Inhaled Beta-2 Agonist Salbutamol for the Treatment of TransientTachypnea of the Newborn

Didem Armangil, MD, Murat Yurdak€ok, MD, Ayse Korkmaz, MD, Sule Yi�git, MD, and G€ulsevin Tekinalp, MD

Objective To evaluate the efficacy of inhaled salbutamol, a beta-2 adrenergic agonist, for the treatment of tran-sient tachypnea of the newborn (TTN) and to determine whether inhaled salbutamol is safe in newborn infants.Study design Inhaled salbutamol or normal saline solution was administered to 54 infants with gestational agesranging from 34 to 39 weeks and TTN. The response to salbutamol therapy was evaluated by determining respira-tory rate, clinical score of TTN, level of respiratory support, and fraction of inspired oxygen before and at 30minutesand 1 and 4 hours after salbutamol nebulization.Results Among the 54 infants with TTN, 32 received salbutamol and 22 received normal saline solution. After onedose, the salbutamol group showed significant improvements in respiratory rate, clinical score of TTN, fraction ofinspired oxygen, and level of respiratory support (P < .05). After treatment, the mean pH, partial pressure of arterialoxygen, and partial pressure of arterial carbon dioxide values were better in the salbutamol group when comparedwith the placebo group (P < .05). Duration of hospitalization in the neonatal intensive care unit was also shorter forthe salbutamol group (P < .05).Conclusion Inhaled salbutamol treatment was effective with respect to both clinical and laboratory findings ofTTN and without adverse events. (J Pediatr 2011;159:398-403).

In the neonatal period, transient tachypnea of the newborn (TTN) is the most frequent cause of early respiratory distressbecause of delayed resorption of the fetal lung fluid, which fills the fetal airways.1,2 Lung liquid clearance at birth is associatedwith 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 adenosine triphosphatase(Na+-K+-ATPase) activity.3 The inability of the fetal lung to switch from fluid secretion to fluid absorption and an immaturityin the expression of the ENaC may play an important role in the development of TTN.4

Stimulation of b-adrenergic receptors with beta-2 adrenergic agonists (b2AA) up-regulates alveolar epithelial Na+ transportby increasing the activity of ENaC and Na+-K+-ATPase and protein abundance at the plasma membrane.5,6 The potential ther-apeutic role of b2AA in hastening the resolution of alveolar pulmonary edema was suggested from animal and ex vivo humanlung studies.7,8 We conducted a randomized, double-blinded clinical trial of inhaled salbutamol for the treatment of TTN. Wehypothesized that inhaled salbutamol would increase the rate of absorption of fetal lung fluid in newborns with TTN, therebyimproving clinical outcomes. Our objective was to evaluate the efficacy of inhaled salbutamol, a b2AA, for this new indication,and to determine whether inhaled salbutamol is safe in newborn infants.

b2AA Beta-2 adrenergic ag

ENaC Epithelial Na+-channe

Fio2 Fraction of inspired o

K+ Potassium

Na+ Sodium

Na+-K+-ATPase Sodium-potassium ad

NICU Neonatal intensive ca

O2 Sat Blood oxygen saturat

Paco2 Partial pressure of art

Pao2 Partial pressure of art

TTN Transient tachypnea o

398

Methods

The studywas performed at theNeonatal Intensive CareUnit (NICU) ofHacettepeUniversity Children’sHospital, Ankara, Tur-key, between January 2007 and January 2009. A total of 54 infants with TTNwere randomly allocated in a double-blind placebo-controlled study to receive either inhaled salbutamol (n= 32) or an equal volumeof normal saline solution placebo (n=22) at thetime of diagnosis. Informed consent was obtained from parents, and the study was approved by the local ethical committee.

Patients were eligible for enrollment if they were diagnosed with TTN and were <6 hours old. The diagnosis of TTN wasaccording to the criteria of Rawlings and Smith9 on the basis of radiologic and laboratory findings of (1) onset of tachypnea

onists

ls

xygen

enosine triphosphatase

re unit

ion

erial carbon dioxide

erial oxygen

f the newborn

(respiratory rate exceeding 60 breaths/min) within 6 hours after birth; (2) persis-tence of tachypnea for at least 12 hours; (3)chest radiograph indicating at least one ofthe following: prominent central vascular

From the Department of Pediatrics, Faculty of Medicine,Hacettepe University, Ankara, Turkey

The authors declare no conflicts of interest.

