Is Salbutamol and Adrenalin Inhalation Effective in Management of Transient Tachypnia of Newborn?

work carried out in collaboration between all authors. Authors FN and HAA designed the study, the protocol and wrote the first draft of the manuscript. Author SH managed the literature searches and analyses of the study performed the spectroscopy analysis. Author MAEM managed the experimental process. Author HAA identified the species of plant. All authors read and approved the ABSTRACT Background: In Conclusion: Inhaled Salbutamol resulted in better outcome in decreasing the respiratory rate, TTN clinical score, lower FIO 2 , higher O 2 saturation, decreasing the duration of respiratory support along with the total duration of hospitalization.


INTRODUCTION
Postnatal respiratory complications among term infants are common. The most commonly reported cause of neonatal respiratory distress in late preterm is transient tachypnea of the newborn [1].
The disorder is reported to be benign and selflimiting, with resolution usually occurring by 2 to 5 days of age. In uncommon severe courses of transient tachypnea of the newborn, complications such as pneumothorax need for extracorporeal membrane oxygenation, and death have been reported [2].
There are increasing data to suggest that transient tachypnea of the newborn increases a newborn's risk for developing a wheezing syndrome early in life [3]. Throughout gestation, the presence of an adequate amount of lung fluid is critical for normal lung growth and for the development of the fetal lung to complete transition from intrauterine to extra uterine life [4]. Most interstitial lung liquid moves into the pulmonary circulation and some drains via the lung lymphatic vessels [5]. Transient tachypnea of the newborn is believed to result from delayed resorption of fluid from the lungs of the newborn, which is an important diagnostic and therapeutic dilemma in the NICU [6]. Lung liquid clearance at birth is associated with the surge in fetal catecholamines acting via b-adrenergic receptors located in alveolar type II cells and driven by active sodium (Na+) absorption by increased epithelial Na+-channels (ENaC) and sodium-potassium adenosinetriphosphatase (Na+-K+-ATPase) activity [7].
The inability of the fetal lung to switch from fluid secretion to fluid absorption and an immaturity in the expression of the ENaC may play an important role in the development of TTN [8].
Both experimental and limited clinical data in adult patients suggest that inhaled or intravenous beta adrenergic agonists accelerate clearance of excess fluid from the alveolar airspace, creating the possibility of their use for treatment of pulmonary edema and acute lung injury [9].
To prevent the systemic side effects of beta agonists, aerosolized beta agonists have been used in the therapy of transient tachypnea of the newborn [10].
Evaluation of inhalation therapy by BETA-2 agonist salbutamol and epinephrine for the management of transient tachypnea of newborn.

Patients
The study was a prospective randomized control study. It included 60 neonates (35 males and 25 females) diagnosed clinically and radiologicaly as TTN, who was selected from NICU of Sayed Galal University Hospital between June 2013 and June 2014. The study was approved by the Institutional Ethical Committee.

The studied neonates were divided into three groups randomly:
Group 1: It included 20 neonates with gestational age >35 weeks and postnatal age <6 hours old, diagnosed clinically and radiologicaly as TTN and received one dose of inhaled epinephrine (the dose is 0.05 ml/kg). The drug was nebulized with 100% oxygen. Group 2: It included 20 neonates with gestational age >35 weeks and postnatal age <6 hours old, diagnosed clinically and radiologicalyas TTN and received one dose of inhaled salbutamol (the dose is 0.15 mg/kg). The drug was nebulized with 100% oxygen. Group 3: It included 20 neonates with gestational age >35 weeks, postnatal age <6hours old and Downs' score >4, diagnosed clinically and radiologicaly as TTN as a control group they inhaled saline 0.45%.
Written informed consents were obtained from all the parents of the study patients.
Chest radiograph indicating at least one of the following: Prominent central vascular marking, Widened interlobar fissures of pleural fluid Symmetrical perihilar congestion and Hyperaeration as evidenced by flattening and depression of the diaphragmatic domes or increased anteroposterior diameter or both.
The excluded neonates were one of the following: Gestational age <35 weeks, Respiratory distress syndrome, Sepsis and pneumonia, Meconium aspiration, Congenital cardiac diseases, Perinatal asphyxia, Congenital lung malformation, Non respiratory causes of respiratory distress (hypocalcaemia, metabolic acidosis, persistent hypoglycemia and polycythemia), Persistent pulmonary hypertension of the newborn and Newborn with ventilation support or arrhythmia.

