|Year : 2020 | Volume
| Issue : 3 | Page : 847-851
The effects of inhaled β-adrenergic agonists in transient tachypnea of the newborn
Dalia M Al Lahony1, Hanan M Elsayed1, Ismail S Mohammed2
1 Department of Paediatric and Neonatology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Paediatric and Neonatology, Qaha General Hospital, Qaha, Qalyubia Governorate, Egypt
|Date of Submission||04-Oct-2018|
|Date of Decision||09-Dec-2018|
|Date of Acceptance||15-Dec-2018|
|Date of Web Publication||30-Sep-2020|
Ismail S Mohammed
El Qanater El Khayreya, Qalyubia Governorate
Source of Support: None, Conflict of Interest: None
The objective of this study was to evaluate the efficacy of inhaled salbutamol for the treatment of transient tachypnea of the newborn (TTN).
The most commonly reported cause of neonatal respiratory distress is TTN, with estimated incidence of 0.5–2.8% of all newborn.
Patient and methods
This is a randomized controlled trial study considering patient with even registration number as cases. Inhaled salbutamol or normal saline solution was administered to 60 infants diagnosed as having TTN. The response was evaluated by determining respiratory rate, heart rate, TTN clinical score, and level of respiratory support, before and at 30 min and 1 and 4 h after drugs therapy. The standard dose of salbutamol was 0.15 mg/kg added to 2 ml normal saline. The second group received dose of 2 ml nebulized (0.9%) normal saline only.
The studied neonates were between 36 and 39 weeks of gestation. There were 30 (50%) males and 30 (50%) females. Comparing the two groups after 4 h of inhaled therapy, highly significant lower respiratory rate, oxygen, TTN score, respiratory support, and duration of hospitalization were detected in salbutamol group rather than saline group. Regarding arterial blood gas findings after 4 h of inhaled therapy, pH and partial pressure of arterial oxygen were significantly higher in salbutamol group than saline group. No significant difference was detected between the two groups regarding heart rate and serum potassium.
A single dose of inhaled salbutamol resulted in better clinical aspect and better laboratory outcome measures in cases of TTN.
Keywords: β-2 agonist, newborn, respiratory distress, salbutamol, transient tachypnea
|How to cite this article:|
Al Lahony DM, Elsayed HM, Mohammed IS. The effects of inhaled β-adrenergic agonists in transient tachypnea of the newborn. Menoufia Med J 2020;33:847-51
|How to cite this URL:|
Al Lahony DM, Elsayed HM, Mohammed IS. The effects of inhaled β-adrenergic agonists in transient tachypnea of the newborn. Menoufia Med J [serial online] 2020 [cited 2020 Nov 26];33:847-51. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/847/296661
| Introduction|| |
Transient tachypnea of the newborn (TTN) is a common condition in the full-term or late preterm infant, with an estimated incidence of between 0.5 and 2.8% of all deliveries . TTN is a self-limiting condition. Treatment for TTN comprises supportive care, including supplemental oxygen, withholding of enteral feeds, and administration of intravenous fluids ,. TTN is thus a nontrivial cause of neonatal respiratory distress despite its transient nature; it may lead to the substantial consumption of healthcare resources. Infants rarely require mechanical ventilation and continuous positive airway pressure. Occasionally, some newborns develop severe hypoxemia that requires high concentrations of oxygen. Potential therapies for TTN must be based on an understanding of the physiology of normal fetal lung fluid clearance at birth. In the few minutes after birth, endogenous catecholamine and activation of the β-adrenergic system assist the lung epithelium to transition, from a secretory to an absorptive mode by inducing active sodium transport across the pulmonary epithelium ,,. Stimulation of β-adrenergic receptors with β-2 adrenergic agonists upregulates alveolar epithelial Na + transport by increasing the activity of epithelial Na + channels (ENaC) and Na +–K +-ATPase and protein abundance at the plasma membrane ,.
A wide range of drugs are commonly used to treat TTN, but evidence of their effectiveness is limited.
The aim of this study was to evaluate the efficacy of inhaled salbutamol for the treatment of TTN.
| Patients and Methods|| |
This study was conducted as a randomized control clinical trial of inhaled salbutamol, or saline on 60 neonates who were diagnosed as having TTN in the neonatal ICU of Pediatric Department of Menoufia University Hospital in the period from March 2017 to December 2017. Written informed consents were obtained from parents or care givers, which was approved by Ethical Committee of Faculty of Medicine, Menoufia University. The studied neonates were divided into two groups: group I (saline) and group II (salbutamol). The infants were more than 36 weeks of gestation. There were 30 males and 30 females.
