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The Effects of Inhaled Albuterol in Transient Tachypnea of the Newborn Myo-Jing Kim,1 Jae-Ho Yoo,1 Jin-A Jung,1 Shin-Yun Byun2*

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The Effects of Inhaled Albuterol in Transient Tachypnea of the Newborn Myo-Jing Kim,1 Jae-Ho Yoo,1 Jin-A Jung,1 Shin-Yun Byun2* Original Article Allergy Asthma Immunol Res. 2014 March;6(2):126-130. http://dx.doi.org/10.4168/aair.2014.6.2.126 pISSN 2092-7355 • eISSN 2092-7363 The Effects of Inhaled Albuterol in Transient Tachypnea of the Newborn Myo-Jing Kim,1 Jae-Ho Yoo,1 Jin-A Jung,1 Shin-Yun Byun2* 1Department of Pediatrics, Dong-A University, College of Medicine, Busan, Korea 2Department of Pediatrics, Pusan National University School of Medicine, Yangsan, Korea This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose: Transient tachypnea of the newborn (TTN) is a disorder caused by the delayed clearance of fetal alveolar fluid.ß -adrenergic agonists such as albuterol (salbutamol) are known to catalyze lung fluid absorption. This study examined whether inhalational salbutamol therapy could improve clinical symptoms in TTN. Additional endpoints included the diagnostic and therapeutic efficacy of salbutamol as well as its overall safety. Methods: From January 2010 through December 2010, we conducted a prospective study of 40 newborns hospitalized with TTN in the neonatal intensive care unit. Patients were given either inhalational salbutamol (28 patients) or placebo (12 patients), and clinical indices were compared. Results: The dura- tion of tachypnea was shorter in patients receiving inhalational salbutamol therapy, although this difference was not statistically significant. The dura- tion of supplemental oxygen therapy and the duration of empiric antibiotic treatment were significantly shorter in the salbutamol-treated group. No adverse effects were observed in either treatment group. Conclusions: Inhalational salbutamol therapy reduced the duration of supplemental oxygen therapy and the duration of empiric antibiotic treatment, with no adverse effects. However, the time between salbutamol therapy and clinical improve- ment was too long to allow definitive conclusions to be drawn. Further studies examining a larger number of patients with strict control over dosage and frequency of salbutamol inhalations are necessary to better direct the treatment of TTN. Key Words: Transient tachypnea of the newborn; inhalation; albuterol INTRODUCTION cleared from the lungs shortly after birth. In this process, Sodi- um moves from the alveoli into pulmonary cells via the Na, K- Transient tachypnea of the newborn (TTN) is a respiratory ATPase pump and is then actively transported to the intersti- disorder resulting from inadequate or delayed clearance of fetal tium via amiloride-sensitive epithelial Na channels, thereby re- lung fluid.1 It is commonly seen in full-term or late-preterm in- moving Na and fluid through the lymphatic and vascular sys- fants,2 with an occurrence rate of 5.7 in 1,000 infants.1 The dis- tems.1 order is more prevalent among infants who are male, prema- Absorption of lung fluid is initiated by β-adrenergic agonists ture, born via cesarean section without labor, or born to a such as endogenous steroids and catecholamines, which in- mother with diabetes or asthma, and among infants who have crease during labor.5-7 Infants with TTN have lower levels of cir- perinatal asphyxia.3,4 Clinical symptoms include tachypnea, ex- culating catecholamines than those without TTN. Ex vivo stim- piratory grunting, nasal flaring, and retraction upon or imme- ulation of lung tissue with an exogenous β-adrenergic agonist diately after birth. These symptoms usually resolve naturally has been shown to stimulate lung fluid absorption in both hu- within 48-72 hours after birth, but can last up to 5 days. Treat- man and animal models.8-13 Additionally, recent in vivo and in ment of TTN includes the administration of supplemental oxy- vitro models for pulmonary edema suggest that intravenous in- 1,4 gen and postponement of enteral nutrition. The initial symp- jection of albuterol (salbutamol), a β2-adrenergic agonist, stim- toms of TTN are not easily differentiated from those of neonatal respiratory distress syndrome, pneumonia, and persistent pul- Correspondence to: Shin-Yun Byun, MD, Department of Pediatrics, Busan monary hypertension of the newborn, leading to unnecessary National University Children’s Hospital, 20 Geumo-ro, Yangsan 626-770, Korea. imaging, blood testing, and empiric antibiotic therapy as a re- Tel: +82-51-240-5124; Fax: +82-51-242-2765; E-mail: [email protected] sult of misdiagnoses. Received: February 20, 2013; Revised: April 30, 2013; Accepted: June 3, 2013 Under normal circumstances, fetal lung fluid is rapidly •There are no financial or other issues that might lead to conflict of interest. 