Clinical examination
-Gestational age assessment, weight in kilograms, sex (male or female), Assessment of gestational age, (before inhalation therapy) by new Ballard score.
-Complete examination including cardiac, chest, abdominal, and neurological examination (before inhalation therapy).
-Down's Score for evaluation of respiratory distress before inhalation therapy and after inhalation therapy at 30 minutes, 1 hour and 4 hours. -Heart rate (before inhalation therapy and after inhalation therapy at 30 minutes, 1 hour and 4 hours.). -Respiratory rate (before inhalation therapy and after inhalation therapy at 30 minutes, 1 hour and 4 hours.). -Duration of respiratory support (in hours), and duration of hospitalization (in days).
-FiO 2 (%): (at the time of diagnosis, after 0.5 an hour, after 1 hour, after 4 hours). FiO 2 (fraction of inspired oxygen) and level of respiratory support are measured as follow: FiO2 = (Flow Rate(in LPM) x 4) +21% -O2 saturation: At the time of diagnoses, after 0.5 an hour, after 1 hour, after 4 hours. Heart rate and oxygen saturation were assisted by pulse oxymeter.

Chest X-ray
Chest X-ray was done initially before intervention to confirm the diagnosis.

Statistical Method
Results on continuous measurements are presented as Mean + SD. Data obtained were analyzed by one way analysis of variance through graphpadinstat program.

Demigraphic Data
In this study, 60 neonates diagnosed clinically and radiologicaly as TTN were divided into three groups randomly as Group I (inhaled Epinephrine), Group II (inhaled Salbutamol) and Group III (inhaled saline) for the management of transient tachypnea of newborn.
There was no statistical significant difference between groups in sex distribution or birth weight or gestational age. There was also no significant difference between groups in mean readings of APGAR score (Table 1).

pH and Blood Gases
There were significant differences (p<0.001) between groups in pH, PaO 2 , PaCO 2 after nebulization. Saline group recorded the lowest readings of pH and PaO 2 in comparison to the other groups, but the highest reading in PaCO 2 . In salbutamol group: there was significant increase (p<0.001) in PH, PaO 2 and significant decrease (p<0.001) in PaCO 2 after nebulization.
On the other hand, the difference between after and before exhibited a significant difference in group I and II for pH (see Table 2).

Oxygen Saturation and FiO 2
There was significant difference (p<0.001) between groups in O 2 after 1 & 4 hours.
Adrenaline group recorded the lowest readings in comparison to the other groups. There was significant difference (p<0.001) between groups in FiO 2 after 4 hours, salbutamol group recorded the least readings in comparison to the other groups. For SpO 2 , difference between after and before recorded a significant difference in group II (p<0.001). Also, the same result for FiO 2 was recorded (for more details see Table 3).

Heart Rate and Respiratory Rate
There was significant difference between groups in heart rate before and after nebulization. Adrenaline group recorded the highest readings in comparison to the other groups after nebulization. There was significant difference between groups in respiratory rate after 1(p<0.01) & 4 (p<0.001) hours, salbutamol group recorded the least readings in comparison to the other groups. In salbutamol group: there was no significant change in heart rate but significant decrease (p<0.001) in respiratory rate 4 hours after nebulization in comparison to base line readings. No significant difference was recorded for HR in the difference between after 4h and before. However, a significant difference (p<0.001) was recorded in RR group II for the difference between after 4h and before (for more details see Table 4).

Downes' Score
There was a significant difference (p<0.001) between groups in Downes' score after 1 & 4 hours, salbutamol group recorded the least readings in comparison to the other groups. On the other hand, a significant difference (p<0.0001) was exhibited in group II for the difference in Downes' scores before and after 4h (see Table 5).

Duration of Respiratory Support and Duration of Hospital Stay
There was a significant difference (p<0.001) between groups in duration of respiratory support and duration of hospital stay. Salbutamol group recorded the least duration in both parameters in comparison to the other groups.