Patients were eligible for enrollment if they had completed more than 36 weeks of gestational age, were less than 6 h old at the time of enrollment, and had TTN. The diagnosis of TTN was established according to the criteria of Rawlings and Smith on the basis of radiologic and laboratory findings . Chest radiography, acute-phase reactants, complete blood counts, blood glucose, and calcium levels were determined in all cases.
At enrollment (by the 6th hour), respiratory rate (breaths/min), heart rate (beats/min), blood oxygen saturation, complete blood count, blood glucose and potassium (K +), arterial blood gases [pH, partial pressure of arterial oxygen (PaO2), partial pressure of arterial carbon dioxide (PaCO2)], and TTN clinical scores were recorded. The scoring system of the Respiratory Distress Assessment Instrument was used for our hospital assessment of the TTN clinical score. Parameters of this score are signs of respiratory distress (nasal flaring, expiratory grunting, subcostal retraction, and cyanosis), with each parameter of four scores according to its severity (0, 1, 2, and 3 points) .
Inhaled salbutamol, or normal saline solution was administered to 60 infants with gestational ages more than 36 weeks of gestation and diagnosed as having TTN. The response to inhaled drugs therapy will be evaluated by determining respiratory rate, heart rate, and clinical score of TTN and level of respiratory support, before and at 30 min and 1 and 4 h after drugs therapy. The duration and level of total respiratory support will be assigned along with the duration of hospitalization. The standard dose of salbutamol is 0.15 mg/kg added to 2 ml normal saline then given with nebulizer with continuous flow of oxygen at 5–6 l/min . One dose was administered over the course of 20 min, and the second group received dose of 2 ml nebulized 0.9% normal saline only.
Respiratory rate, heart rate, TTN clinic score, PaO2, PaCO2, pH, blood glucose, level of respiratory support, and blood K + values of 0.5, 1, and 4 h were separately assessed for each patient in both groups and recorded. The level of respiratory support was categorized into five levels (no oxygen, intraincubator oxygen, hood pox, nasal cannula, and nasal continuous positive airway pressure). All the patients in the two groups were in level of 3 for respiratory support. Intravenous fluids (60 ml/kg/day) were given for the first postnatal day; in no case was antibiotic therapy administered, and no infants required mechanical ventilation and continuous positive airway pressure.
Mann–Whitney U and Kolmogorov–Smirnov tests were used with abnormal distributions. Statistical analyses were performed using the statistical package for social sciences, version 16 (SPSS Inc., Chicago, Illinois, USA). For categorical variables, the chi square test was used. For group comparisons, the Student t-test was used with parametric data, and the Mann Whitney U test and Friedman test were used for repeated measurements for nonparametric data. For descriptive statistics, percentage, minimum–maximum, median, mean, and SD were used in accordance with the type and distribution of the variable. A result was considered statistically significant for values of P less than 0.05. Significant results of Friedman test were followed by post-hoc analysis for multiple comparisons using Bonferroni's adjusted Wilcoxon test at adjusted P value of 0.008 to detect the significant pairs.
| Results|| |
The studied neonates were between 36 and 39 weeks of gestation. There were 30 (50%) males and 30 (50%) females, with mean gestational age of 37.9 ± 0.88 weeks and mean birth weight of 3.22 ± 0.35 kg. Cesarean section was the mode of delivery in 41 (68.3%) neonates, and only three (5%) neonates had history of premature rupture of membrane. Four (6.7%) neonates had history of maternal diabetes mellitus, whereas two (3.3%) had history of maternal asthma.
The demographic characteristics of the two groups were not different [Table 1].
|Table 1: The demographic characteristics of the infants and maternal factors|
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The median duration of hospitalization was 1 day shorter in the salbutamol group than in the control group.
Numerical values of the TTN score, respiratory rate, heart rate, PaO2, PCO2, pH, blood glucose, and blood K + are given in [Table 2], [Table 3], [Table 4].
|Table 2: Numerical values of the partial pressure of arterial oxygen, partial pressure of arterial carbon dioxide, and pH|
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|Table 3: Numerical values of the transient tachypnea of the newborn score, respiratory rate, and heart rate|
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After salbutamol administration
There is a highly significant improvement in salbutamol group regarding arterial blood gas findings (pH, PaO2, and PaCO2) after 4 h of therapy rather than saline group, in the form of higher pH and PaO2 after 4 h and lower PaCO2 after 4 h.
There is increase in blood glucose level after 4 h of therapy in salbutamol rather than saline group.
There is a significant lower TTN score and respiratory rate detected in salbutamol group after 1 and 4 h.
There is an insignificant difference between both groups of the study regarding serum K + level or in the heart rate before and after 4 h of therapy.
| Discussion|| |
TTN is a clinical syndrome associated with respiratory distress usually seen shortly after delivery in infants. Delayed-desorption of pulmonary fluid has been accepted as the central problem in TTN . Fluid fills the air spaces and moves into the interstitial. It pools in perivascular tissues and interlobar fissures and is eventually cleared by the lymphatic or absorbed into small blood vessels. The excess lung water in TTN leads to decreased pulmonary compliance. Tachypnea develops to compensate for the increased work of breathing associated with reduced compliance.