0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc.

All rights reserved. 10.1016/j.jpeds.2011.02.028

Table II. Level of respiratory support

Level Respiratory support Oxygen concentration (%)

1 No oxygen —2 Intra-incubator oxygen 303 Hood 404 Nasal cannula 50 (5 L/min)5 nCPAP (PEEP: 5 cmH2O) 50–60

nCPAP, Nasal continuous positive airway pressure; PEEP, positive end-expiratory pressure.

Vol. 159, No. 3 � September 2011

markings, widened interlobar fissures of pleural fluid, sym-metrical perihilar congestion, hyperaeration as evidencedby flattening and depression of the diaphragmatic domesor increased anteroposterior diameter, or both; and (4) ex-clusion of other known respiratory disorders (meconiumaspiration, respiratory distress syndrome, pneumonitis,congenital heart diseases), and nonrespiratory disorders(hypocalcemia, persistent hypoglycemia, polycythemia)likely to cause tachypnea. Excluding criteria for acute respi-ratory distress syndrome were as follow: no predisposingfactor such as diffuse pulmonary opacities on radiography,severe hypoxia, sepsis, the syndrome of multiple organ fail-ure, disseminated intravascular coagulation, and iatrogeniclung injury (higher respiratory support techniques such ashigh tidal volumes and pressure support). Respiratory dis-tress syndrome was excluded if there was no reticulogranu-ler pattern on the x-ray film and no surfactant therapy.Meconium aspiration syndrome was excluded if therewere no x-ray findings (irregular pattern of increased den-sity throughout the lung) and no meconium staining of theskin. Infants who received diuretics and antibiotics wereexcluded from the study.

At enrollment (by the 6th hour), complete blood count,blood glucose and potassium (K+), arterial blood gases(pH, partial pressure of arterial oxygen [PaO2], partial pres-sure of arterial carbon dioxide [PaCO2]), respiratory rate(breaths/min), heart rate (beats/min), blood oxygen satura-tion (O2 Sat), fraction of inspired oxygen (FiO2), and TTNclinical score were determined for all patients. A clinicalevaluation of respiratory distress was performed witha new TTN clinical score that we developed by use of theRespiratory Distress Assessment Instrument scoring sys-tem,10 which was used for babies with wheezing. Expiratorygrunting, supraclavicular retraction, subcostal retraction,cyanosis, and nasal flaring were evaluated separately andscored from 0 to 3 as in Table I. The TTN clinical scorewas determined before treatment and after treatment at30 minutes and 1 and 4 hours (0.5, 1, and 4 hours)(range 0-13 points).

The TTN scores were determined by one physician. Thebedside nurse was blinded to group assignment and thus tothe administered drug. A respiratory rate of more than 60breaths/min was defined as tachypnea.11

Salbutamol or Placebo TreatmentPatients were randomized in a blinded manner to receive onenebulized dose of either 0.9% normal saline solution 4 mL(placebo), or a solution of salbutamol 4 mL (Ventolin

Table I. Clinical scorring of TTN

Score 0 point 1 point 2 points 3 points

Expiratory grunting None Intermittent Continuous —Supraclavicular retraction None Mild Moderate SevereSubcostal retraction None Mild Moderate SevereCyanosis None At extremities Central —Nasal flaring None Mild Moderate Severe

Nebules 2.5 mg) in 0.9% saline solution. The standard doseof salbutamol was 0.15 mg/kg.12 Solutions were given witha jet type nebulizer with continuous flow of oxygen at 5 to6 L/min. One dose was administered over the course of 20minutes, and vital signs were monitored for 4 hours. Prepa-ration and administration of nebulized solutions wereperformed by a NICU nurse. Parents and investigators re-mained blinded to the administered medications throughoutthe study period.At 0.5, 1, and 4 hours after drug administration, respira-

tory rate, heart rate, O2 Sat, FiO2, and the clinical TTN scorewere recorded. The goal was to keep the O2 Sat between 85%to 93%. The level of respiratory support was assigned as inTable II. The duration of total respiratory support wascalculated in hours as a total oxygen support via theincubator, nasal cannule, oxygen hood, or nasal continuouspositive airway pressure.At 4 hours after treatment, arterial blood gases, serum K+,

and glucose levels were measured again. The duration of totalrespiratory support was recorded along with the duration ofhospitalization. The intravenous fluids were given as 60 mL/kg/d for term babies and 80 mL/kg/d for preterm infants forthe first postnatal day. Demographic characteristics of new-borns are listed in Table III.

