comparison of three different administration positions for intratracheal beractant in preterm newborns with respiratory distress syndrome

Accepted Manuscript Comparison of Three Different Administration Positions for Intratracheal Beractant in Preterm Newborns with Respiratory Distress Syndrome Ahmet Karadag, MD, Associate Professor, Ramazan Ozdemir, MD, Associate Professor, Halil Degirmencioglu, MD, Fellow, Nurdan Uras, MD, Associate Professor, Ugur Dilmen, MD, Professor, Gokmen Bilgili, MD, Assistant Professor, Omer Erdeve, MD, Assistant Professor, Ufuk Cakir, MD, ; Fellow, Begum Atasay, MD, Professor PII: S1875-9572(15)00093-5 DOI: 10.1016/j.pedneo.2015.04.012 Reference: PEDN 482 To appear in: Pediatrics & Neonatology Received Date: 17 December 2014 Revised Date: 26 March 2015 Accepted Date: 15 April 2015 Please cite this article as: Karadag A, Ozdemir R, Degirmencioglu H, Uras N, Dilmen U, Bilgili G, Erdeve O, Cakir U, Atasay B, Comparison of Three Different Administration Positions for Intratracheal Beractant in Preterm Newborns with Respiratory Distress Syndrome, Pediatrics and Neonatology (2015), doi: 10.1016/j.pedneo.2015.04.012 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain PEDN-D-14-00263_After Eng Edited_final ACCEPTED MANUSCRIPT Comparison of Three Different Administration Positions for Intratracheal Beractant in Preterm Newborns with Respiratory Distress Syndrome Running Title: Comparison of Three Different Surfactant Administration Positions RI PT Article Category: Original Article Ahmet Karadag1, Ramazan Ozdemir1, Halil Degirmencioglu2, Nurdan Uras2, Ugur M AN U SC Dilmen2, Gokmen Bilgili3, Omer Erdeve4, Ufuk Cakir4 and Begum Atasay4 Inonu University, School of Medicine, Division of Neonatology, Department of Pediatrics, Malatya, Turkey Neonatal Intensive Care Unit, Zekai Tahir Burak Maternity and Teaching Hospital, Ankara, Turkey TE D Celal Bayar University, School of Medicine, Division of Neonatology, Department of Pediatrics, Manisa, Turkey EP Ankara University, School of Medicine, Division of Neonatology, Department of Pediatrics, Ankara, Turkey AC C Ahmet Karadag: MD; Associate Professor, Inonu University, School of Medicine, Division of Neonatology, Department of Pediatrics, Malatya, Turkey, email: ahmetkaradag@gmail.com Phone: +90 422 341 0660 /5344 Ramazan Ozdemir: MD; Associate Professor, Inonu University, School of Medicine, Division of Neonatology, Department of Pediatrics, Malatya, Turkey, email: ramazanoz@yahoo.com.tr Phone: +90 422 341 0660 /5310 Halil Degirmencioglu: MD; Fellow, Neonatal Intensive Care Unit, Zekai Tahir Burak Maternity and Teaching Hospital, Ankara, Turkey, hdegirmencioglu@gmail.com Phone: +90 312 310 1100 Nurdan Uras: MD; Associate Professor, Neonatal Intensive Care Unit, Zekai Tahir Burak Maternity and Teaching Hospital, Ankara, Turkey, nurdanuras@yahoo.com Phone: +90 312 310 1100 ACCEPTED MANUSCRIPT Ugur Dilmen: MD; Professor, Neonatal Intensive Care Unit, Zekai Tahir Burak Maternity and Teaching Hospital, Ankara, Turkey, ugurdilmen@gmail.com Phone: +90 312 310 1100 Gokmen Bilgili: MD; Assistant Professor; 3Celal Bayar University, School of Medicine, Division of Neonatology, Department of Pediatrics, Manisa, Turkey, gokmenbilgili@yahoo.com Phone: +90 236 24121 41/ 1290 RI PT Omer Erdeve: MD; Associate Professor, Ankara University, School of Medicine, Division of Neonatology, Department of Pediatrics, Ankara, Turkey, omererdeve@yahoo.com Phone: +90 312 595 60 00 SC Ufuk Cakir: MD; Fellow, Ankara University, School of Medicine, Division of Neonatology, Department of Pediatrics, Ankara, Turkey, drufukcakir@hotmail.com Phone: +90 312 595 60 00 M AN U Begum Atasay; MD, Professor, Ankara University, School of Medicine, Division of Neonatology, Department of Pediatrics, Ankara, Turkey, begumatasay@hotmail.com Phone: +90 312 595 60 00 Corresponding Author: TE D Ramazan Ozdemir, MD Division of Neonatology, Department of Pediatrics, Inonu University School of Medicine, Turgut Ozal Medical Center, EP 44280, Malatya, Turkey Fax: +90 422 3410736 E mail: ramazanoz@yahoo.com.tr AC C Phone: +90 422 3410660 Funding source: No external funding was secured for this study Conflict of interest: The authors have no conflicts of interest relevant to this article to disclose ACCEPTED MANUSCRIPT Abstract Background: The aim of this study was to compare the efficacy and adverse effects of various intratracheal beractant administration positions in preterm newborns with respiratory RI PT distress