obtained in EDTA- and aprotinin-containing tubes. Three-milliliter venous samples were taken, and BNP levels were measured with electrochemiluminescence immunoassay immediately. ADVIA Centaur BNP lite reagent and Solid Phase kit were used. The echocardiographic evaluation was performed within the first 24 hour of BNP measurement. The echocardiographic evaluations (2 dimensions, M mode) were performed by a pediatric car- diologist with Philips Ultrasound System and S8-3 probe. The conven- tional echocardiographic measurements were calculated according to the American ECO Association recommendations [13]. The left ventric- ular dimensions were measured on Parasternal long axis with M mode ECO, and ejection fraction (EF) and fractional shortening were calculated with Teicholz formulation [14].

The effect of plasma BNP level to sex, age, and heart rate was evalu- ated, then the effect of BNP level to clinical findings (oxygen saturation, respiration rate, follow-up duration, and treatment), the presence of cardiac disease, or heart failure.

The analysis was performed by SPSS 17.0 statistic program (Chicago, IL). The mean and SDs of digital values were calculated. Mann-Whitney U test was used to compare 2 groups because the groups were not homogenous. Kruskal-Wallis test was used to compare mean BNP levels of 3 groups (presence of heart disease or not and control group). ?² test was used in categorical data, and Fisher exact test was used when the expected numbers were lower. The findings were accepted significant if P b .05.

Results

A total of 68 patients (22 girls, 32%) were enrolled to the study. The control group was consisted of 30 children, and 27% [8] of them were girls. The patient and control groups mean ages were 5.9 +- 5.0 (1-26) and 6.5 +- 5.4 months, respectively, and there were no significant difference in age and sex between these groups (P = .82 and P = .89). The mean oxygen saturation, respiration rate, and follow-up duration were shown in Table 1. Before oxygen therapy, in 10 patients (15%), oxygen saturation was above 92%. In 20 patients (29%), respira- tion rate was greater than 60/min, and 11 (16%) patients were hospital-

ized more than 10 days.

It was observed that age (P = .397), sex (P = .187), and heart rate (P = .240) had no significant effect on BNP levels. Subsequently, the

Table 1

The mean age, follow-up duration, respiration rate, and oxygen saturation

patient group and control group and the patients with heart disease or not were compared according to BNP levels. P value was .004 and

.001, respectively. The differences between these groups were found significant (Table 2) (Figure). The mean BNP levels of patients with heart disease were significantly higher. When the respiratory rates and respiratory scores were compared in patients with congenital heart disease and without congenital heart disease according to BNP levels, no significant difference was found (Table 3).

The BNP levels of 35 patient (11 of them had coronary heart disease) were taken again when they came to control after hospitalization. Although the mean control BNP levels of patients with congenital heart disease was 210 +- 50.5 pg/mL, it was 40 +- 28 pg/mL in patients without congenital heart disease.

By echocardiographic evaluation, mean EF was found 68.3 +- 8.3 (42-79) in patient group. The difference was found significant when the EF of patient with heart disease and patients with no heart disease were compared. The mean EF were 64.0 +- 10.5, 70.0 +- 6.7; P = .007, respectively.

The comparison of greater than or equal to 10 days’ follow-up with less than 10 days’ follow-up, oxygen saturation less than 92% with great- er than or equal to 92%, respiration rate less than or equal to 40/min with greater than 40/min, and mild-moderate respiratory score with severe respiratory score according to BNP levels were shown in Table 2. It was shown that follow-up duration, oxygen saturation, and respiratory score had no significant effect on BNP levels (Table 2).

The mean BNP levels of patients with congestive heart failure (in 14 patients, 21%, 13 of them had heart disease) were significantly higher than patients with no congestive heart failure (P b .001) (Table 4).

It was seen that 44 patients (66%) took systemic steroid, 18 patients (27%) took intravenous diuretic, and 17 patients (25%, all of them had heart disease) took digoxin treatment. According to the respiratory score, 7 (10%) patients had mild, 45 (66%) patients had moderate, and 16 (24%) patients had severe respiratory distress. The BNP levels of the study group were compared according to the applied medical treat- ment (Table 4). Although no significant difference was found between patients who had taken systemic steroid and patients who had not taken (P = .731), the BNP levels were significantly higher in patients who had taken intravenous diuretics when compared with patients who had not taken (P = .001) (Table 4).

Discussion

The major clinical findings are tachypnea, tachycardia, fatigue, decreased activity, and hepatomegaly in cardiac failure secondary to acquired or congenital heart diseases (coarctation of aorta, car- diomyopathy, and pulmonary hypertension, etc). Even with a care- ful history, physical examination and the presence of pulmonary congestion, the diagnosis of cardiac failure may be difficult [3],

Table 2

The relationship between BNP levels and follow-up duration, oxygen saturation, and fre- quency of respiration

		Mean BNP	P
		levels (pg/mL)
Study group	Patient, n = 68	320.7 +- 852.2	.004
	Control, n = 30	11.6 +- 9.40
Heart disease	(+), n = 19	841.2 +- 1475.8	.001
	(-), n = 49	118.9 +- 219.5