Statistical EvaluationStatistical analyses were performed with the Statistical Pack-age for Social Sciences-SPSS version 15 software (SPSS Inc,Chicago, Illinois). For categorical variables, the c2 test wasused. For group comparisons, the Student t test was usedin normal distribution and the Mann-Whitney U testwas used in case of abnormal distribution. For repeatingmeasurements, variance analyses and Friedman varianceanalyses were used. For descriptive statistics, percent,minimum-maximum-median, mean, and standard deriva-tion were used in accordance with the type and distributionof the variable. A P value <.05 was considered statisticallysignificant.

Results

The gestational ages (mean � SD) ranged between 34 and 39weeks (Table III). There were no differences between the twogroups in demographic characteristics (P > .05). The medianduration of hospitalization was 2 days shorter for thesalbutamol group than the control group.

399

Table III. The demographic characteristics of theinfants and maternal risk factors

Salbutamolgroup(n = 32)

Controlgroup(n = 22) P value

Sex (F/M) 11/21 5/17 .357Gestational age (weeks � SD)* 37.0 � 1.6 36.7 � 1.6 .570Birth weight (g � SD)* 2991 � 536 2990 � 574 .994White blood cell count (/mm3) 15.871 � 4262 15.763 � 4716 .989Hemoglobin (g/dL) 16.7 � 1.95 16.7 � 1.95 1.000Elective cesarean delivery 25 (78%) 12 (55%) .067AGA/SGA/LGA 27/1/4 21/0/1 .332Apgar score (5th min)† 9 (7.25-10) 10 (8-10) .114O2 saturation (%) 90 � 6.6 89 � 5 .990Duration of respiratorysupport (h)†

30 (12-72) 48 (24-96) .112

Duration of hospitalization (d)† 4 (2-5) 6 (4-7) .002Maternal age (y)* 31.7 � 5.4 30.6 � 4.5 .402Maternal diabetes 4 (12.5%) 2 (9%) 1.000Maternal asthma 1 (3.1%) 3 (13.5%) .293PROM 1 (3.1%) 1 (4.5%) 1.000Maternal drug useSalbutamol 1 (3.1%) 1 (4.5%) 1.000Oxytocin 1 (3.1%) 0 (0%) 1.000Aspirin 9 (28%) 4 (18%) .401Heparin 6 (18.7%) 2 (9%) .449

AGA/SGA/LGA, appropriate/small/large for gestational age; PROM, premature rupture of themembranes.*Mean.†Median (IQR).

Table IV. Values before and 4 hours after theadministration of salbutamol and normal saline solution

Salbutamolgroup(n = 32)

Controlgroup(n = 22) P value

TTN clinical score (n)Before treatment 8 (8-10)* 7 (7-8)* >.05After treatment 2.5 (0.25-4)* 7 (6.75-8)* <.001P value <.001 >.05

Respiratory rate (breaths/min)Before treatment 70 � 19 74 � 13 >.05After treatment 62 � 14 77 � 15 <.01P value <.01 >.05

Heart rate (beats/min)Before treatment 144 � 16 149 � 10 >.05After treatment 139.6 � 12.3 143 � 10 >.05P value >.05 <.05

FiO2 (%)Before treatment 70 (50-85)* 60 (50-70)* >.05After treatment 21 (21-40)* 60 (45-66)* <.001P value <.001 >.05

PaO2 (mm Hg)Before treatment 55 � 20 56 � 19 >.05After treatment 62 � 17 50 � 16 <.05P value <.05 <.05

PaCO2 (mm Hg)Before treatment 44 � 9 47 � 10 >.05After treatment 43 � 7 50 � 8 <.05P value >.05 >.05