126 http://e-aair.org © Copyright The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease AAIR Transient Tachypnea of the Newborn ulates lung fluid absorption.14-16 mg/kg. Each dose was nebulized with a jet-type nebulizer (Pa- In this context, we hypothesized that inhalational salbutamol, riBoy®, Pari-Werk, Stanberg, Germany) with continuous flow of a β2-adrenergic agonist widely used to treat bronchopulmonary oxygen at 5 L/min and was administered over the course of 10 dysplasia in premature infants, would stimulate lung fluid ab- minutes. During the hospitalization period, the respiratory rate, sorption in patients with TTN. The primary goal of this study heart rate, and oxygen saturation level of each patient were ob- was to examine the efficacy of inhalational salbutamol in -re served. The target oxygen saturation level was between 90% ducing tachypnea, oxygen treatment, and hospitalization for and 95%. Tachypnea was defined as a respiratory rate >60 infants with TTN. Our secondary goal was to assess the safety of breaths/min; and tachycardia, as a heart rate >180 beats/min. inhalational salbutamol for the new indication of TTN. We agreed to stop treatment if any patient were to develop tachycardia or an arrhythmia. Supportive treatment began after MATERIALS AND METHODS the inhalational treatment was complete. To assess the efficacy of salbutamol for TTN, we investigated Subjects the extent and duration of tachypnea, the duration of oxygen We conducted a randomized, double-blind clinical trial of in- treatment, the use of continuous positive airway pressure or a haled salbutamol for infants hospitalized with TTN in the neo- ventilator, the duration of empiric antibiotic therapy, the time natal intensive care unit of Dong-A Medical Center, Busan, Ko- of initiating enteral nutrition, and the duration of hospitaliza- rea from January 2010 through December 2010. Infants with tion. To assess the safety of salbutamol, we monitored for tachy- TTN were determined based on the following clinical symp- cardia and arrhythmias. toms and chest radiography results: 1) at least 35 weeks gesta- tional age; 2) respiratory distress less than 6 hours after birth Statistics (i.e., respiratory rate greater than 60/min, grunting, nasal flar- SPSS 18.0 for Windows (SPSS Inc., Chicago, IL, USA) was used ing, or retraction); and 3) typical chest radiography findings (i.e., for all analyses. Values are shown as averages ± standard devi- fluid in minor fissures, hyperinflation, prominent vascular/ ation. Two-tailed tests were used for all statistical tests, with sta- perihilar markings). Patients were excluded if they exhibited tistical significance defined as P≤0.05. To compare the fre- any of the following: 1) meconium aspiration; 2) other causes of quency and proportion of categorical variables, a Chi-squared tachypnea (e.g., neonatal respiratory distress syndrome, persis- test (Fisher’s exact test) was used. Student’s t-test was used to tent pulmonary hypertension of the newborn, pneumonia, ear- analyze differences between the averages of 2 independent ly-onset neonatal sepsis, polycythemia, or hypoglycemia); 3) groups. heart murmur; and 4) tachycardia (heart rate greater than 180/ min) or arrhythmia. Meconium aspiration syndrome was ex- Ethics statement cluded when there were no abnormal chest radiography find- The study was approved by the Institutional Review Board of ings (irregular pattern of increased density throughout the the Dong-A Medical Center, Busan, Korea (IRB No. 11-36). In- lung) and no meconium staining of the skin. Respiratory dis- formed consent was confirmed by the IRB. Consent was re- tress syndrome was excluded when there were no reticulogran- ceived from the mother or the infant’s legal representative at uler patterns on the chest radiograph and no surfactant thera- the time of hospital admission. py. Persistent pulmonary hypertension of the newborn was ex- cluded when the level of preductal oxygen saturation was <5% RESULTS above postductal oxygen saturation. Sepsis was excluded when there were no perinatal risk factors, WBC >5,000/mm,3 imma- Characteristics of study patients ture-to-total neutrophil (I:T) ratio <0.25, negative C-reactive A total of 40 infants were included in this study: 28 patients protein, and no focal infiltration on chest radiography. Oxygen were randomized into the treatment group (salbutamol inhala- was supplemented to maintain oxygen saturation at 90%-95%. tion); and 12, into the control group (saline inhalation). The av- Empirical antibiotic therapy was considered prior to culture re- erage gestational age of all patients was 37.6±1.0 weeks, and sults when there was no clinical improvement despite oxygen the birth weight was 3,124±545 g. Twenty-four of the subjects supplementation and supportive care. were male (60.0%). Twenty-nine infants were born via C-sec- tion (72.5%), of which 26 were born without labor (65.0%). The Study design average Apgar score was 7.8±1.2 at 1 minute and 9.0±0.8 at 5 Infants were randomly allocated in a double-blind fashion to minute. On average, neonatal tachypnea was first detected 1.3 receive 1 dose of 2 mL nebulized 0.9% normal saline (placebo) ±2.1 hours after birth, and the initial respiration rate was 74± or 0.1 mL salbutamol (Ventolin Respiratory Solution, salbuta- 12.8 breaths/min.
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