syndrome Methods: This study was performed on preterm newborns with respiratory distress syndrome The inclusion criteria were being between 26-32 weeks of gestational age, having a birth SC weight between 600-1500 grams, having received clinical and radiological confirmation for the diagnosis of RDS within three hours of life, having been born in one of the centers where M AN U the study was carried out, and having fractions of inspired oxygen (FiO2) ≥ 0.40 to maintain oxygen saturation by pulse oximeter at 88-96% Beractant was administered in four positions to Group I newborns, in two positions to Group II, and in neutral position to Group III Results: Group I and II consisted of 42 preterm infants in each while the third group included TE D 41 No significant differences were detected among the groups with regards to maternal and neonatal risk factors Groups were also similar in terms of the following complications: PDA, pneumothorax, IVH, CLD, ROP, NEC, death within first three days of life, death within first EP 28 days of life, and re-hospitalization within one month after the discharge Neither any AC C statistically significant differences among the parameters related with surfactant administration, nor any significant statistical differences among the FiO2 levels and the saturation levels before and after the first surfactant administration among the groups were determined Conclusion: In terms of efficacy and side effects, no important difference was observed among the recommended four-position beractant application and the two-position administration or the neutral position ACCEPTED MANUSCRIPT RI PT Key Words: beractant; preterm infant; respiratory distress syndrome; administration position Abbreviations: CPAP: Continuous Pressure FDA: Food and Drug Administration ROP: Retinopathy of Prematurity PIP: Peak Inspiratory Pressure M AN U NEC: Necrotising Enterocolitis Airway PDA: Patent Ductus Arteriosus CLD: Chronic Lung Disease IVH: Intraventricular Hemorrhage Positive SC RDS: Respiratory Distress Syndrome PEEP: Positive-End Expiratory Pressure FiO2: Fraction of Inspired Oxygen AC C EP TE D sPO2: Saturation of Peripheral Oxygen ACCEPTED MANUSCRIPT Introduction Respiratory distress syndrome (RDS) remains the most frequent cause of mortality and morbidity in preterm newborns However, it is known that administration of exogenous surfactants improves alveolar oxygenation and reduces mortality and morbidity rates among RI PT preterm newborns with RDS.1-4 Several types of surfactant preparations, both synthetic, which are protein-free, and natural, from bovine or porcine origin, have been used in the treatment of SC RDS.5-9 Beractant is a bovine originated natural surfactant used in preventing and treating RDS in M AN U premature newborns Survanta® (AbbVie Inc North Chicago, Illinois, U.S.A,) is the only beractant preparation administered worldwide Food and Drug Administration (FDA) has approved the administration of Survanta® for prevention and treatment of RDS in newborns since 1991.10 The manufacturer company has acquired the FDA approval for the product by TE D explaining the administration of the beractant preparation with the following statement: for a homogenous distribution of Survanta® throughout the lungs, each total dose is divided into four quarter-doses, also known as aliquots (four aliquots = one total dose) However, there are EP some difficulties concerning the administration of the surfactant in four positions In the application of certain surfactant preparations, infants are not obliged to be in position.10 In AC C addition, the fact that surfactant can be administered in neutral position has also established a tendency in neonatologists to apply surfactant in positions other than the four positions offered by the manufacturer In different countries, many neonatologists use the beractant either in the two positions or in neutral position despite manufacturer’s instructions Although quite widespread in practicality, there are no data or concerning the efficacy and diverse effects of the beractant application apart from those of the four positions in early and late periods ACCEPTED MANUSCRIPT In this randomized controlled multicentric study, we aim to compare the efficacy and side effects of beractant application in the four positions suggested by the manufacturer, in two positions, and in the neutral position in early and late periods RI PT Patients and Methods The following randomized controlled multicentric study was conducted