PHBefore treatment 7.30 � 1.0 7.30 � 0.6 >.05After treatment 7.40 � 0.6 7.30 � 0.5 <.05P value <.01 >.05

Serum K+ (mEq/L)Before treatment 4.2 � 1.1 4.0 � 1.0 >.05After treatment 4.5 � 1.0 4.3 � 1.1 >.05P value >.05 >.05

Serum glucose (mg/dL)Before treatment 78 � 15 83 � 12 >.05After treatment 81 � 12 78 � 14 >.05P value >.05 >.05

*Median (IQR).

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The TTN clinical scores, respiratory rates, heart rates, FiO2,PaO2, PaCO2, pH, serum K+, and serum glucose values beforeand 4 hours after the administration of salbutamol and nor-mal saline solution are shown in Table IV. After salbutamoltreatment, the TTN clinical score, respiratory rate, and FiO2were significantly lower than pretreatment levels. When thePO2 values before and after salbutamol treatments werecompared, there was a significant increase in PO2 comparedwith before salbutamol treatment. Furthermore, the PCO2

levels in the control group were significantly greater thanin the salbutamol group, and pH values improvedsignificantly with salbutamol treatment.

There are no differences between the salbutamol and controlgroups for serum K+ or glucose levels. There were also no dif-ferences in heart rates between the two groups (Figure 1, A).

The respiratory rates, FiO2 and TTN clinical scores in thesalbutamol group were lower than in the control group(Figure 1, B, C, D).

With the salbutamol nebulization the level of respiratory sup-port decreased over time in 12 patients and remained at thesame level in 20 patients. The level of respiratory support didnot increase in any of the patients. For the control group, thelevel of respiratory support did not decrease in any of the pa-tients. In this group, the level remained the same in 15 patients,and in the remaining seven patients, level of respiratory supportincreased over time (Figure 2; available at www.jpeds.com).

Discussion

TTN is believed to result from delayed resorption of fluidfrom the lungs of the newborn, which is an important diag-

400

nostic and therapeutic dilemma in the NICU.13 Throughoutgestation, the presence of an adequate amount of lung fluid iscritical for normal lung growth and for the development ofthe fetal lung to complete transition from intrauterine to ex-trauterine life.14 The currently accepted mechanism of trans-epithelial movement of lung fluid at the time of birth isby passive movement of Na+ through ENaC, believed tobe closed during fetal life but activated by adrenergicstimulation near birth.15 The epinephrine stimulation ofamiloride-sensitive ENaC-mediated alveolar fluid clearanceis mediated by cyclic adenosine monophosphate and Ca+2,likely acting as an intracellular second messenger.16,17 Na+

then moves into the interstitium via ouabain-sensitive baso-lateral Na+-K+-ATPase.18 Movement of Na+ into the intersti-tium moves chloride and water passively through theparacellular and intracellular pathways.19 Most interstitiallung liquid moves into the pulmonary circulation andsome drains via the lung lymphatic vessels.15 At birth, epi-nephrine, oxygen, glucocorticoid, and thyroid hormones in-teract to augment Na+ transport by the epithelium andincrease gene expression of ENaC.15,20 Delayed resorption

Armangil et al

Figure 1. A, The changes in the heart rate (P > .05), B, respiratory rate (P < .05), C, FiO2 (P < .05), and D, TTN clinical score (P <.05) over time in the salbutamol and control groups. Open circles, control; filled circles, salbutamol.

September 2011 ORIGINAL ARTICLES

of this pulmonary fluid has been accepted as the central prob-lem in TTN.13

The most pronounced finding in TTN is tachypnea, start-ing in the first 1 to 2 hours after delivery, and the respiratoryrate can reach 60 to 120 breaths/min.13 Prolonged tachypneacan increase the duration of hospitalization, the use of anti-biotics and parental anxiety.21 Kasap et al22 determined therespiratory rate over 90 breaths/min at 36th hour after deliv-ery, as a predictive value in terms of prolonged tachypnea.The prolonged tachypnea correlated with prolonged hospi-talization and use of antibiotics; nevertheless, parenteral fu-rosemide had no effect on clinical improvement. In thisstudy, the duration of hospitalization decreased after salbuta-mol treatment. When the effect of salbutamol treatment onrespiratory rate was analyzed along with the respiratoryrate at 0.5, 1, and 4 hours after treatment, the respiratoryrate did not decrease in the control group, and it decreasedover time in the salbutamol group. With salbutamol treat-ment, the severity of tachypnea decreased over time.