On the basis of this physiopathology, previous studies have sought to determine if the use of oral or intravenous furosemide could provide excretion of the extra fluid in the lung interstitial. It has been determined, however, that furosemide had no effect on the course of TTN ,.
Fluid restriction may nevertheless be beneficial in the management of severe TTN only. In a trial of 73 preterm and term infants with TTN, a post-hoc analysis demonstrated that fluid restriction, compared with standard therapy, reduced the duration of respiratory support for the subset of patients (n = 26) who had severe TTN (defined as requiring respiratory support for >48 h) without adverse effects .
The currently accepted mechanism of transepithelial movement of lung fluid at the time of birth is by passive movement of Na + through ENaC, which is believed to be closed during fetal life but activated by adrenergic stimulation near birth .
It is thought that there is a relationship between the level of endogenous catecholamine release during birth and lung fluid clearance. From this point of view, Aslan et al.  investigated the association between TTN and β-adrenergic receptor (ADRB 1–2) polymorphisms that are found in type II alveolar cells and that activate Na +–K +-ATPase by increasing ENaC expression, thus providing absorption of transepithelial sodium. As a result of that study the B1GIy49GIy polymorphism was found to be significantly higher in patients diagnosed with TTN as compared with the control group. The presence of homozygote ADRB1, Ser49Gly, was found to be a risk factor in these patients.
Ex-vivo stimulation of lung tissue with an exogenous β-adrenergic agonist has been shown to stimulate lung fluid absorption in both human and animal models ,,,. In addition, recent in-vivo and in-vitro models for pulmonary edema suggest that intravenous injection of albuterol (salbutamol), a β-adrenergic agonist, stimulates lung fluid absorption ,.
In another study, Greenough and Lagercrantz  investigated catecholamine abnormalities in newborns diagnosed with TTN. It was thought that TTN was associated with relatively low levels of epinephrine, which is known to mediate fetal lung fluid absorption.
Kao et al.  investigated if providing exogenous epinephrine could be a valuable diagnostic and therapeutic intervention for this common condition. They did not find a difference between the two groups regarding the rate of tachypnea resolution.
In contrast, for newborns with a diagnosis of TNN, an increase in the persistence of a wheezy chest, childhood asthma, and a familial atopic predisposition later in life were found . Impairment of the β-adrenergic system, if persistent, would predispose such children to have subsequent difficulty with asthma ,. This is consistent with the recent prospective study that suggested that decreased lung function is a predisposing factor for the development of wheezing .
On the basis of these data and the study of Armangil et al., the treatment protocol used in the newborn ICU of our hospital was changed. A single-dose administration of inhaled salbutamol was initiated in newborns admitted to the neonatal ICU with the diagnosis of TTN. In this study, TTN newborns who received humidified oxygen therapy alone were retrospectively compared with those administered single-dose salbutamol therapy. The decreases in respiratory rate, TTN clinical score, and duration of hospitalization were significant in the salbutamol group. These findings suggest that β-2 adrenergic agonist is an effective treatment option for the clinical course of TTN and reduces the severity of tachypnea over time. A Respiratory Distress Assessment Instrument scoring system was used in our clinic to define the TTN clinical score; this scoring system was preferred because it is noninvasive, easily determined, and shows low interobserver variability .
In our clinical trial study, the decrease in the respiratory support score demonstrates the effectiveness of salbutamol therapy. No recorded adverse effect was observed after a single-dose treatment with salbutamol. Nevertheless, larger prospective studies are necessary to verify the efficacy of inhaled salbutamol as a therapeutic intervention for this common respiratory condition.
Salbutamol nebulization can be attempted alone to decrease the duration of hospital stay and the severity of TTN, to have a better neonatal outcome.
Further studies are necessary to confirm the efficacy of inhaled salbutamol in this common respiratory condition.
| Conclusion|| |
This study showed that a single dose of inhaled salbutamol resulted in better clinical and laboratory outcome measures in cases of TTN in similar degree.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Agrawal V, David RJ, Harris VJ. Classification of acute respiratory disorders of all newborns in a tertiary care center. J Natl Med Assoc 2003; 95
Cloherty J, Eichenwald EC, Stark AR. Manual of neonatal care
ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2004.