DISCUSSION
In an attempt to evaluate the role of inhaled salbutamol versus inhaled epinephrine in the treatment of TTN this study was conducted on 60 neonates (35 males and 25 females) diagnosed clinically and radiologicaly as TTN.
In this study there was predominance for males than females (58.3%: 41.6%) this was in agreement with [4]; [10] who observed male predominance in TTN. Caesarian section was the mode of delivery of 37 neonates (61.6%) and no recorded neonates had history of PROM (which may need more cases). Eight neonates (0.13%) had history of maternal gestational diabetes while 6 (10%) had history of maternal asthma.
Similarly, [8] found that main risk factors for TTN are cesarean delivery, large birth weight, maternal gestational diabetes, maternal asthma, twin pregnancy, and male gender.
In this study, caesarian section was the mode of delivery of 37 neonates (61.6%) and this is similar to several studies that documented the high incidence of respiratory distress, TTN and NICU admissions in infants born by cesarean delivery before the onset of spontaneous labor [11][12][13][14][15][16][17].
Vaginal delivery has two mechanisms by which it decreases the risk of TTN, the first is: mechanical effect as fetal thorax compression during labor leads to the loss of large volumes (25-35%) of liquid from the lung. Although 'vaginal squeeze 'during the progression of the chest through the birth canal is thought to be the main physical force, uterine contraction during labor impose fetal postural changes leading to compression of the thorax [18]. The second mechanism is through the release of fetal adrenaline that occurs late in labor which stimulates pulmonary epithelial cells to stop secreting and start absorbing lung fluids. Labor increases clearance of alveolar fluid even in infants delivered by CS. TTN occurs less frequently in neonates delivered after the onset of labor compared with those delivered before labor [1].
In our study there were 6 asthmatic mothers (10%). Maternal asthma is considered to be an independent factor for TTN. Infants with TTN at birth are at risk of developing asthma or (wheezing) later in life. Genetic predisposition for β-adrenergic hyper responsiveness may cause TTN in newborn period, and asthma/wheezing in older age group. It seems that TTN may be the first sign of asthma [3,19].
The most profound finding in TTN is tachypnea, starting in the first 1 to 2 hours after delivery, and the respiratory rate can reach 60 to 120 breaths/min [6]. Prolonged tachypnea can increase the duration of hospitalization, the use of antibiotics and parental anxiety [20]. [21] determined the respiratory rate over 90 breaths/min at 36th hour after delivery, as a predictive value in terms of prolonged tachypnea.
In our study we observed that the respiratory rate decreased with salbutamol inhalation than control and epinephrine group that was in agreement with [22].
In our study there was transient rise in the heart rate in salbutamol and epinephrine groups. That was in agreement with [10], but was not in agreement with [22], who did not record increase in heart rate.
The duration of respiratory support and hospitalization duration decreased with salbutamol inhalation than control. That was in agreement with [22]. The duration of respiratory support and hospitalization duration decreased with epinephrine inhalation than control. In comparison between salbutamol and epinephrine inhalation, the duration of respiratory support and the duration of hospitalization were less with salbutamol than epinephrine inhalation.
Comparing studied groups after intervention, highly significant lower respiratory rate, Downs' scores, respiratory support and duration of hospital stay was detected in group II (salbutamol group) while no significant difference between groups regarding heart rate after 4 hours from intervention. Similar to our results, [4] found that inhaled salbutamol in infants with TTN, decreases in respiratory rate, and TTN clinical score significantly while non-significant difference regarding heart rate was detected; also they found the improvement in the level of respiratory support was statistically significant with inhaled salbutamol that was in agreement with [22]. On the other hand [10], found no significant difference between inhaled epinephrine and saline inhalation regarding clinical data.
Regarding ABG findings after intervention, PH, PaO 2 and O 2 saturation were significantly higher in group II (inhaled salbutamol), PaCO 2 , FiO 2 were significantly lower in group II. No significant difference was detected between groups regarding serum glucose and serum potassium that coincides with [23,24] who said that, serious bronchospasm, arrhythmias, hypokalemia, and hyperglycemia caused by glycogenolysis have been reported rarely. We didn't report any other adverse effects.
Similar to our results [4], found significantly higher PH, PaO 2 and significantly lower PaCO 2 , FiO 2 in salbutamol group.

CONCLUSIONS
This prospective trial showed that a single dose of inhaled Salbutamol resulted in better outcome in decreasing the respiratory rate, TTN clinical score, lower FiO 2 , higher O 2 saturation, decreasing the duration of respiratory support along with the total duration of hospitalization.
Salbutamol inhalation was better than Epinephrine inhalation in decreasing the respiratory rate, TTN clinical score, higher O 2 saturation, and decreasing the duration of respiratory support and the total duration of hospitalization.

RECOMMENDATIONS
1. Inhaled salbutamol can be used in treatment of transient tachypnea of newborn to improve respiratory distress and outcome 2. Larger studies are recommended to verify the efficacy of inhaled salbutamol or epinephrine as a therapeutic intervention for this common respiratory condition.