Both furosemide and racemic epinephrine were studied forpossible benefit in patients with TTN. A double-blinded, ran-domized, and placebo-controlled study was performed onthe basis of the finding that epinephrine, which plays a rolein fetal lung liquid clearance, is in low concentrations in

Inhaled Beta-2 Agonist Salbutamol for the Treatment of Transien

babies with TTN. However, the resolution of tachypneawas no different between the racemic epinephrine–adminis-tered group and control subjects.23 Furosemide passes thelung fluid from the interstitium to the pulmonary microcir-culation, and it decreases transvascular liquid filtration, whileincreasing lymphatic flow.24 On the basis of these findings,furosemide was investigated as a possible treatment forTTN. Wiswell et al25 concluded that oral furosemide treat-ment for TTN did not affect the duration of tachypnea, oxy-gen requirement and length of hospitalization. Furosemidewas not effective when given by the parenteral route and iteven increased the respiratory rate at 36 hours.22 In anotherstudy comparing intravenous furosemide with placebo, furo-semide had no effect on oxygen requirement, duration of ta-chypnea, and duration of hospitalization.26 There are noreports in the current literature proving the effect of epineph-rine and furosemide in the treatment of TTN.23,25-27 Thus,a therapy that reduces the duration and severity of this disor-der may have practical value. A therapy that is effective earlyin the course of TTN would decrease treatment burden andresource utilization.On the basis of the literature favoring b2AAs for increasing

the liquid clearance of the lung,28,29 our study was performedwith the aim of investigating the efficacy of inhaled

t Tachypnea of the Newborn 401

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salbutamol in the treatment of TTN. When salbutamoltreated patients were compared with the control group, thedecreases in respiratory rate, FiO2, TTN clinical score and du-ration of hospitalization were significant. These findings leadto the thought that b2AAs are an effective treatment for theclinical course of TTN and the severity of tachypnea de-creased over time. In this study, the ‘‘TTN clinical score,’’ de-veloped with the Respiratory Distress Assessment Instrumentscoring system,10 was used, and this scoring system was pre-ferred because it is noninvasive and easily applicable andshows low interobserver variability.

In our study, although the airway pressure and resistancevalues were not evaluated in the salbutamol group, the levelof respiratory support decreased over time in 12 patients,and it remained at the same level in 20 patients, and the im-provement in the level of respiratory support was statisticallysignificant. We believe that the decreasing respiratory sup-port score shows the effectiveness of salbutamol therapy.We also evaluated the salbutamol group for adverse effects.In the literature, serious bronchospasm, arrhythmias, hypo-kalemia, and hyperglycemia caused by glycogenolysis havebeen reported rarely.30-33 However, no adverse effects wereobserved after single-dose treatment with salbutamol in ourstudy.

Even with all the advancements in perinatology and neo-natology, TTN is still common and causes significant mor-bidity resulting in longer hospitalizations for term andpreterm infants. Thus, identifying new treatment choicesthat could decrease the duration and severity of disease is im-portant. In conclusion, this prospective double-blind pla-cebo-controlled trial showed that a single dose of inhaledsalbutamol resulted in better outcome measures in cases ofTTN. We did not identify any adverse events during treat-ment. Larger studies are necessary to verify the efficacy of in-haled salbutamol as a therapeutic intervention for thiscommon respiratory condition. n

Submitted for publication Aug 10, 2010; last revision received Feb 17, 2011;

accepted Feb 23, 2011.

Reprint requests: Didem Armangil, MD, Hacettepe University School of

Medicine, Department of Pediatrics Neonatology Unit, 06100 Ankara, Turkey.

E-mail: darmangil@gmail.com

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Figure 2. The changes in level of respiratory support overtime in the salbutamol and control groups.

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403.e1 Armangil et al