Hack M, Fanaroff AA, Klaus MH, Mendelawitz BD, Merkatz IR. Neonatal respiratory distress following elective delivery. A preventable disease? Am J Obstet Gynecol 1976; 126
Barker PM, Olver RE. Invited review: clearance of lung liquid during the perinatal period. J Appl Physiol (1985) 2002; 93
Jain I, Eaton DC. Physiology of lung fluid clearance and the effect of labor. Semin Perinatol 2006; 30
Aslan E, Tutdibi E, Martens S, Han Y, Monz D,
Gortner L. Transient tachypnea of the newborn: a role for polymorphisms in the beta-adrenergic receptor (ADRB) encoding genes? Acta Paediatr 2008; 97
Mutlu GM, Koch WJ, Factor P. Alveolar epithelial β-2-adrenergic receptors: their role in regulation of alveolar active sodium transport. Am J Respir Crit Care Med 2004; 170
Minakata Y, Suzuki S, Grygorczyk C, Dagenais A, Berthiaume Y. Impact of β-adrenergic agonist on Na +
channel and Na +
-ATPase expression in alveolar type II cells. Am J Physiol Lung Cell Mol Physiol 1998; 275
Rawling JS, Smith FR. Transient tachypnea of the newborn: an analysis of neonatal and obstetric risk factors. Am J Dis Child 1984; 138
Lowell DI, Lister G, von Koss H, McCarthy P. Wheezing in infants: the response to epinephrine. Pediatrics 1987; 79
Bertrand P, Araníbar H, Castro E, Sánchez I. Efficacy of nebulized epinephrine versus salbutamol in hospitalized infants with bronchiolitis. Pediatr Pulmonol 2001; 29
Guglani L, Lakshminrusimha S, Ryan RM. Transient tachypnea of the newborn. Pediatr Rev 2008; 9
Wiswell TE, Rawlings JS, Smith RE, Goo ED. Effect of furosemide on the clinical course of transient tachypnea of the newborn. Pediatrics 1985; 75
Karabayir N. Intravenous furosemide therapy in transient tachypnea of the newborn. Pediatr Int 2010; 52
Stroustrup A, Trasande L, Holzman IR. Randomized controlled trial of restrictive fluid management in transient tachypnea of the newborn. J Pediatr 2012; 160
Bland RD, Carlton DP, Jain L. Lung fluid balance during development and in neonatal lung disease. In: Bancalari E, Polin RA, editors. The newborn lung neonatology questions and controversies
. Philadelphia, PA: Saunders Elsevier; 2008. pp. 141–165.
Sakuma T, Tuchihara C, Ishigaki M, Osanai K, Nambu Y, Toga H, et al
. Denopamine, a beta (1)-adrenergic agonist, increases alveolar fluid clearance in ex vivo
rat and guinea pig lungs. J Appl Physiol (1985) 2001; 90
Sakuma T, Folkesson HG, Suzuki S, Okaniwa G, Fujimura S, Matthay MA. Beta-adrenergic agonist stimulated alveolar fluid clearance in ex vivo
human and rat lungs. Am J Respir Crit Care Med 1997; 155
Mutlu GM, Factor P. Alveolar epithelial beta2-adrenergic receptors. Am J Respir Cell Mol Biol 2008; 38
Ronca AE, Abel RA, Ronan PJ, Renner KJ, Alberts JR. Effects of labor contractions on catecholamine release and breathing frequency in newborn rats. Behav Neurosci 2006; 120
Perkins GD, Gao F, Thickett DR. In vivo
and in vitro
effects of salbutamol on alveolar epithelial repair in acute lung injury. Thorax 2008; 63
Perkins GD, McAuley DF, Richter A, Thickett DR, Gao F. Bench-to-bedside review: beta2-agonists and the acute respiratory distress syndrome. Crit Care 2004; 8
Greennough A, Lagercrantz H. Catecholamine abnormalities in transient tachypnea of the premature newborn. J Perinat Med 1992; 20
Kao B, Stewart de Ramirez SA, Belfort MB, Hansen A. Inhaled epinephrine for the treatment of transient tachypnea of the newborn. J Perinatol 2008; 28
Demissie K, Marcella SW, Breckenridge MB, Rhoads GG. Maternal asthma and transient tachypnea of the newborn. Pediatrics 1998; 102
Birnkrant DJ, Picone C, Markowitz W, El Khwad M, Shen WH, Tafari N. Association of transient tachypnea of the newborn and childhood asthma. Pediatr Pulmonol 2006; 41
Cakan M, Nalbantoǧlu B, Nalbantoǧlu A, Demirsoy U, Say A. Correlation between transient tachypnea of the newborn and wheezing attack. Pediatr Int 2011; 3
Martinez FD, Morgan WJ, Wright AL, Holberg CJ, Taussig LM. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. N Engl J Med 1988; 19
Armangil D, Yurdakök M, Korkmaz A, Yiǧit S, Tekinalp G. Inhaled beta-2 agonist salbutamol for the treatment of transient tachypnea of the newborn. J Pediatr 2010; 159
[Table 1], [Table 2], [Table 3], [Table 4]