Follow-up duration >=10 d, n = 25 132.2 +- 218.3 .962

b10 d 129.0 +- 147.9

Oxygen saturation b92%, n = 17 213.8 +- 256.3 .053

No. of patients, n = 68	Mean (+-2 SDs)	Interval	Frequency of respiration	>=92% <=40/min, n = 9	90.0 +- 85.5 301.5 +- 242.6	.061
Age (mo)	5.9 +- 5.0	1-26		N 40/min	111.6 +- 152.2
Follow-up duration (d)	9.0 +- 5.2	1-31	Respiratory score	Mild-moderate,	258.4 +- 691.0	.935
Respiration rate (/min)	55.3 +- 12.7	17-80		n= 52
Oxygen saturation (%)	93.7 +- 4.6	80-100		Severe	243.6 +- 403.4

T. Sahingozlu et al. / American Journal of Emergency Medicine 33 (2015) 697-700 699

Figure. The mean BNP levels of patients with isolated bronchiolitis, patients with congen- ital heart disease, and control group (P b .001). One patient with isolated bronchiolitis and 2 patients with congenital heart disease BNP levels were too high from their groups’ mean BNP levels.

as these symptoms can be seen in many childhood disease (viral in- fections, reactive airway disease, sepsis, etc)[1]. The diagnosis may be more difficult if pneumonia and bronchiolitis accompany with chronic heart failure and may be difficult to understand whether it is an early finding of heart failure [3]. Because of that, a specific bio- marker for heart disease will be very useful to differentiate such pa- tients [1]. Although the natriuretics are described recently, as they have an important role in cardiovascular system, they are useful markers in heart disease that may cause heart failure [12]. To deter- mine the diagnosis, prognosis, and response to treatment of conges- tive heart failure, the usage of plasma BNP level measurements is increasing in daily practice [10,12,15-17]. The usage and clinical im- portance were investigated in few studies, and they reported that BNP levels can be used in children [3,4,11,12,18]. Its usage in clinical practice in children with heart disease is increasing gradually [1].

In a study, which was done by Hammerer-Lercher et al [10], they showed no significant difference in Nt-proBNP levels between control group and lung disease group. The NT-proBNP levels of patients with heart disease were significantly higher than lung disease group and con- trol group in the same study. Similar to this study, the NT-proBNP levels of children aged older than 14 years were compared and found signifi- cantly high in heart failure group [8]. Koch and Singer [19] compared 23 infants who had previously diagnosed heart disease and presented with respiratory distress and 26 infants who presented with noncardiac respiratory distress. The infants with noncardiac respiratory distress had mean BNP level of 45.2 pg/mL, whereas the infants with cardiac disease and respiratory distress had a mean BNP level of 693 pg/mL. A study by Cohen et al [3], who used BNP, demonstrated no significant elevation in BNP levels for infants with respiratory distress, whereas infants with congestive heart failure had Elevated BNP levels, with no overlap to the respiratory disease group. Similar to that study, we found that BNP levels were significantly higher in patients with heart disease and/or heart failure than isolated bronchiolitis. Although mean plasma BNP levels were 118.9 +- 219.5 pg/mL in patients with isolated bronchiolitis, it was 841.2 +- 1475.8 pg/mL in patients with congenital

Table 4

Comparing the BNP levels between patients with heart failure and with no heart failure, and between patients using systemic steroid, diuretic or not

	Patient group, n = 68	Mean BNP levels (pg/mL)	P
Heart failure	(+), n = 14	1122.1 +- 1653.3	b.001
	(-)	112.9 +- 184.5
Systemic steroid	(+), n = 44	238.9 +- 745.8	.731
	(-)	295.8 +- 355.1
Diuretics	(+), n = 18	663.9 +- 1121.2	.001
	(-)	107.7 +- 165.1

heart disease. Among infants with respiratory distress, plasma BNP measurements can differentiate heart disease and lung disease and can be used to monitor the effects of treatment for infants with heart failure.

Kunii et al [4] reported that mean plasma BNP levels were 5.3 +- 3.8 pg/mL in 253 heathy children aged 0 to 16 years. Kawamura et al [20] reported that maximum plasma BNP level was 32.7 pg/mL in 26 patients aged 2 months to 10 years with viral infections. As similar, the BNP levels of control group were low (11.6 +- 9.40 pg/mL) in our study. Although there were acute bronchiolitis patients with systemic steroid need (238.9 +- 745.8 pg/mL) and high respiratory score (243.6 +- 403.4 pg/mL), BNP levels were not as high as the patients with heart failure and/or heart disease (1122.1 +- 1653.3 and 841.2 +- 1475.8 pg/mL, respectively). It is no matter how severe the clinic of iso- lated acute bronchiolitis is; the BNP levels were lower than patients with heart disease. For this reason, the plasma BNP level was thought to be affected much more in heart-related respiratory distress.

Conclusion

It was shown that respiratory-related parameters such as systemic steroid usage, respiratory score, and oxygen saturation did not have a significant effect on BNP levels. Controversely, BNP levels of patients with heart disease and/or heart failure were significantly higher. It was shown that plasma BNP levels were affected much more in cardiac disease rather than lung disease. Among infants with respiratory dis- tress, plasma NT-proBNP measurements can differentiate heart disease and lung disease. As the BNP levels were decreased by clinical improve- ment, the BNP levels can be used to monitor the effects of treatment for infants with heart failure.

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   Table 3

   Comparing the BNP levels, respiratory rates, and respiratory scores between patients with heart disease and without heart disease and control group

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