in four different centers in Turkey Preterm newborns were considered eligible for the study when they met the SC following inclusion criteria: being between 26-32 weeks of gestational age, having a birth weight between 600-1500 grams, having received clinical and radiological confirmation for M AN U the diagnosis of RDS within three hours of life, having been born in one of the centers where the study was carried out, and having fractions of inspired oxygen (FiO2) ≥ 0.40 to maintain oxygen saturation by pulse oximeter at 88-96% Preterms with chromosomal defects, asphyxia, congenital heart and lung diseases, and those who had or needed chest compression TE D or drug use in the delivery room, along with preterm babies who were delivered from mothers with membrane rupture for more than two weeks were all excluded from the study The Institutional Ethics Committee of Inonu University approved the initiation of the study, and EP parental consent was obtained for all participants AC C All newborns in the study were diagnosed with RDS both clinically and radiologically Tachypnea (>60 breaths/min), retractions, nasal flaring, grunting, the need to maintain the oxygen saturation at ≥86% with FiO2 ≥0.40 in addition to the chest radiograph results with ≥2 Grade RDS findings confirmed the RDS diagnosis The classification of pulmonary X-ray findings for RDS included the following criteria: Grade 1: slight reticular (slight granular) decrease in transparency of the lung with no certain difference from normal findings; Grade 2: soft decrease in transparency with an air-bronchogram overlapping the heart; Grade 3: gradual ACCEPTED MANUSCRIPT but strong decrease in transparency, as well as a blurry diaphragm and heart; and Grade 4: practically homogenic lung opacity.11 The patients were randomized into three different groups according to surfactant RI PT administration positions In Group I, the surfactant was administered in four positions whereas it was administered in two positions in Group II, and in neutral position in Group III (Figures 1, and 3) In Group I, the manufacturer’s suggested positions were followed: head and body inclined 5-10° down with the head turned to the right; head and body inclined 5-10° SC down with the head turned to the left; head and body inclined 5-10° up while the head is M AN U turned to the right; and head and body inclined 5-10° up while the head is turned to the left The two positions administered in Group II were as follows: head and body inclined 5-10° up with the head turned to the right and head and body inclined 5-10° up with the head turned to the left In the Group III patients in the neutral position were positioned in supine position with head and feet level in line and without turning the head sideways According to the TE D manufacturer’s dosage suggestions, all patients in each group were administered a total dose of 100 mg of phospholipids/kg birth weight (4 mL/kg) divided into quarter-doses Beractant EP was taken into the disposable injectors with a large gauge needle (least 20 G) without shaking Following attachment of the injectors to French end-hole catheters pre-measured according AC C to the lengths of endotracheal tubes of each baby, A the discretion of the clinician, the endotracheal tube was suctioned before administering surfactant The infant was allowed to stabilize before proceeding with dosing In Group I, after injection of each quartile dose (1 mL/kg) of surfactant in two seconds, the catheter was rapidly withdrawn from the endotracheal tube, and the babies were manually ventilated for 30 sec at a rate of 60 breaths/min via a hand-bag with sufficient oxygen to prevent cyanosis The same process was repeated for each position After the last quarter dosing and 30 sec manual ventilation, the ACCEPTED MANUSCRIPT infant was extubated if the need for FiO2 was 2 mm and left atrial diameter/aortic root ratio of >1.5 mm together with left ventricular M AN U enlargement NEC was also among diagnosed problems; NEC was classified according to Bell’s criteria.14 ROP was confirmed by following international classification.15 Only conventional ventilation was used in this study The ventilator strategies and initiating and weaning procedures were standardized The standard initiating settings for mechanical TE D ventilation were as follows: PIP 15-20 cmH2O, PEEP 4-6 cmH2O, flow rate 6-8 L/min, ventilator rate 30-40/min, and aspiratory/expiratory ration 1:2 The weaning was started when the infant required FiO2